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7/24/15, 11:48Prostate Cancer, Nutrition, and Dietary Supplements - National Cancer Institute

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Prostate Cancer, Nutrition, and DietarySupplements (PDQ®)

IntroductionMen$in$the$United$States$get$prostate$cancer$more$than$any$other$type$of$cancer$except$skincancer.$It$is$found$mainly$in$older$men.$In$the$United$States,$about$one$out$of$five$men$will$bediagnosed$with$prostate$cancer.$Most$men$diagnosed$with$prostate$cancer$do$not$die$of$it.

Complementary$and$alternative$medicine$(CAM)$is$a$form$of$treatment$used$in$addition$to(complementary)$or$instead$of$(alternative)$standard$treatments.$CAM$treatments$generally$arenot$considered$standard$medical$approaches.$Standard$treatments$go$through$a$long$and$carefulresearch$process$to$prove$they$are$safe$and$effective,$but$less$is$known$about$most$types$of$CAM.

CAM$use$among$prostate$cancer$patients$is$reported$to$be$common.$CAM$treatments$used$byprostate$cancer$patients$include$certain$foods,$dietary$supplements,$herbs,$vitamins,$andminerals.

This$PDQ$CAM$summary$gives$general$information$about$using$foods$and$dietary$supplements$tolower$the$risk$of$developing$prostate$cancer$or$for$treating$prostate$cancer,$its$symptoms,$or$sideeffects$of$disease$treatment.$In$addition,$this$summary$has$sections$for$several$specific$foods$ordietary$supplements:

Calcium

Green$Tea

Lycopene

Modified$Citrus$Pectin

Pomegranate

Selenium

Soy

Vitamin$D

Vitamin$E

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http://www.cancer.gov/

http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=445079&version=Patient&language=English

http://www.cancer.gov/about-cancer/treatment/cam/patient/prostate-supplements-pdq/#link/_446

Combination$Therapies

Other$Prostate$Health$Supplements

More$topics$will$be$added$over$time.$These$sections$include$the$following$information$for$eachfood$or$dietary$supplement:

How$it$is$given$or$consumed.

Reviews$of$laboratory$and$animal$studies.

Results$of$population$studies$and$clinical$trials.

Side$effects$or$risks.

Food$and$Drug$Administration$(FDA)$information.

Overview of CAM Use in Prostate CancerStudies$of$CAM$use$to$treat$prostate$cancer$have$shown$the$following:

Men$who$have$prostate$cancer$are$more$likely$to$take$dietary$supplements$than$men$who$donot$have$prostate$cancer.

Prostate$cancer$patients$with$the$healthiest$eating$habits$(for$example,$eating$lots$of$fish$richin$omega-3$fatty$acids$and$vegetables)$are$the$most$likely$to$take$dietary$supplements.

Reasons$given$by$prostate$cancer$patients$for$using$CAM$treatments$include$boosting$theimmune$system,$improving$quality$of$life,$and$lowering$the$risk$of$the$cancer$coming$back.

Studies$of$CAM$use$to$lower$the$risk$of$developing$prostate$cancer$or$to$prevent$it$from$comingback$have$shown$the$following:

A$study$of$men$with$a$family$history$of$prostate$cancer$found$that$over$half$used$vitamins$orother$dietary$supplements,$including$those$sold$for$prostate$health$or$cancer$prevention,such$as$some$of$those$listed$in$this$summary.

A$study$of$men$at$a$prostate$cancer$screening$clinic$found$that$well$over$half$tookmultivitamins$and$a$smaller$number$took$herbal$supplements.

A$study$of$prostate$cancer$survivors$found$that$up$to$one-third$took$vitamins$or$minerals.

Although$many$prostate$cancer$patients$use$CAM$therapies,$only$about$half$of$them$tell$theirdoctors$about$their$use$of$CAM.

Studies$of$why$prostate$cancer$patients$do$or$don't$decide$to$use$CAM$show$that$their$choice$is

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based$on$many$factors,$including$their$medical$history,$their$beliefs$about$the$safety$and$sideeffects$of$CAM$compared$to$standard$treatments,$and$their$need$to$feel$in$control$of$theirtreatment.

Questions and Answers About Calcium1.$ What%is%calcium?

Calcium$is$a$mineral$that$is$needed$for$basic$blood$vessel,$muscle,$and$nerve$functions,$cell-to-cell$signaling,$and$hormone$release.$It$is$the$most$common$mineral$in$the$body.$The$bodystores$calcium$mainly$in$bone$tissue.$Calcium$naturally$occurs$in$some$foods$and$is$added$toother$foods.$It$is$also$available$as$a$dietary$supplement.

2.$ How%is%calcium%administered%or%consumed?

The$main$sources$of$calcium$in$the$American$diet$are$foods$and$dietary$supplements.$Aboutone-third$of$dietary$calcium$comes$from$milk$and$milk$products$like$cheese$and$yogurt.Vegetable$sources$include$Chinese$cabbage,$kale,$and$broccoli.$Spinach$contains$calcium$butit$is$not$in$a$form$that$is$well$absorbed$by$the$body.$Foods$with$calcium$added$include$manyfruit$juices$and$drinks,$tofu,$and$cereals.

In$the$United$States,$almost$half$the$population$takes$dietary$supplements$containingcalcium.$However,$most$research$about$calcium$and$prostate$cancer$risk$has$studied$onlycalcium$consumed$in$the$diet$and$not$calcium$taken$in$supplements.

3.$ Have%any%preclinical%(laboratory%or%animal)%studies%been%conducted%using%calcium?

Laboratory$and$animal$research$has$been$done$to$study$the$effects$of$calcium$in$prostatecancer.

Studies$of$calcium$in$the$laboratory$have$shown$the$following:

In$a$2011$study,$prostate$cancer$cells$were$treated$with$cow$milk,$almond$milk,$soymilk,$casein,$or$lactose.$Growth$of$prostate$cancer$cells$(LNCaP)$was$stimulated$whenthey$were$treated$with$cow$milk.$Treatment$with$soy$milk$did$not$affect$the$growth$ofprostate$cancer$cells,$and$treatment$with$almond$milk$treatment$slowed$the$growth$ofprostate$cancer$cells.

Studies$of$calcium$in$animal$models$of$prostate$cancer$have$shown$the$following:

Strains$of$mice$which$developed$prostate$cancer$that$acts$like$human$cancer$were$fedlow-calcium$diets$or$high-calcium$diets.$Prostate$cancer$growth$was$found$to$besimilar$in$mice$fed$either$low-$or$high-calcium$diets.

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Dietary$vitamin$D$and$calcium$were$studied$in$mice$injected$with$prostate$cancer$cellsand$fed$specific$diets$(including$high-calcium$plus$vitamin$D$or$normal$calcium$and$novitamin$D).$The$mice$that$received$the$normal$calcium$and$no$vitamin$D$diet$had$moreprostate$cancer$growth$than$mice$fed$the$other$diets.

4.$ Have%any%clinical%trials%(research%studies%with%people)%of%calcium%been%conducted?

Studies$of$people$in$many$parts$of$the$world$have$been$done$to$find$out$if$there$is$a$linkbetween$dairy$products,$calcium,$and$prostate$cancer$risk.

Population%studies

Population$studies$look$for$risk$factors$and$ways$to$control$disease$in$large$groups$of$people.

Population$studies$of$dairy$products,$dietary$calcium,$and$prostate$cancer$risk$have$shownmixed$results.$These$studies$may$be$hard$to$interpret$because$other$major$nutrients$in$dairyproducts,$such$as$fats,$and$factors$such$as$age$and$body$mass$index$have$not$been$taken$intoaccount.

Overall,$however,$studies$suggest$that$high$total$calcium$intake$may$be$linked$with$increasedrisk$of$advanced$and$metastatic$prostate$cancer$compared$with$lower$amounts$of$calcium.More$studies$are$needed$about$the$effects$of$calcium$and/or$dairy$products$on$prostatecancer$risk$and$how$these$effects$develop$in$the$body.

Clinical%trial%of%preventing%prostate%cancer

In$a$randomized$clinical$trial$reported$in$2005,$men$were$given$calcium$(1200$mg/day)$or$aplacebo$for$4$years$and$were$followed$up$for$12$years.$During$the$first$6$years$of$the$study,there$were$markedly$fewer$cases$of$prostate$cancer$in$the$calcium$group$compared$to$theplacebo$group.$After$10$years,$however,$there$was$no$meaningful$difference$in$the$number$ofprostate$cancers$in$the$calcium$group$compared$to$the$placebo$group.

Reviews%of%many%studies%combined

Reviews$of$many$studies$combined$showed$mixed$findings$about$whether$consumingcalcium$and$dairy$products$affects$the$risk$of$prostate$cancer:

A$2005$review$of$many$studies$found$a$possible$link$between$an$increased$risk$ofprostate$cancer$and$a$diet$high$in$dairy$products$and$calcium.$See$the$PDQ$summaryon$Prostate$Cancer$Prevention$for$more$information.

A$2008$review$of$45$observational$studies$found$no$link$between$consuming$dairyproducts$and$the$risk$of$prostate$cancer.

A$review$of$cohort$studies$published$between$1996$and$2006$found$that$consuming

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http://www.cancer.gov/types/prostate/patient/prostate-prevention-pdq

milk$and$dairy$products$did$increase$the$risk$of$prostate$cancer.

A$2013$review$for$the$U.S.$Preventive$Services$Task$Force$found$that$taking$Vitamin$Dand/or$calcium$supplements$showed$no$overall$effect$on$rates$of$cancer$or$deathsfrom$cancer,$including$prostate$cancer.

5.$ Is%calcium%approved%by%the%U.S.%Food%and%Drug%Administration%(FDA)%for%use%as%a%cancertreatment%in%the%United%States?

The$U.S.$Food$and$Drug$Administration$has$not$approved$the$use$of$calcium$as$a$treatmentfor$cancer$or$any$other$medical$condition.

Calcium$is$available$in$the$United$States$in$food$products$and$dietary$supplements.$Becausedietary$supplements$are$regulated$as$foods,$not$as$drugs,$FDA$approval$is$not$requiredunless$specific$claims$about$disease$prevention$or$treatment$are$made.

Current Clinical Trials

Check$NCI’s$list$of$cancer$clinical$trials$for$CAM$clinical$trials$on$calcium$carbonate$for$prostatecancer$and$calcium$citrate$for$prostate$cancer$that$are$actively$enrolling$patients.

General$information$about$clinical$trials$is$also$available$from$the$NCI$website.

Questions and Answers About Green Tea1.$ What%is%green%tea?

Tea$has$been$consumed$in$Asia$since$ancient$times.$Sailors$first$brought$tea$to$England$in$the17th$century.$Other$than$water,$tea$is$the$most$widely$consumed$beverage$in$the$world.$Teacomes$from$the$Camellia sinensis$plant.$The$way$the$leaves$of$this$plant$are$processeddetermines$the$type$of$tea$produced.

Many$of$the$possible$health$benefits$studied$in$green$tea$are$thought$to$be$from$compoundscalled$polyphenols.$Polyphenols$are$a$large$group$of$plant$chemicals$that$include$catechins(antioxidants$that$help$protect$cells$from$damage$caused$by$free$radicals).

Catechins$make$up$most$of$the$polyphenols$in$green$tea.$The$most$active$catechin$in$greentea$is$epigallocatechin-3-gallate$(EGCG).

To$make$green$tea,$the$tea$leaves$are$roasted$in$a$wok$(or,$historically,$steamed)$to$preservethe$catechins$and$retain$freshness.$Black$tea$is$made$using$a$process$that$causes$thecatechins$and$other$compounds$in$the$leaves$to$oxidize,$producing$darker$colored$tea.Oolong$tea$is$made$from$partially$oxidized$leaves.

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http://www.cancer.gov/about-cancer/treatment/clinical-trials/search/results?protocolsearchid=12233933&vers=1

http://www.cancer.gov/about-cancer/treatment/clinical-trials

Some$studies$suggest$that$green$tea$may$protect$against$cardiovascular$disease$and$sometypes$of$cancer,$including$prostate$cancer.$Clinical$trials$designed$to$study$whether$green$teais$useful$in$treating$prostate$cancer$are$in$the$early$stages.$There$is$not$enough$evidence$toshow$whether$green$tea$is$effective$in$treating$prostate$cancer.

2.$ How%is%green%tea%administered%or%consumed?

Green$tea$may$be$consumed$as$a$beverage$or$taken$in$dietary$supplements.

3.$ Have%any%preclinical%(laboratory%or%animal)%studies%been%conducted%using%green%tea?

Laboratory$and$animal$research$has$been$done$to$study$the$effects$of$green$tea$in$prostatecancer.

Studies$of$green$tea$in$the$laboratory$have$shown$the$following:

EGCG$was$shown$to$block$the$stimulating$effect$of$androgen$(a$male$sex$hormone)$onhuman$prostate$tumor$cells,$slow$their$spread,$and$increase$cell$death.

Prostate$cancer$cells$were$treated$with$either$EGCG$or$EGCG-loaded$nanoparticles.While$both$treatments$decreased$cell$spread$and$increased$cell$death,$thenanoparticle$treatment$was$more$effective$at$lower$levels,$suggesting$this$type$ofdelivery$system$for$EGCG$may$make$it$easier$for$the$body$to$use$and$improve$EGCG'santicancer$activity.

Green$tea$polyphenols$may$cause$anticancer$effects$by$blocking$histone$deacetylases(HDAC)$which$are$found$in$large$amounts$in$cancer$cells,$including$those$in$prostatecancer.$Treating$prostate$cancer$cells$with$green$tea$polyphenols$lowered$HDACactivity$and$caused$cell$death.

Studies$of$green$tea$in$animal$models$of$prostate$cancer$have$shown$the$following:

Strains$of$mice$created$to$develop$prostate$cancer$that$acts$like$human$cancer$weregiven$either$plain$water$or$water$treated$with$green$tea$catechins$(comparable$to$ahuman$drinking$6$cups$of$green$tea/$day).$After$24$weeks,$the$mice$given$plain$waterhad$developed$prostate$cancer$while$the$mice$given$water$with$green$tea$catechinsshowed$only$prostatic$intraepithelial$neoplasia$(PIN)$lesions.$The$findings$suggestedthat$green$tea$catechins$may$help$delay$the$development$of$prostate$cancer$byblocking$a$protein$involved$in$cancer$growth.

In$a$study$of$EGCG,$mice$were$implanted$with$prostate$cancer$cells$and$injected$withEGCG$or$placebo$3$times/$week.$The$mice$that$received$the$EGCG$treatment$had$lowerlevels$of$proteins$needed$for$androgen$activity$than$those$treated$with$placebo.$Thefindings$suggested$that$EGCG$blocks$the$stimulating$effect$of$androgen$on$tumor$cells

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in$a$way$that$may$be$useful$in$prostate$cancer$that$can$be$treated$with$hormonetherapy$and$also$in$prostate$cancer$that$does$not$respond$to$hormone$therapy.

In$another$study$of$EGCG,$strains$of$mice$created$to$develop$prostate$cancer$that$actslike$human$cancer$were$given$EGCG$in$drinking$water$(comparable$to$a$humandrinking$6$cups$of$green$tea/$day)$starting$at$either$12$weeks$of$age$or$28$weeks$ofage.$EGCG$treatment$prevented$high-grade$PIN$lesions$in$mice$that$began$treatmentat$12$weeks$but$not$in$those$that$began$treatment$at$28$weeks$of$age.

In$a$study$of$green$tea$polyphenols,$these$strains$of$mice$were$given$polyphenols$indrinking$water$starting$at$different$ages$(to$match$different$stages$of$prostate$cancer).All$the$green$tea-fed$mice$were$tumor-free$longer$than$water-fed$control$mice,$andthe$mice$that$were$fed$with$green$tea$the$earliest$benefitted$the$most.

In$another$study$of$green$tea$polyphenols,$these$strains$of$mice$were$fed$polyphenolsby$mouth$(comparable$to$a$human$drinking$6$cups$of$green$tea/$day).$As$measured$byMRIs$over$time,$tumor$development$was$delayed$and$tumor$growth$was$slowed$in$thepolyphenol-fed$mice$compared$to$water-fed$mice.$In$addition,$the$polyphenols$causedhigh$levels$of$cell$death,$possibly$limiting$the$spread$of$cancer$to$distant$parts$of$thebody.

Safety$studies$of$Polyphenon$E$(a$green$tea$extract$with$a$mixture$of$catechins)$havebeen$done$in$dogs$given$various$doses$by$mouth.$Mixed$findings$of$safety$and$harmsin$fasting$dogs$compared$to$fed$dogs$using$different$types$of$Polyphenon$E$are$beingreviewed.

4.$ Have%any%clinical%trials%(research%studies%with%people)%of%green%tea%been%conducted?

Population$studies$and$clinical$trials$have$been$done$to$find$out$if$green$tea$may$be$useful$inpreventing$or$treating$prostate$cancer.

Population%studies

A$review$of$many$population$studies$combined,$mainly$from$Asia,$showed$mixed$findingsabout$whether$green$tea$had$a$protective$effect$or$no$effect$on$prostate$cancer$risk.$Manyfactors$may$be$involved$in$these$mixed$results,$including$study$location,$tobacco$and$alcoholuse,$and$other$dietary$differences.$Black$tea$was$not$found$to$affect$prostate$cancer$risk.

Overall,$population$studies$suggest$that$green$tea$may$help$protect$against$prostate$cancerin$Asian$populations.$As$more$people$drink$green$tea$worldwide,$including$in$the$UnitedStates,$further$population$studies$will$add$to$information$about$whether$green$tea$or$green

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tea$catechins$may$help$protect$against$prostate$cancer.

Clinical%trials%of%preventing%prostate%cancer

A$study$assigned$60$men$with$high-grade$prostatic$intraepithelial$neoplasia$(HGPIN)$to$takegreen$tea$catechin$capsules$(600$mg$/$day)$or$a$placebo.$After$1$year,$9$men$in$the$placebogroup$were$diagnosed$with$prostate$cancer$compared$to$1$man$in$the$green$tea$catechingroup.$The$findings$suggest$that$green$tea$catechins$may$lower$the$risk$of$prostate$cancer$inpatients$at$high$risk$for$the$disease.$Two$year$follow-up$showed$that$this$effect$was$long-lasting.$A$larger,$multicenter$trial$is$underway.

Clinical%trials%of%treating%prostate%cancer

Clinical$trials$designed$to$study$whether$green$tea$is$useful$in$treating$prostate$cancer$haveshown$the$following:

Patients$scheduled$to$undergo$radical$prostatectomy$were$assigned$to$drink$green$tea,$blacktea,$or$soda$five$times/$day$for$5$days.$Bioavailable$tea$polyphenols$were$found$in$prostatetissue$samples$of$patients$who$drank$either$green$tea$or$black$tea.$In$addition,$prostatecancer$cells$treated$with$blood$taken$from$patients$after$they$drank$tea$grew$and$dividedmore$slowly$than$cells$treated$with$blood$taken$from$patients$before$they$drank$tea.

Fifty$patients$scheduled$to$undergo$radical$prostatectomy$were$assigned$to$take$PolyphenonE$(800$mg$EGCG)$or$a$placebo$daily$for$3$to$6$weeks.$Patients$treated$with$Polyphenon$E$hadlower$blood$levels$of$prostate$specific$antigen$(PSA)$and$insulin-like$growth$factor$-1$(aprotein$linked$with$increased$risk$of$prostate$cancer)$than$patients$treated$with$placebo,$butthese$differences$were$not$meaningful.$The$findings$suggest$that$the$possible$anticancereffects$of$green$tea$polyphenols$may$need$to$be$studied$in$longer$treatment$trials.

Patients$scheduled$to$undergo$radical$prostatectomy$were$assigned$to$drink$either$green$tea,black$tea,$or$water.$In$this$study,$men$drinking$green$tea$showed$a$decrease$in$PSA$levelsalong$with$a$decrease$in$NF-kappa$B$levels.

A$small$group$of$hormone-refractory$prostate$cancer$patients$were$given$capsules$of$greentea$extract$(375$mg$of$polyphenols/$day)$for$up$to$5$months.$The$study$showed$that$thegreen$tea$treatment$was$well$tolerated$by$most$of$the$patients.$However,$no$patient$had$ameaningful$decrease$in$PSA$levels$and$all$19$patients$had$disease$progression$within$1$to$5months.

Patients$with$androgen-independent$prostate$cancer$that$had$spread$to$other$places$in$thebody$consumed$powdered$green$tea$extract$(6$grams$/$day$for$up$to$4$months).$Of$the$forty-two$participants,$one$had$a$meaningful$decrease$in$blood$PSA$levels$which$did$not$last$longerthan$2$months.$Green$tea$extract$was$well$tolerated$by$most$of$the$study$patients.$However,

there$were$6$reports$of$serious$side$effects,$including$insomnia,$confusion,$and$fatigue.$Thefindings$suggest$that$green$tea$extract$may$have$limited$benefits$in$patients$with$advancedprostate$cancer.

5.$ Have%any%side%effects%or%risks%been%reported%from%green%tea?

Four$phase$I$studies$of$Polyphenon$E$in$single$doses$or$multidoses$were$done$in$healthyvolunteers.$Polyphenon$E$was$given$in$a$range$of$doses$and$found$to$be$well$tolerated.$Sideeffects$were$generally$mild,$with$no$serious$side$effects$reported.$The$most$frequentlyreported$side$effects$thought$to$be$related$to$the$drug$include$headache,$nausea,$abdominalpain,$diarrhea,$upset$stomach,$dizziness,$and$weakness.$Gastrointestinal$side$effects$wereusually$mild,$occurring$most$often$in$patients$taking$the$drug$on$an$empty$stomach$and$atthe$highest$doses.

The$FDA$Division$of$Drug$Oncology$Products$recommends$that$Polyphenon$E$should$betaken$with$food$by$patients$in$clinical$trials$and$that$liver$function$tests$should$be$doneduring$treatment.

Various$types$and$doses$of$green$tea$extracts$taken$by$mouth$have$been$linked$with$severalcases$of$liver$damage$in$recent$years.$Most$of$those$affected$were$women$and$many$weretaking$green$tea$extract$for$weight$loss.$Most$patients$recovered$within$4$months$afterstopping$the$green$tea$extract.$However,$there$is$one$case$report$of$acute$liver$failure$in$awoman$who$then$needed$a$liver$transplant.$Her$doctors$concluded$that$her$condition$waslikely$caused$by$over-the-counter$green$tea$extract$capsules$for$weight$loss.

Green$tea$has$been$well$tolerated$in$clinical$studies$of$patients$with$prostate$cancer.$Onestudy$found$that$the$most$commonly$reported$side$effects$of$green$tea$were$gastrointestinalsymptoms.$These$were$mild$except$for$two$reports$of$severe$anorexia$and$moderatebreathing$problems.

6.$ Is%green%tea%approved%by%the%U.S.%Food%and%Drug%Administration%(FDA)%for%use%as%acancer%treatment%in%the%United%States?

The$U.S.$Food$and$Drug$Administration$has$not$approved$the$use$of$green$tea$as$a$treatmentfor$cancer$or$any$other$medical$condition.

Green$tea$is$available$in$the$United$States$in$food$products$and$dietary$supplements.$Becausedietary$supplements$are$regulated$as$foods,$not$as$drugs,$FDA$approval$is$not$requiredunless$specific$claims$about$disease$prevention$or$treatment$are$made.

Check$NCI’s$list$of$cancer$clinical$trials$for$CAM$clinical$trials$on$green$tea$for$prostate$cancer$and

green$tea$extract$for$prostate$cancer$that$are$actively$enrolling$patients.

Questions and Answers About Lycopene1.$ What%is%lycopene?

Lycopene$is$a$carotenoid$(a$natural$pigment$made$by$plants).$Lycopene$protects$plants$fromlight-related$stress$and$helps$them$use$the$energy$of$the$sun$to$make$nutrients.$Lycopene$isfound$in$fruits$and$vegetables$like$tomatoes,$apricots,$guavas,$and$watermelons.

The$main$source$of$lycopene$in$the$American$diet$is$tomato-based$products.$Lycopene$ismore$bioavailable$(easier$for$the$body$to$use)$in$processed$tomato$products$like$tomatopaste$and$tomato$puree$than$in$raw$tomatoes.

Eating$carotenoids,$including$lycopene,$along$with$dietary$fat$may$help$the$body$absorbthem.$For$example,$one$study$showed$that$more$lycopene$was$absorbed$from$dicedtomatoes$cooked$with$olive$oil$than$diced$tomatoes$cooked$without$olive$oil.

Lycopene$in$the$diet$may$affect$antioxidant$activity$and$communication$between$cells.Laboratory$and$animal$studies$have$shown$that$lycopene$may$help$lower$the$risk$of$prostate,skin,$breast,$lung,$and$liver$cancers.$However,$clinical$trials$of$whether$lycopene$lowerscancer$risk$have$shown$mixed$results.

2.$ How%is%lycopene%administered%or%consumed?

Lycopene$may$be$consumed$in$the$diet$or$taken$in$dietary$supplements.

3.$ Have%any%preclinical%(laboratory%or%animal)%studies%been%conducted%using%lycopene?

Laboratory$research$and$animal$studies$have$been$done$to$find$out$if$lycopene$may$be$usefulin$preventing$or$treating$prostate$cancer.

Studies$of$lycopene$in$the$laboratory$have$shown$the$following:

Prostate$cancer$cells$treated$with$lycopene$had$changes$in$their$cell$division$cycle,leading$to$less$cancer$cell$growth.

In$prostate$cancer$cells$treated$with$lycopene,$cholesterol$levels$were$lower,$leading$toless$cancer$cell$growth$&$more$cancer$cell$damage.

Treating$prostate$cancer$cells$with$lycopene$may$change$the$way$androgen$(malehormone)$is$taken$up$and$used$in$the$cells,$causing$less$cancer$cell$growth.

Combining$lycopene$with$standard$cancer$drugs$may$help$stop$the$spread$of$different

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types$of$prostate$cancer$cells$more$than$when$drugs$are$used$alone.$Used$togetherwith$a$cancer$drug,$lycopene$may$block$the$way$insulin-like$growth$factor$(IGF)$istaken$up$by$the$cells,$causing$less$cancer$cell$spread.

Studies$of$animal$models$of$prostate$cancer$treated$with$lycopene$have$shown$the$following:

Strains$of$mice$created$to$develop$prostate$cancer$that$acts$like$human$cancer$werefed$a$diet$with$either$lycopene$beadlets$or$tomato$paste.$Mice$on$the$lycopene$beadletdiet$had$a$greater$decrease$in$prostate$cancer$rates$than$mice$on$the$tomato$pastediet.$This$suggests$that$lycopene$might$have$more$cancer$protective$effects$thantomato$paste.

Combining$lycopene$with$a$substance$found$in$dried$tomatoes$(FruHis)$slowed$thegrowth$of$prostate$cancer$cells$in$rats$more$than$either$lycopene$or$FruHis$alone.

A$study$of$mice$injected$with$human$prostate$cancer$cells$showed$that$mice$treatedwith$either$lycopene$or$beta$carotene$supplements$had$less$tumor$growth.

A$study$of$mice$injected$with$human$prostate$cancer$cells$and$treated$with$a$certainchemotherapy$drug,$lycopene,$or$both$showed$that$those$treated$with$chemotherapyand$lycopene$lived$longer$and$had$smaller$tumors$than$those$treated$withchemotherapy$alone.

4.$ Have%any%population%studies%or%clinical%trials%(research%studies%with%people)%of%lycopenebeen%conducted?

Several$population$studies$and$clinical$trials$have$been$done$to$find$out$if$lycopene$may$beuseful$in$preventing$or$treating$prostate$cancer.

Population%studies

Population$studies$look$for$risk$factors$and$ways$to$control$disease$in$large$groups$of$people.Population$studies$of$prostate$cancer$risk$have$shown$the$following$mixed$results:

Population$studies$in$men$have$found$that$high$amounts$of$lycopene$in$the$diet$arelinked$with$a$lower$risk$of$developing$prostate$cancer.

Some$studies$have$shown$that$lycopene$levels$in$the$blood$and$tissue$of$patients$withcancer$are$lower$than$in$those$who$do$not$have$cancer.$However,$other$studies$havenot$shown$this.

A$2013$review$of$several$studies$combined$found$that$men$who$ate$large$amounts$ofraw$or$cooked$tomatoes$may$have$a$slightly$lower$risk$of$prostate$cancer.

A$study$found$no$link$between$lycopene$and$tomatoes$in$the$diet$and$prostate$cancer

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risk$in$the$overall$population.$However,$in$men$with$a$family$history$of$the$disease,higher$amounts$of$lycopene$in$the$diet$were$linked$with$a$lower$risk$of$prostatecancer.$Another$study$in$the$same$group$of$men$found$no$difference$in$blood$levels$oflycopene$between$healthy$men$and$men$who$developed$prostate$cancer.

Many$issues$may$be$involved$in$these$mixed$findings,$including$sources$and$types$oflycopene,$other$dietary$differences,$obesity,$tobacco$and$alcohol$use,$and$genetic$risk$factors.

Clinical$trials$designed$to$study$whether$lycopene$is$useful$in$preventing$prostate$cancerhave$shown$the$following:

Men$with$benign$prostate$hyperplasia$(BPH)$or$prostate$cancer$were$given$tomatosauce$dishes$for$3$weeks$before$scheduled$surgery$to$remove$the$prostate.$The$studyfound$that$they$had$markedly$lower$prostate$specific$antigen$(PSA)$levels$and$morecancer$cell$death$found$in$the$prostate$when$examined$after$surgery$than$a$similargroup$of$patients$who$did$not$receive$the$tomato$sauce$dishes.

Men$with$high-grade$prostatic$intraepithelial$neoplasia$(HGPIN)$who$took$lycopenesupplements$for$2$years$had$a$greater$decrease$in$PSA$levels$and$fewer$cases$ofprostate$cancer$than$those$who$did$not.$This$indicated$that$lycopene$may$be$useful$inpreventing$HGPIN$from$developing$into$prostate$cancer.$In$another$study$of$men$athigh$risk$of$prostate$cancer$(such$as$men$with$HGPIN),$those$who$took$a$dailymultivitamin$with$no$lycopene$and$those$who$took$the$same$multivitamin$pluslycopene$(30$mg/$day)$for$4$months$showed$no$difference$in$PSA$levels.

Clinical$trials$designed$to$study$whether$lycopene$is$useful$in$treating$prostate$cancer$haveshown$the$following:

Men$with$prostate$cancer$that$had$not$spread$were$given$lycopene$supplements(30mg/$day)$for$3$weeks$before$surgery$to$remove$the$prostate.$Those$who$receivedlycopene$supplements$had$smaller$tumors$and$lower$PSA$levels$than$those$who$didnot.$This$study$suggests$that$lycopene$may$be$helpful$in$treating$prostate$cancer.Another$study$of$men$with$prostate$cancer$that$had$not$spread$showed$that$men$whotook$lycopene$supplements$(10mg/$day$for$1$year)$had$lower$PSA$velocity$(a$measureof$how$fast$PSA$levels$in$the$blood$increase$over$time)$after$treatment.

Men$who$had$biochemical$relapse$of$prostate$cancer$(a$rise$in$the$blood$level$of$PSAafter$treatment$with$surgery$or$radiation)$were$given$different$doses$of$lycopene

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supplements$(ranging$from$15$mg/$day$to$120$mg/$day)$for$1$year.$Study$resultsshowed$that$lycopene$seemed$safe$&$had$no$side$effects,$but$did$not$change$PSAlevels$in$biochemically$relapsed$prostate$cancer.

Men$with$hormone-refractory$prostate$cancer$(HRPC)$(tumors$that$do$not$respond$totreatment$with$hormones)$were$given$lycopene$supplements$for$periods$of$3$or$6months$in$2$different$studies.$These$studies$showed$mixed$results$in$lowering$PSAlevels$in$men$with$HRPC.

Men$with$androgen-independent$prostate$cancer$(tumors$that$do$not$need$androgento$grow)$consumed$lycopene$in$either$tomato$paste$or$tomato$juice$daily$for$4months.$Study$results$showed$that$lycopene$may$not$be$effective$in$lowering$PSAlevels$in$androgen-independent$cancer.

5.$ Have%any%side%effects%or%risks%been%reported%from%lycopene?

Lycopene$has$been$consumed$by$prostate$cancer$patients$with$very$few$side$effects$in$manyclinical$trials.$Doses$ranging$from$10$to$120$mg/$day$have$caused$only$occasionalgastrointestinal$symptoms$(e.g.$diarrhea,$nausea$and$vomiting,$bloating,$gassiness$andstomach$irritation).$In$one$study,$symptoms$went$away$when$lycopene$was$taken$with$meals.

6.$ Is%lycopene%approved%by%the%U.S.%Food%and%Drug%Administration%(FDA)%for%use%to%preventor%treat%cancer%in%the%United%States?

The$U.S.$Food$and$Drug$Administration$has$not$approved$the$use$of$lycopene$as$a$treatmentfor$cancer$or$any$other$medical$condition.

Lycopene$is$available$in$the$United$States$in$food$products$and$dietary$supplements.$Becausedietary$supplements$are$regulated$as$foods,$not$as$drugs,$FDA$approval$is$not$requiredunless$specific$claims$about$disease$prevention$or$treatment$are$made.$An$FDA$review$in2007$found$that$there$was$not$enough$evidence$to$allow$a$claim$that$lycopene$helps$lowercancer$risk.

Check$NCI’s$list$of$cancer$clinical$trials$for$CAM$clinical$trials$on$lycopene$for$prostate$cancer$thatare$actively$enrolling$patients.

Questions and Answers About Modified Citrus

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Pectin1.$ What%is%modified%citrus%pectin?

Pectin$is$a$type$of$polysaccharide$(a$carbohydrate$with$many$small$sugar$molecules$that$arechemically$linked).$Pectin$is$found$in$the$cell$walls$of$most$plants$and$has$gel-like$qualitiesthat$are$useful$in$making$many$types$of$food$and$medicine.

Citrus$pectin$is$found$in$the$peel$and$pulp$of$citrus$fruits$such$as$oranges,$grapefruit,$lemons,and$limes.$Citrus$pectin$can$be$modified$with$high$pH$and$heat$to$break$its$molecules$intosmaller$pieces.$Modified$citrus$pectin$(also$called$MCP)$can$be$digested$and$absorbed$by$thebody.

2.$ How%is%MCP%administered%or%consumed?

MCP$may$be$taken$by$mouth$in$powder$or$capsule$form.

3.$ Have%any%preclinical%(laboratory%or%animal)%studies%been%conducted%using%MCP?

A$study$in$prostate$cancer$cells$compared$3$different$kinds$of$pectin:$citrus$pectin,$PectaSol$(adietary$supplement$with$MCP),$and$fractionated$pectin$powder.$Prostate$cancer$cells$treatedwith$the$pectin$powder$had$more$damage$than$those$treated$with$citrus$pectin$or$PectaSol.However,$when$citrus$pectin$was$modified$by$heating$it,$it$caused$the$same$amount$ofdamage$to$prostate$cancer$cells$as$the$pectin$powder.

Only$a$few$studies$have$reported$the$effects$of$MCP$in$animal$models$of$cancer,$includingone$prostate$cancer$study.$Rats$injected$with$prostate$cancer$cells$and$treated$with$MCPshowed$less$spread$of$the$cancer$to$the$lungs$but$no$effect$on$tumor$growth$at$the$originalcancer$site.

4.$ Have%any%population%studies%or%clinical%trials%(research%studies%with%people)%of%MCPbeen%conducted?

A$few$studies$in$prostate$cancer$patients$suggest$that$MCP$may$have$some$anticancerbenefits.

In$a$study$of$patients$with$advanced$solid$tumors,$including$prostate$cancers,$MCP$powder$inwater$was$given$3$times/$day$for$at$least$8$weeks.$The$study$showed$some$quality$of$lifeimprovements$in$physical$functioning,$overall$health,$fatigue,$pain,$and$insomnia.$About$one-fourth$of$patients$showed$stable$disease$after$8$weeks$of$treatment$and$a$smaller$numberhad$stable$disease$for$more$than$24$weeks.$Since$the$study$did$not$include$a$group$ofpatients$who$did$not$receive$MCP$for$comparison,$it$was$not$designed$to$be$able$to$tell$if$anyof$these$changes$were$due$to$the$addition$of$MCP.$The$primary$goal$of$the$study$was$todetermine$if$MCP$would$be$well$tolerated$by$cancer$patients,$and$it$was.

In$a$study$of$the$effect$of$MCP$on$prostate-specific$antigen$(PSA)$doubling$time$(how$long$ittakes$PSA$levels$in$the$blood$to$increase$by$100$percent),$prostate$cancer$patients$who$hadrising$PSA$levels$were$given$6$PectaSol$capsules$3$times/$day$for$12$months.$After$treatment,7$out$of$10$patients$showed$a$slowing$of$PSA$doubling$time.

5.$ Have%any%side%effects%or%risks%been%reported%from%MCP?

Two$studies$of$MCP$showed$that$most$patients$had$very$few$side$effects.$Itching,$stomachupset,$and$gassiness$were$reported$in$one$study.$In$another$study,$3$patients$had$abdominalcramps$and$diarrhea$that$went$away$when$their$treatment$was$stopped.

6.$ Is%MCP%approved%by%the%U.S.%Food%and%Drug%Administration%(FDA)%for%use%to%prevent%ortreat%cancer%in%the%United%States?

The$U.S.$Food$and$Drug$Administration$has$not$approved$the$use$of$MCP$as$a$treatment$forcancer$or$any$other$medical$condition.

MCP$is$available$in$the$United$States$in$food$products$and$dietary$supplements.$Becausedietary$supplements$are$regulated$as$foods,$not$as$drugs,$FDA$approval$is$not$requiredunless$specific$claims$about$disease$prevention$or$treatment$are$made.

Check$NCI’s$list$of$cancer$clinical$trials$for$CAM$clinical$trials$on$modified$citrus$pectin$for$prostatecancer$that$are$actively$enrolling$patients.

Questions and Answers About Pomegranate1.$ What%is%pomegranate?

The$pomegranate$fruit$(Punica granatum$L.)$is$native$to$Asia$and$grown$throughout$theMediterranean,$Southeast$Asia,$East$Indies,$Africa,$and$the$United$States.$Pomegranate$hasbeen$used$for$medicinal$purposes$since$ancient$times.

Different$parts$of$the$pomegranate$fruit$have$bioactive$compounds$(chemicals$found$in$smallamounts$that$have$actions$in$the$body$that$may$promote$good$health).$These$include:

The$peel,$which$makes$up$half$the$fruit$and$contains$bioactive$compounds$such$asphenolics,$flavonoids,$and$ellagitannins$(the$main$source$of$antioxidant$activity);

The$seeds,$which$contain$punicic$acid,$an$omega-5$fatty$acid;$and

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The$aril$(outer$layer$surrounding$the$seeds),$which$contains$phenolics$and$flavonoidsincluding$anthocyanins,$which$give$the$pomegranate$fruit$and$juice$their$red$color.

2.$ How%is%pomegranate%administered%or%consumed?

Pomegranate$may$be$consumed$in$the$diet$or$taken$in$dietary$supplements.

3.$ Have%any%preclinical%(laboratory%or%animal)%studies%been%conducted%usingpomegranate?

Laboratory$studies$of$pomegranate$in$cancer$cell$lines$include$the$following:

A$study$of$13$pomegranate$compounds$showed$some$were$able$to$slow$the$growthand$spread$of$prostate$cancer$cells$and$to$cause$cell$death.$Higher$doses$were$foundto$be$more$effective.$Punicic$acid$(a$bioactive$compound$found$in$pomegranate$seeds)was$shown$to$have$the$strongest$effect$in$causing$cell$death.

Three$types$of$prostate$cancer$cell$lines$were$treated$with$either$pomegranate$extract,pomegranate$juice,$or$two$of$their$bioactive$compounds.$All$pomegranate$treatmentswere$shown$to$increase$cell$death$and$decrease$the$spread$of$cancer$cells,$with$higherdoses$found$to$be$more$effective.$In$the$cell$line$that$was$dependent$on$androgen(male$hormone)$for$growth,$all$treatments$affected$the$way$androgen$was$taken$upand$used.

Other$studies$in$cancer$cell$lines$found$that$the$anticancer$activity$of$pomegranateincluded$effects$on$certain$enzymes$and$pathways$involved$in$cancer,$such$as$theinsulin-like$growth$factor$(IGF)$system.

Studies$of$animal$models$of$prostate$cancer$in$which$the$animals$were$given$pomegranatehave$shown$the$following:

A$study$of$mice$injected$with$prostate$tumor$-forming$cells$found$that$mice$that$drankpomegranate$extract$in$water$had$tumors$that$were$smaller$and$took$longer$todevelop$than$tumors$in$mice$that$drank$normal$water.

In$a$study$of$strains$of$mice$created$to$develop$prostate$cancer$that$acts$like$humancancer,$all$mice$that$were$given$normal$water$for$28$weeks$developed$tumors.$Onlyone-fifth$to$one-third$of$the$mice$that$received$pomegranate$extract$in$waterdeveloped$tumors,$with$the$mice$that$received$the$highest$amounts$of$pomegranateextract$having$the$fewest$tumors.

4.$ Have%any%clinical%trials%(research%studies%with%people)%of%pomegranate%been%conducted?

Two$clinical$trials$that$studied$pomegranate$in$prostate$cancer$patients$have$been$fully

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reported.

In$a$study$of$48$patients$with$rising$prostate-specific$antigen$(PSA)$levels$after$surgery$orradiation$therapy,$patients$were$given$8$ounces$of$pomegranate$juice$daily$for$up$to$33months.$Drinking$pomegranate$juice$was$related$to$a$slowing$of$PSA$doubling$time$(howlong$it$takes$PSA$levels$in$the$blood$to$increase$by$100$percent).$In$addition,$when$prostatecancer$cells$(LNCaP)$in$the$lab$were$treated$with$study$patients’$blood$before$and$after$thestudy,$there$was$a$decrease$in$cell$growth$and$increase$in$cell$death$following$pomegranatetreatment.

In$a$phase$II$study$of$patients$with$rising$PSA$levels$after$therapy$for$localized$prostatecancer,$patients$were$given$1$gram$or$3$gram$doses$of$pomegranate$extract.$Both$doses$ofpomegranate$extract$were$related$to$a$slowing$of$PSA$doubling$time$with$no$adverse$effects.

5.$ Have%any%side%effects%or%risks%been%reported%from%pomegranate?

Two$studies$of$pomegranate$juice$in$either$prostate$cancer$patients$or$patients$with$erectiledysfunction$reported$no$serious$side$effects.

6.$ Is%there%any%reason%people%should%avoid%pomegranate%juice?

Some$pomegranate$products$may$contain$added$sugar.$Certain$groups,$such$as$theAmerican$Institute$for$Cancer$Research$(AICR),$recommend$avoiding$sugary$drinks.$For$moreinformation,$see$the$AICR $website.

7.$ Is%pomegranate%approved%by%the%U.S.%Food%and%Drug%Administration%(FDA)%for%use%toprevent%or%treat%cancer%in%the%United%States?

The$U.S.$Food$and$Drug$Administration$has$not$approved$the$use$of$pomegranate$as$atreatment$for$cancer$or$any$other$medical$condition.

Pomegranate$is$available$in$the$United$States$in$food$products$and$dietary$supplements.Because$dietary$supplements$are$regulated$as$foods,$not$as$drugs,$FDA$approval$is$notrequired$unless$specific$claims$about$disease$prevention$or$treatment$are$made.

Check$NCI’s$list$of$cancer$clinical$trials$for$CAM$clinical$trials$on$pomegranate-extract$pill$forprostate$cancer,$pomegranate$juice$for$prostate$cancer,$and$pomegranate$liquid$extract$forprostate$cancer$that$are$actively$enrolling$patients.

http://www.cancer.gov/global/web/policies/exit

http://www.aicr.org/reduce-your-cancer-risk/recommendations-for-cancer-prevention/recommendations_03_sugary_drinks.html

Questions and Answers About Selenium1.$ What%is%selenium?

Selenium$is$a$trace$mineral$(a$nutrient$that$is$essential$to$humans$in$tiny$amounts).$Seleniumis$found$in$certain$proteins$that$are$active$in$many$body$functions,$including$reproductionand$immunity.$Food$sources$of$selenium$include$meat,$vegetables,$and$nuts.$The$amount$ofselenium$found$in$the$food$depends$on$the$selenium$content$of$the$soil$where$the$foodgrows.$Selenium$is$stored$in$the$thyroid$gland,$liver,$pancreas,$pituitary$gland,$and$kidneys.

Selenium$is$found$in$an$enzyme$called$glutathione$peroxidase$which$acts$as$an$antioxidant.However,$in$high$amounts,$selenium$may$act$as$a$pro-oxidant$(a$substance$that$can$makeoxygen$byproducts$that$may$damage$cells).

Selenium$may$play$a$role$in$many$diseases,$including$cancer.$Animal$and$population$studieshave$suggested$that$supplementing$the$diet$with$selenium$may$lower$the$risk$of$cancer.Results$from$the$Nutritional$Prevention$of$Cancer$Trial$(NPC)$showed$that,$although$seleniumsupplements$did$not$affect$the$risk$of$skin$cancer,$they$markedly$lowered$the$rates$of$lung,colorectal,$and$prostate$cancer.$However,$studies$of$how$selenium$levels$in$the$blood$affectthe$risk$of$developing$of$prostate$cancer$have$shown$mixed$results.

The$Selenium$and$Vitamin$E$Cancer$Prevention$Trial$(SELECT)$was$begun$by$the$NationalInstitutes$of$Health$in$2001$to$study$the$effects$of$selenium$and/or$vitamin$E$on$thedevelopment$of$prostate$cancer.

2.$ How%is%selenium%administered%or%consumed?

Selenium$may$be$consumed$in$the$diet$or$taken$in$dietary$supplements.$For$adults,$therecommended$daily$allowance$for$selenium$is$55$µg/day.

3.$ Have%any%preclinical%(laboratory%or%animal)%studies%been%conducted%using%selenium?

Laboratory$studies$to$find$out$if$selenium$may$be$useful$in$preventing$or$treating$prostatecancer$have$shown$the$following:

Different$forms$of$selenium$have$been$shown$to$slow$the$growth$and$spread$ofprostate$cancer$cells.

Selenium$nanoparticles$may$be$less$toxic$to$normal$tissues$than$other$seleniumcompounds.

Studies$of$selenium$in$animal$models$of$prostate$cancer$have$shown$the$following:

A$study$in$mice$looked$at$the$effect$of$dietary$selenium$on$prostate$cancer$preventionstarting$at$different$ages.$Adult$mice$and$younger$mice$were$fed$selenium-enriched

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diets$or$diets$with$no$selenium$for$6$months$or$4$weeks$and$then$injected$with$humanprostate$cancer$cells.$Adult$mice$with$selenium$in$their$diets$developed$fewer$tumorsthan$adult$mice$with$diets$lacking$in$selenium.$However,$in$younger$mice,$dietaryselenium$had$no$effect$on$tumor$development.

Strains$of$mice$which$developed$prostate$cancer$that$acts$like$human$cancer$weretreated$with$2$forms$of$selenium,$MSeA$and$methylselenocysteine$(MSeC),$or$wateronly.$In$the$selenium-treated$mice,$growth$of$precancerous$lesions$was$slowed$andcancer$cell$death$was$increased$compared$to$the$water-treated$mice.$MSeA$treatmentalso$increased$survival$time$of$the$study$mice.$The$mice$that$received$MSeA$treatmentstarting$at$10$weeks$of$age$had$less$aggressive$prostate$cancer$than$did$mice$startingtreatment$at$16$weeks$of$age,$suggesting$early$treatment$with$MSeA$may$be$moreeffective$than$later$treatment.

4.$ Have%any%population%studies%or%clinical%trials%(research%studies%with%people)%of%seleniumbeen%conducted?

Population$studies$and$clinical$trials$have$been$done$to$find$out$if$selenium$may$be$useful$inpreventing$or$treating$prostate$cancer.

Population%studies

Studies$of$how$selenium$levels$in$the$blood$affect$the$risk$of$developing$of$prostate$cancerhave$shown$mixed$results.$One$study$tracking$subjects$for$up$to$10$years$found$that$menwith$higher$levels$of$selenium$in$their$blood$had$a$lower$risk$of$prostate$cancer.$Anotherstudy$found$that$prostate$cancer$patients$had$lower$whole$blood$selenium$levels$than$didhealthy$men.$However,$a$2009$study$of$prostate$cancer$patients$found$that$men$with$higherselenium$levels$in$their$blood$were$at$greater$risk$of$being$diagnosed$with$aggressiveprostate$cancer.$These$differences$may$be$due$to$genetic$variations$among$individualpatients.

Clinical%trials%of%preventing/%treating%prostate%cancer

Clinical$trials$of$the$effects$of$selenium$on$prostate$specific$antigen$(PSA)$levels$or$thedevelopment$of$prostate$cancer$have$shown$mixed$results,$including$the$following:

In$a$study$reported$in$2013,$men$at$high$risk$for$prostate$cancer$were$given$eitherdaily$doses$of$high-selenium$yeast$(200$µg$or$400$µg)$or$a$placebo$for$up$to$5$years.There$were$no$differences$in$prostate$cancer$rates$or$PSA$velocity$in$men$who$tookthe$selenium$supplement$compared$to$those$who$took$the$placebo.

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In$an$earlier$study,$men$with$high-grade$prostatic$intraepithelial$neoplasia$(HGPIN)were$given$either$a$selenium$supplement$(200$µg/$day)$or$a$placebo$for$3$years$oruntil$they$were$diagnosed$with$prostate$cancer.$The$results$suggested$that$seleniumsupplements$had$no$effect$on$prostate$cancer$risk.

Sixty$men$were$given$either$a$selenium$glycinate$supplement$(200$µg/$day)$or$aplacebo$for$6$weeks.$Blood$samples$were$collected$at$the$start$and$the$end$of$thestudy.$Compared$to$the$placebo$group,$men$who$received$selenium$supplementsshowed$higher$activity$of$two$selenium$enzymes$in$their$blood$and$lower$levels$of$PSAat$the$end$of$the$study.

The$Health$Professionals$Follow-Up$Study$included$4,459$men$diagnosed$with$prostatecancer$that$had$not$spread.$The$study$found$that$taking$selenium$supplements$(140$ormore$µg/$day)$after$diagnosis$may$increase$the$risk$of$death$from$prostate$cancer$andrecommended$that$men$with$prostate$cancer$use$caution$in$taking$seleniumsupplements.

The%Selenium%and%Vitamin%E%Cancer%Prevention%Trial%(SELECT)

The$Selenium$and$Vitamin$E$Cancer$Prevention$Trial$(SELECT)$was$a$large$clinical$trial$begunby$the$National$Institutes$of$Health$in$2001$to$study$the$effects$of$selenium$and/or$vitamin$Eon$the$development$of$prostate$cancer.$Over$35,000$men,$aged$50$years$and$older,$wererandomly$assigned$to$receive$one$of$the$following$combinations$daily$for$7-12$years:

Vitamin$E$(alpha-tocopherol$acetate,$400$IU$/$day)$and$a$placebo;

Selenium$(L-selenomethionine,$200$mcg/$day)$and$a$placebo;

Vitamin$E$and$selenium;$or

Two$placebos.

First$results$of$SELECT$reported$in$2009$found$no$meaningful$difference$in$the$rate$ofprostate$cancer$among$the$4$groups.$In$the$Vitamin$E$alone$group,$there$was$a$slightincrease$in$the$rate$of$prostate$cancer$and$in$the$selenium$alone$group,$there$was$a$slightincrease$in$the$rate$of$diabetes.$Even$though$these$changes$were$not$clearly$shown$to$be$dueto$the$supplement,$the$men$in$the$study$were$advised$to$stop$taking$the$study$supplements.

Updated$results$of$SELECT$in$2011$showed$that$selenium$supplements$had$no$meaningfuleffect$on$prostate$cancer$risk;$however,$men$taking$vitamin$E$alone$had$a$17%$increase$inprostate$cancer$risk$compared$to$men$in$the$placebo$group.

In$2014,$further$results$of$SELECT$showed$that$selenium$supplements$in$men$with$lowselenium$levels$at$the$start$of$the$trial$had$no$effect$on$prostate$cancer$risk;$however,

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selenium$supplements$in$men$who$had$high$levels$of$selenium$at$the$start$of$the$trialincreased$the$risk$of$high-grade$prostate$cancer.

Several$factors$may$have$affected$study$results,$including$the$dose$of$vitamin$E$chosen$andthe$form$of$selenium$used.

5.$ Have%any%side%effects%or%risks%been%reported%from%selenium?

Selenium$supplements$were$well$tolerated$in$many$clinical$trials.$In$two$published$trials,there$were$no$differences$reported$in$adverse$effects$between$placebo$or$treatment$groups.However,$in$the$SELECT$trial,$selenium$supplements$were$linked$with$a$slight$increase$in$therate$of$diabetes$mellitus.

6.$ Is%selenium%approved%by%the%U.S.%Food%and%Drug%Administration%(FDA)%for%use%as%acancer%treatment%in%the%United%States?

The$U.S.$Food$and$Drug$Administration$has$not$approved$the$use$of$selenium$supplementsfor$the$treatment$or$prevention$of$cancer$or$any$other$medical$condition.

Selenium$is$available$in$the$United$States$in$food$products$and$dietary$supplements.$Becausedietary$supplements$are$regulated$as$foods,$not$as$drugs,$FDA$approval$is$not$requiredunless$specific$claims$about$disease$prevention$or$treatment$are$made.

Check$NCI$’s$list$of$cancer$clinical$trials$for$CAM$clinical$trials$on$selenium$for$prostate$cancer$thatare$actively$enrolling$patients.

Questions and Answers About Soy1.$ What%is%soy?

The$soybean$plant$has$been$grown$in$Asia$for$food$since$ancient$times.$Soy$first$arrived$inEurope$and$North$America$in$the$18th$century.$The$soybean$can$be$processed$into$a$widevariety$of$products$including$soy$milk,$miso,$tofu,$soy$flour,$and$oil.

Soy$foods$contain$many$phytochemicals$that$may$have$health$benefits.$Isoflavones$are$themost$widely$researched$compounds$in$soy.$Major$isoflavones$in$the$soybean$includegenistein$(which$may$be$the$most$bioactive$isoflavone),$daidzein,$and$glycitein.$Isoflavonesprotect$the$soybean$plant$from$stress$and$have$antioxidant,$antimicrobial,$and$antifungalactions.

http://www.cancer.gov/about-cancer/treatment/clinical-trials/search/view?cdrid=617778&version=Patient&protocolsearchid=12112361

Isoflavones$are$phytoestrogens$(estrogen$-like$substances$found$in$plants)$that$attach$toestrogen$receptors$in$cells.$Genistein$has$been$shown$to$affect$many$pathways$in$prostatecancer$cells$involved$in$the$growth$and$spread$of$cancer.

2.$ How%is%soy%administered%or%consumed?

Soy$may$be$consumed$in$the$diet$or$taken$in$dietary$supplements.

3.$ Have%any%preclinical%(laboratory%or%animal)%studies%been%conducted%using%soy?

Laboratory$research$and$animal$studies$have$been$done$to$find$out$if$soy$may$be$useful$inpreventing$or$treating$prostate$cancer.

Studies$of$soy$in$the$laboratory$have$shown$the$following:

Several$laboratory$studies$have$found$that$treating$human$prostate$cancer$cells$withisoflavones$(such$as$genistein$or$daidzein)$interferes$with$pathways$in$prostate$cancercells$related$to$inflammation$and$cancer$growth$and$spread.

Some$laboratory$studies$have$found$that$treating$prostate$cancer$cells$with$whole$soyextract$(containing$all$the$major$isoflavones)$or$combining$other$plant-basedcompounds$with$isoflavones$may$have$more$anticancer$effects$than$using$singleisoflavones.$One$study$compared$treating$human$prostate$cancer$cells$with$soyisoflavones,$curcumin$(a$yellow$pigment$of$the$spice$turmeric$that$is$being$studied$incancer$prevention),$or$a$combination$of$the$two$compounds.$Results$showed$thatcombining$curcumin$and$isoflavones$was$more$effective$in$lowering$prostate-specificantigen$(PSA)$levels$than$using$either$compound$alone.

Studies$of$animal$models$of$prostate$cancer$treated$with$soy$have$shown$the$following$mixedresults:

Strains$of$mice$created$to$develop$prostate$cancer$that$acts$like$human$cancer$werefed$a$diet$with$genistein$or$a$control$diet.$Compared$with$mice$on$the$control$diet,$themice$fed$the$genistein$diet$had$less$prostate$cancer$cell$growth$and$lower$levels$ofgrowth$promoting$proteins.

A$study$of$mice$that$were$genetically$modified$to$produce$prostate$cancer$found$thatmice$fed$a$low-dose$genistein$diet$had$more$spread$of$cancer$than$mice$fed$either$ahigh-dose$genistein$diet$or$a$diet$with$no$genistein.$This$suggests$that$the$effects$ofgenistein$on$prostate$cancer$may$vary$depending$on$dose$and$on$how$early$it$is$given.

A$study$in$mice$implanted$with$advanced$human$prostate$cancer$found$that$thosegiven$daily$genistein$in$peanut$oil$developed$more$tumors$in$other$parts$of$the$bodythan$mice$given$peanut$oil$without$genistein.

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In$a$study$of$combining$radiation$therapy$with$soy$isoflavones,$mice$implanted$withprostate$cancer$cells$were$treated$with$genistein,$mixed$isoflavones$(genistein,daidzein,$and$glycitein),$and/$or$radiation.$Mixed$isoflavones$were$found$to$be$moreeffective$than$genistein$in$slowing$prostate$tumor$growth.$Combining$mixedisoflavones$with$radiation$was$found$to$be$most$effective$in$slowing$tumor$growth.

4.$ Have%any%population%studies%or%clinical%trials%(research%studies%with%people)%of%soy%beenconducted?

Many$population$studies$and$clinical$trials$have$been$done$to$find$out$if$soy$may$be$useful$inpreventing$or$treating$prostate$cancer.$Soy$products$studied$include$dietary$supplements,drinks,$and$bread.

Population%studies

Population$studies$look$for$risk$factors$and$ways$to$control$disease$in$large$groups$of$people.Population$studies$of$soy$intake$and$prostate$cancer$risk$have$shown$the$following$mixedresults:

A$2009$review$of$many$studies$combined$showed$that$men$eating$large$amounts$ofnonfermented$soy$foods$(for$example,$tofu$and$soybean$milk)$had$a$lower$risk$ofprostate$cancer.$Eating$large$amounts$of$fermented$foods$(for$example,$miso)$was$notfound$to$affect$the$risk$of$prostate$cancer.

A$2013$review$showed$that$PSA$levels$and$sex$hormone$levels$were$not$markedlydifferent$in$men$treated$with$soy,$compared$with$men$who$were$not$treated$with$soy.

In$a$study$of$Japanese$men$who$underwent$a$prostate$biopsy$but$who$did$not$havecancer,$some$received$a$daily$supplement$of$soy$isoflavones$(40$mg)$and$curcumin(100$mg),$while$others$received$a$placebo.$After$6$months,$there$were$no$differencesin$PSA$levels$between$the$supplement$group$and$the$placebo$group$overall.$However,among$patients$with$higher$PSA$levels$at$the$start,$those$who$received$thesupplement$had$meaningful$decreases$in$PSA$levels$compared$to$patients$in$theplacebo$group.

A$study$was$done$to$find$out$if$a$soy$diet$standard$in$Asia$would$be$practical$forEuropean$men$to$follow.$Healthy$men$ate$either$a$high-soy$(2$daily$soy$servings)$orlow-soy$(usual)$diet$for$3$months,$then$crossed$over$to$the$other$diet.$Lower$PSA$levelswere$seen$with$the$high-soy$diet.$Results$showed$that$study$volunteers$were$able$tofollow$the$high-soy$diet.

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Men$at$risk$for$prostate$cancer$or$with$low-grade$prostate$cancer$were$given$eithersoy$protein,$alcohol$-washed$soy$protein$(which$is$lower$in$isoflavones),$or$milk$protein(which$has$no$isoflavones)$for$6$months.$PSA$levels$did$not$differ$among$the$groups$at3$months$or$6$months.$Fewer$cases$of$prostate$cancer$were$found$after$6$months$inmen$who$consumed$either$type$of$soy$protein$than$in$men$who$consumed$milkprotein.

In$a$trial$of$soy$isoflavones,$prostate$cancer$patients$with$rising$PSA$levels$who$hadbeen$treated$with$radiation$therapy$consumed$a$soy$drink$daily$for$6$months.$The$soydrink$contained$65-90$mg$of$isoflavones.$Results$showed$that$the$soy$drink$had$veryfew$side$effects$and$slowed$PSA$doubling$time$(how$long$it$takes$PSA$levels$in$theblood$to$increase$by$100$percent).$These$findings$indicate$that$consuming$the$soydrink$may$have$helped$slow$the$progression$of$prostate$cancer.

In$a$trial$of$genistein$(a$major$isoflavone),$prostate$cancer$patients$scheduled$forradical$prostatectomy$received$either$a$placebo$or$genistein$(30$mg/$day)$for$3-6weeks$before$surgery.$PSA$levels$in$patients$who$received$genistein$decreased$slightlywhile$PSA$levels$in$those$who$received$the$placebo$increased$slightly.

In$a$trial$of$soy$isoflavone,$prostate$cancer$patients$scheduled$for$prostatectomyreceived$either$capsules$(containing$80$mg/day$of$isoflavones)$or$a$placebo$for$up$to$6weeks$before$surgery.$There$was$no$difference$in$PSA,$testosterone,$or$cholesterollevel$changes$between$the$two$groups.

A$trial$of$a$soy$protein$supplement$(containing$60$mg/$day$of$isoflavones)$studiedpatients$with$early-stage$prostate$cancer.$Those$who$received$the$supplement$for$12weeks$had$slightly$greater$decreases$in$PSA$and$testosterone$levels$than$those$whoreceived$placebo.

Trials$of$whole$soy$were$done$in$men$scheduled$for$surgery$to$remove$the$prostate.$Inone$study,$patients$given$soy$supplements$for$2$weeks$before$surgery$showed$muchhigher$levels$of$isoflavones$in$prostate$tissue$than$in$blood.$In$another$study,$patientswho$ate$high-phytoestrogen$bread$(containing$soy$or$soy$and$linseed)$had$greaterdecreases$in$PSA$levels$than$those$who$ate$wheat$bread.

Two$trials$of$a$soy$isoflavone$supplement$were$done$in$prostate$cancer$patientsreceiving$antiandrogen$therapy.$Side$effects$of$antiandrogen$therapy$may$includesexual$dysfunction,$lower$quality$of$life,$and$changes$in$mental$functioning.$In$bothstudies,$men$who$received$the$isoflavone$supplement$(160$mg/day)$for$12$weeks

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showed$no$improvement$in$side$effects$of$antiandrogen$therapy$compared$to$menwho$received$a$placebo.

5.$ Have%any%side%effects%or%risks%been%reported%from%soy?

Soy$products$and$isoflavones$have$been$consumed$by$prostate$cancer$patients$with$very$fewside$effects$in$many$clinical$trials.$The$most$commonly$reported$side$effects$were$minorgastrointestinal$symptoms.

6.$ Is%soy%approved%by%the%U.S.%Food%and%Drug%Administration%(FDA)%for%use%to%prevent%ortreat%cancer%in%the%United%States?

The$U.S.$Food$and$Drug$Administration$has$not$approved$the$use$of$soy$as$a$treatment$forcancer$or$any$other$medical$condition.

Soy$is$available$in$the$United$States$in$food$products$and$dietary$supplements.$Becausedietary$supplements$are$regulated$as$foods,$not$as$drugs,$FDA$approval$is$not$requiredunless$specific$claims$about$disease$prevention$or$treatment$are$made.

Check$NCI’s$list$of$cancer$clinical$trials$for$CAM$clinical$trials$on$soy$isoflavones$for$prostatecancer$and$soy$protein$isolate$for$prostate$cancer$that$are$actively$enrolling$patients.

Questions and Answers About Vitamin D1.$ What%is%vitamin%D?

Vitamin$D$(also$called$calcipotriol,$cholecarciferol,$or$ergocalciferol)$is$a$fat-soluble$vitaminfound$in$enriched$dairy$products,$fatty$fish,$fish$liver$oil,$and$eggs.

Vitamin$D$has$many$actions$in$the$body$including:

Helping$absorb$calcium$from$food$in$the$small$intestine.

Improving$muscle$strength$and$immune$system$function.

Lowering$inflammation.

Maintaining$levels$of$calcium$and$phosphate$in$the$blood.

Vitamin$D$is$needed$for$bone$growth$and$protects$against$osteoporosis$in$adults.$Vitamin$Dlevel$is$usually$checked$by$measuring$the$amount$of$25-hydroxyvitamin$D$in$the$blood.

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2.$ What%are%the%sources%of%vitamin%D?

Vitamin$D$is$made$naturally$by$the$body$when$exposed$to$sunlight.$Vitamin$D$may$also$beconsumed$in$the$diet$or$taken$in$dietary$supplements.

3.$ Have%any%preclinical%(laboratory%or%animal)%studies%been%conducted%using%vitamin%D?

Laboratory$and$animal$research$studies$suggest$that$vitamin$D$may$have$effects$on$prostatecancer$cells$through$various$pathways.

Preclinical$studies$of$vitamin$D$in$prostate$cancer$have$shown$the$following:

A$study$of$a$form$of$vitamin$D$showed$that$it$may$prevent$prostate$cancer$cells$fromsticking$to$endothelium,$the$thin$layer$of$cells$that$lines$the$inside$of$blood$vessels,lymph$vessels,$and$body$cavities.

In$a$2011$study,$mice$were$fed$a$diet$with$adequate$vitamin$D$or$a$diet$lacking$vitaminD$and$were$then$injected$with$prostate$cancer$cells$into$bone$marrow$or$into$softtissues.$The$mice$lacking$vitamin$D$developed$bone$tumors$that$were$larger$and$grewfaster$than$the$mice$that$had$adequate$levels$of$vitamin$D.$However,$there$was$nodifference$in$soft$tissue$tumors$among$mice$with$different$vitamin$D$levels.$Results$ofthis$study$show$that$a$lack$of$vitamin$D$is$linked$with$growth$of$prostate$cancer$cells$inbone$but$not$in$soft$tissue.

A$study$of$vitamin$D$as$adjuvant$therapy$(therapy$to$make$other$types$of$treatmentmore$effective)$combined$it$with$cryotherapy$(freezing).$Mice$injected$with$prostatecancer$cells$were$treated$with$calcitriol$with$or$without$cryotherapy.$Those$who$weretreated$with$the$combination$of$calcitriol$and$freezing$had$more$cancer$cell$death$andless$cancer$cell$spread$than$those$who$were$treated$with$either$calcitriol$alone$orfreezing$alone.

4.$ Have%any%population%studies%or%clinical%trials%(research%studies%with%people)%of%vitaminD%been%conducted?

Many$population$studies$and$clinical$trials$have$been$done$to$find$out$if$vitamin$D$may$beuseful$in$preventing$or$treating$prostate$cancer.

Population%studies

Population$studies$look$for$risk$factors$and$ways$to$control$disease$in$large$groups$of$people.Population$studies$of$vitamin$D$and$prostate$cancer$risk$have$shown$the$following$mixedresults:

Vitamin$D$levels$in$patients$with$prostate$cancer$that$had$not$spread$were$takenannually$for$5$years.$Throughout$the$course$of$the$study,$lack$of$vitamin$D$was$a

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common$finding$among$these$patients.

Another$study$in$patients$with$prostate$cancer$suggested$that$medium$or$high$levelsof$vitamin$D$in$the$blood$may$be$linked$with$better$outcomes$than$lower$levels.$Thesefindings$indicate$that$vitamin$D$levels$may$play$a$role$in$whether$or$not$the$diseasewill$worsen$and$may$be$a$factor$in$predicting$outcome$in$prostate$cancer$patients.

One$thousand$patients$with$prostate$cancer$and$1000$control$patients$in$the$Alpha-Tocopherol,$Beta-Carotene$Cancer$Prevention$Study$were$followed$for$up$to$20$years.Results$suggested$that$men$with$higher$blood$levels$of$vitamin$D$had$a$greater$risk$ofdeveloping$prostate$cancer$than$men$with$lower$vitamin$D$levels.

In$a$case-cohort$analysis$from$the$Selenium$and$Vitamin$E$Cancer$Prevention$Trial(SELECT),$men$who$had$moderate$blood$levels$of$vitamin$D$(45–70$nmol/L)$were$foundto$have$a$markedly$lower$risk$of$aggressive$prostate$cancer$than$men$who$had$eitherlower$or$higher$levels$of$vitamin$D.

Vitamin$D$from$sunlight$exposure$has$been$studied$for$possible$effects$on$prostatecancer$rates.$A$2006$study$found$that$PSA$levels$rise$at$a$slower$rate$during$the$springand$summer$compared$to$other$times$of$the$year,$suggesting$this$may$be$due$tohigher$vitamin$D$levels$during$those$months.$Another$study$found$that$while$menwith$low$levels$of$sun$exposure$had$increased$risk$of$all$prostate$cancers,$those$withprostate$cancer$who$had$less$sun$exposure$showed$lower$risk$of$advanced$disease.

Geographic$patterns$of$deaths$in$the$United$States$from$1950$to$1994$showed$thathigher$death$rates$from$prostate$cancer$occurred$in$parts$of$the$country$with$lowerlevels$of$UV$radiation$from$sunlight.$This$effect$is$strongest$in$places$more$than$40degrees$north$of$the$equator,$where$sunlight$is$weakest$during$the$winter$months.These$findings$support$the$theory$that$lack$of$vitamin$D$increases$the$risk$for$prostatecancer.

Reviews%of%many%population%studies%combined

A$2008$review$of$45$observational$studies$combined$found$no$link$between$intake$of$vitaminD$and$prostate$cancer$risk.

A$2011$review$of$25$studies$combined$found$no$link$between$either$vitamin$D$in$the$diet$orblood$levels$of$vitamin$D$and$the$risk$of$prostate$cancer.

A$2014$review$of$21$studies$combined$found$that$high$levels$of$vitamin$D$in$the$blood$may$belinked$with$a$higher$risk$of$prostate$cancer.$Many$factors$may$affect$these$findings,$sincesome$studies$propose$men$from$higher$income$groups$may$have$higher$vitamin$D$levels$andare$more$likely$to$get$PSA$testing,$leading$to$higher$rates$of$reported$prostate$cancer.

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Clinical$trials$in$patients$with$prostate$cancer$have$shown$the$following:

A$clinical$trial$treated$patients$with$prostate$cancer$that$had$recurred$(come$back)$withcalcitriol$(the$active$form$of$vitamin$D)$and$naproxen$for$1$year.$Results$showed$thatthe$combination$of$calcitriol$and$naproxen$was$effective$in$slowing$the$rate$of$risingPSA$levels$in$study$patients,$suggesting$it$may$slow$disease$progression.

In$a$2010$study,$patients$with$prostate$cancer$that$did$not$respond$to$hormonetherapy$were$treated$with$calcitriol$and$dexamethasone.$The$results$indicated$thatwhile$the$treatment$was$well$tolerated,$it$did$not$have$an$effect$on$PSA$levels$in$thestudy$patients.

In$a$2009$study,$patients$with$locally$advanced$or$metastatic$prostate$cancer$weretreated$with$vitamin$D.$The$study$reported$that$one$in$every$5$patients$who$tookvitamin$D$had$improved$PSA$levels,$suggesting$that$vitamin$D$may$be$an$effectivetherapy$for$patients$with$advanced$prostate$cancer.

5.$ Is%vitamin%D%approved%by%the%U.S.%Food%and%Drug%Administration%(FDA)%for%use%as%acancer%treatment%in%the%United%States?

The$U.S.$Food$and$Drug$Administration$has$not$approved$the$use$of$vitamin$D$as$a$treatmentfor$cancer$or$any$other$medical$condition.

Vitamin$D$is$available$in$the$United$States$in$food$products$and$dietary$supplements.$Becausedietary$supplements$are$regulated$as$foods,$not$as$drugs,$FDA$approval$is$not$requiredunless$specific$claims$about$disease$prevention$or$treatment$are$made.

Check$NCI$’s$list$of$cancer$clinical$trials$for$CAM$clinical$trials$on$vitamin$D$for$prostate$cancer$thatare$actively$enrolling$patients.

Questions and Answers About Vitamin E1.$ What%is%vitamin%E?

Vitamin$E$is$a$nutrient$that$may$protect$against$chronic$diseases$such$as$cardiovasculardisease.$Vitamin$E$is$being$studied$in$the$prevention$of$some$types$of$cancer.

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There$are$eight$different$forms$of$vitamin$E:$four$tocopherols$(alpha-,$beta-,$gamma-,$andsigma-)$and$four$tocotrienols$(alpha-,$beta-,$gamma-,$and$sigma-).$Compared$with$othertocopherols,$alpha-tocopherol$(the$form$of$vitamin$E$commonly$found$in$dietarysupplements)$is$found$in$greater$amounts$in$the$body$and$is$the$most$active.$Most$vitamin$Ein$the$diet$comes$from$gamma-tocopherol.$Food$sources$of$vitamin$E$include$vegetable$oils,nuts,$and$egg$yolks.

Many$of$the$possible$health$benefits$of$Vitamin$E$may$be$from$its$antioxidant$activity.$VitaminE$is$a$powerful$antioxidant$that$protects$cell$membranes$from$damage$caused$by$freeradicals.$Vitamin$E$also$has$other$functions$involved$in$cell$signaling$pathways$and$geneexpression.

2.$ How%is%vitamin%E%administered%or%consumed?

Vitamin$E$may$be$consumed$in$the$diet$or$taken$in$dietary$supplements.

3.$ Have%any%clinical%trials%(research%studies%with%people)%of%vitamin%E%been%conducted?

Population$studies$and$clinical$trials$have$been$done$to$find$out$if$vitamin$E$may$be$useful$inpreventing$or$treating$prostate$cancer.

Population%studies

Population$studies$look$for$risk$factors$and$ways$to$control$disease$in$large$groups$of$people.Population$studies$of$vitamin$E$in$prostate$cancer$risk$have$shown$the$following:

The$NIH$-AARP$Diet$and$Healthy$Study$studied$whether$vitamin$E$in$supplements$andin$the$diet$of$volunteers$may$prevent$prostate$cancer.$After$5$years,$no$link$betweenvitamin$E$supplements$and$prostate$cancer$risk$was$found.$However,$a$lower$risk$ofadvanced$prostate$cancer$was$found$in$those$who$had$high$intakes$of$one$form$ofvitamin$E$(gamma-tocopherol).

In$a$2010$study$that$measured$blood$levels$of$trace$elements$and$vitamin$E,$those$whohad$prostate$cancer$had$markedly$lower$blood$levels$of$vitamin$E$than$those$who$didnot$have$prostate$cancer.$In$addition,$those$who$had$higher$PSA$levels$had$lowerlevels$of$vitamin$E$in$their$blood.

Blood$levels$of$alpha-tocopherol$and$gamma-tocopherol$and$prostate$cancer$risk$werestudied$in$participants$in$the$Prostate,$Lung,$Colorectal$and$Ovarian$(PLCO)$ScreeningTrial.$Men$with$higher$levels$of$alpha-tocopherol$had$lower$rates$of$prostate$cancer,but$this$was$noted$only$in$current$smokers$and$those$who$had$recently$quit.

In$a$review$of$many$studies$combined$involving$370,000$men$from$several$countries,higher$blood$levels$of$alpha-tocopherol$were$linked$with$a$lower$risk$of$prostate

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cancer$in$all$patients,$not$just$smokers.

Clinical%trials%of%preventing%or%treating%prostate%cancer

In$the$Physicians’$Health$Study$II,$men$received$either$vitamin$E$supplements$(400$IUsynthetic$alpha-tocopherol$taken$every$other$day)$and/or$vitamin$C$supplements$(500mg$synthetic$ascorbic$acid$taken$daily)$and$were$followed$for$an$average$of$8$years.The$overall$rates$of$prostate$cancer$were$very$similar$in$the$men$who$received$vitaminE$supplements$and$in$those$who$did$not,$suggesting$that$vitamin$E$may$not$preventprostate$cancer.$Furthermore,$vitamin$E$did$not$have$an$effect$on$total$cancer$or$deathrates$in$these$participants.

The$Alpha-Tocopherol,$Beta$Carotene$Cancer$Prevention$Study$(ATBC)$trial$measuredblood$levels$of$alpha-tocopherol$and$dietary$intake$of$vitamin$E$in$men$who$werefollowed$for$up$to$19$years.$Findings$showed$no$link$between$vitamin$E$in$the$diet$andprostate$cancer$risk,$but$showed$that$higher$levels$of$alpha-tocopherol$in$the$bloodmay$be$linked$with$a$lower$risk$for$developing$advanced$prostate$cancer.

Men$in$the$ATBC$trial$who$developed$prostate$cancer$were$studied$to$find$out$if$serumalpha-tocopherol$levels$affected$survival$time.$Higher$serum$alpha-tocopherol$levels,at$both$time$of$diagnosis$and$at$the$3-year$time$point,$were$linked$with$improvedprostate$cancer$survival.

A$2011$study$of$men$who$took$part$in$The$Carotene$and$Retinol$Efficacy$Trial$(CARET)found$that,$among$those$who$were$current$smokers,$higher$levels$of$serum$alpha-tocopherols$and$gamma-tocopherols$were$linked$with$lower$risk$of$aggressiveprostate$cancer.

The%Selenium%and%Vitamin%E%Cancer%Prevention%Trial%(SELECT)

The$Selenium$and$Vitamin$E$Cancer$Prevention$Trial$(SELECT)$was$a$large$clinical$trial$begunby$the$National$Institutes$of$Health$in$2001$to$study$the$effects$of$selenium$and/or$vitamin$Eon$the$development$of$prostate$cancer.$Over$35,000$men,$aged$50$years$and$older,$wererandomly$assigned$to$receive$one$of$the$following$combinations$daily$for$7-12$years:

Vitamin$E$(alpha-tocopherol$acetate,$400$IU/$day)$and$a$placebo;

Selenium$(L-selenomethionine,$200$mcg/$day)$and$a$placebo;

Vitamin$E$and$selenium;$or

Two$placebos.

First$SELECT$results$reported$in$2009$found$no$meaningful$differences$in$rates$of$prostate

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••••

cancer$among$the$4$groups.$In$the$Vitamin$E$alone$group,$there$was$a$slight$increase$in$therate$of$prostate$cancer$and$in$the$selenium$alone$group,$there$was$a$slight$increase$in$therate$of$diabetes.$Based$on$those$findings,$the$men$in$the$study$were$advised$to$stop$takingthe$study$supplements.

Updated$SELECT$results$in$2011$showed$that$selenium$supplements$had$no$meaningful$effecton$prostate$cancer$risk;$however,$men$taking$vitamin$E$alone$had$a$17%$increase$in$prostatecancer$risk$compared$to$men$in$the$placebo$group.

In$2014,$further$SELECT$results$showed$that$vitamin$E$supplements$alone$had$no$effect$onprostate$cancer$risk$in$men$with$high$levels$of$selenium$at$the$start$of$the$trial;$however,vitamin$E$supplements$increased$the$risk$of$low-grade$and$high-grade$prostate$cancer$inmen$with$lower$levels$of$selenium$at$the$start$of$the$trial.

Several$factors$may$have$affected$study$results,$including$the$dose$of$vitamin$E$chosen$andthe$form$of$selenium$used.

4.$ Have%any%side%effects%or%risks%been%reported%from%vitamin%E?

Alpha-tocopherols$are$deemed$Generally$Recognized$as$Safe$by$the$U.S.$Food$and$DrugAdministration.

In$the$Physicians’$Health$Study$II,$there$were$no$marked$differences$in$rates$ofgastrointestinal$symptoms,$fatigue,$drowsiness,$skin$discoloration$or$rashes,$or$migrainebetween$men$who$took$vitamin$E$(400$IU$every$other$day$of$alpha-tocopherol)$and$those$whotook$a$placebo.$However,$there$was$a$higher$number$of$hemorrhagic$strokes$in$men$whotook$vitamin$E$than$in$men$who$took$a$placebo.$In$the$Alpha-Tocopherol,$Beta$CaroteneCancer$Prevention$Study$Group,$there$was$also$an$increase$in$hemorrhagic$strokes$amongmen$in$the$group$that$took$vitamin$E$(50$mg/$day$of$alpha-tocopherol).

Earlier$results$from$the$SELECT$trial$showed$no$marked$differences$in$rates$of$less$severeadverse$effects$(such$as$hair$loss,$inflamed$skin,$and$nausea)$in$the$groups$that$took$vitaminE$(400$IU/$day$of$all-rac-alpha-tocopherol)$compared$to$the$other$treatment$groups.$Laterfollow-up$of$SELECT$participants$showed$an$increased$risk$of$prostate$cancer$among$men$inthe$vitamin$E$alone$group.

5.$ Is%vitamin%E%approved%by%the%U.S.%Food%and%Drug%Administration%(FDA)%for%use%as%acancer%treatment%in%the%United%States?

The$U.S.$Food$and$Drug$Administration$has$not$approved$the$use$of$vitamin$E$as$a$treatmentfor$cancer$or$any$other$medical$condition.

Vitamin$E$is$available$in$the$United$States$in$food$products$and$dietary$supplements.$Becausedietary$supplements$are$regulated$as$foods,$not$as$drugs,$FDA$approval$is$not$required

unless$specific$claims$about$disease$prevention$or$treatment$are$made.

Check$NCI$’s$list$of$cancer$clinical$trials$for$CAM$clinical$trials$on$vitamin$E$for$prostate$cancer$thatare$actively$enrolling$patients.

Combination Therapies

Pomegranate, Green Tea, Broccoli, and Turmeric

Polyphenols$are$compounds$found$in$many$plants$and$give$some$flowers,$fruits,$and$vegetablestheir$color.$Polyphenols$have$antioxidant$activity$that$helps$protect$cells$from$damage$caused$byfree$radicals.

A$food$supplement$high$in$polyphenols$was$studied$in$a$group$of$men$who$had$prostate$cancerthat$had$not$spread.$This$supplement$contained$a$combination$of$the$following:

Pomegranate$whole$fruit$powder.

Broccoli$powder.

Turmeric$powder.

Green$tea$extract.

In$a$randomized$clinical$trial,$199$men$were$given$either$the$food$supplement$or$a$placebo$for$6months.$Before$the$study$began,$slightly$less$than$half$of$the$men$had$rising$prostate-specificantigen$(PSA)$levels$after$being$treated$with$local$therapy,$and$slightly$more$than$half$of$the$menwere$on$active$surveillance$(not$yet$treated).$In$the$group$that$took$the$supplement,$median$PSAlevels$rose$much$less$than$in$the$group$that$took$the$placebo.$The$food$supplement$was$welltolerated$and$there$were$no$marked$differences$reported$in$adverse$effects$between$supplementand$placebo$groups.$However,$patients$in$the$supplement$group$were$more$likely$to$havegastrointestinal$symptoms$(i.e.,$more$gas$and$loose$bowels).

Questions and Answers About Zyflamend

1.$ What%is%Zyflamend?

Zyflamend$is$a$dietary$supplement$that$contains$extracts$of$10$different$herbs:

••••

Rosemary.

Turmeric.

Ginger.

Holy$basil.

Green$tea.

Hu$zhang$(Polygonum cuspidatum).

Chinese$goldthread.

Barberry.

Oregano.

Baikal$skullcap.

The$extracts$found$in$Zyflamend$have$anti-inflammatory$activity$and$possible$anticancerbenefits.$There$is$limited$evidence$about$how$Zyflamend$may$act$against$tumor$growth.Zyflamend$has$been$shown$to$interfere$with$the$activity$of$COX-1$and$COX-2$enzymes,$whichare$involved$in$the$development$of$inflammation$and$possibly$cancer.$Zyflamend$may$alsoact$against$the$NF-kappa$B$and$lipoxygenase$(LOX)$families$of$proteins$that$stimulate$tumorgrowth.

2.$ How%is%Zyflamend%administered%or%consumed?

Zyflamend$is$taken$as$a$dietary$supplement$in$capsule$form.

3.$ Have%any%preclinical%(laboratory%or%animal)%studies%been%conducted%using%Zyflamend?

Laboratory$and$animal$research$has$recently$been$done$to$study$the$effects$of$Zyflamend$incancer.

Studies$of$Zyflamend$in$the$laboratory$have$shown$the$following:

Human$prostate$cancer$cells$treated$with$different$doses$of$Zyflamend$had$lowerandrogen$(male$hormone)$receptor$and$prostate-specific$antigen$(PSA)$levelscompared$with$cells$treated$with$a$control$substance;$higher$doses$of$Zyflamend$werefound$to$be$more$effective.$Prostate$cancer$cells$treated$with$both$Zyflamend$andbicalutamide$(a$nonsteroidal$antiandrogen$drug)$showed$lower$levels$of$cell$growth,PSA,$and$cancer$survival$proteins$than$prostate$cancer$cells$treated$with$Zyflamend$orbicalutamide$alone.

A$study$in$human$prostate$cancer$cells$found$that$a$higher$concentration$ofZyflamend$blocked$both$COX-1$and$COX-2$activity;$a$lower$concentration$of$Zyflamend

••••••••••

•

blocked$COX-2$activity$but$had$less$effect$on$COX-1.$Zyflamend$was$also$found$to$limitthe$growth$of$prostate$cancer$cells.$However,$the$prostate$cancer$cells$in$the$study$didnot$have$high$levels$of$COX-2,$suggesting$that$Zyflamend$may$have$effects$on$prostatecancer$cells$that$are$not$related$to$COX$activity.

Prostate$cancer$cells$were$treated$with$insulin-like$growth$factor$-1$(IGF-1,$a$proteinlinked$with$increased$risk$of$prostate$cancer)$alone$or$together$with$Zyflamend.$Cellstreated$with$IGF-1$alone$grew$and$spread$more,$while$cells$treated$with$both$IGF-1and$Zyflamend$grew$and$spread$less.$Zyflamend$was$also$shown$to$decrease$levels$ofthe$IGF-1$receptor$and$androgen$receptor$in$prostate$cancer$cells.

Studies$of$Zyflamend$in$animal$models$of$cancer$have$shown$the$following:

Mice$implanted$with$pancreatic$tumor$cells$received$either$Zyflamend$or$a$controltreatment.$The$mice$treated$with$Zyflamend$showed$lower$levels$of$cancer$survivalproteins$and$higher$levels$of$anticancer$activity$than$mice$in$the$control$group.

Mice$implanted$with$pancreatic$tumor$cells$received$either$Zyflamend,$gemcitabine,$orboth.$Tumor$cells$from$mice$that$received$the$combination$of$Zyflamend$andgemcitabine$showed$a$much$greater$decrease$in$tumor$growth$than$tumor$cells$frommice$that$received$Zyflamend$or$gemcitabine$alone.$The$findings$suggested$thatZyflamend$may$have$made$the$pancreatic$tumors$more$sensitive$to$treatment$withgemcitabine.

4.$ Have%any%clinical%trials%(research%studies%with%people)%of%Zyflamend%been%conducted?

A$report$of$one$patient$with$high-grade$prostatic$intraepithelial$neoplasia$(HGPIN)$whoreceived$Zyflamend$3$times/$day$for$18$months$showed$that$PSA$levels$were$not$affected.However,$at$the$end$of$18$months$of$treatment,$repeat$biopsies$of$the$prostate$did$not$showHGPIN$or$cancer.

In$a$phase$I$safety$study$of$Zyflamend,$patients$with$HGPIN$took$Zyflamend$(780$mg)$3times/$day$for$18$months$with$additional$dietary$supplements$(probiotic$supplement,multivitamin,$green$and$white$tea$extract,$Baikal$skullcap,$docosahexaenoic$acid,$holy$basil,and$turmeric).$Zyflamend$and$the$added$dietary$supplements$were$well$tolerated$and$therewere$no$serious$side$effects.$At$the$end$of$18$months$of$treatment,$more$than$half$of$patientshad$benign$biopsy$results,$about$one-fourth$had$HGPIN,$and$about$one$in$8$had$prostatecancer.

5.$ Have%any%side%effects%or%risks%been%reported%from%Zyflamend?

A$phase$I$safety$study$of$Zyflamend$(described$above)$reported$no$toxicity$or$serious$side

•

effects.$Some$of$the$patients$had$mild$heartburn$that$went$away$when$Zyflamend$was$takenwith$food.

6.$ Is%Zyflamend%approved%by%the%U.S.%Food%and%Drug%Administration%(FDA)%for%use%as%acancer%treatment%in%the%United%States?

The$U.S.$Food$and$Drug$Administration$has$not$approved$the$use$of$Zyflamend$as$atreatment$for$cancer$or$any$other$medical$condition.

Zyflamend$is$available$in$the$United$States$as$a$dietary$supplement.$Because$dietarysupplements$are$regulated$as$foods,$not$as$drugs,$FDA$approval$is$not$required$unlessspecific$claims$about$disease$prevention$or$treatment$are$made.

Other Prostate Health Supplements

Overview

Many$widely$available$dietary$supplements$are$marketed$to$support$prostate$health.$AfricanCherry$(pygeum africanum)$and$beta-sitosterol$are$two$related$supplements$that$have$beenstudied$as$possible$prostate$cancer$treatments.

African Cherry / P. africanum

African$cherry$or$Pygeum africanum$is$a$tree$that$grows$in$tropical$climates.$It$is$found$in$anumber$of$African$countries$including$Kenya,$Madagascar,$Uganda,$and$Nigeria.$Bark$from$the$P.africanum$tree$was$used$by$African$tribes$to$relieve$urinary$symptoms$and$stomach$pain.$In$the18th$century,$European$travelers$learned$from$South$African$tribes$that$P. africanum$could$treatbladder$discomfort$and$“old$man’s$disease”$(enlarged$prostate).

Since$1969,$bark$extracts$from$P. africanum$have$been$available$as$prescription$drugs$in$Europeand$have$been$widely$used$to$treat$benign$prostatic$hyperplasia$(BPH).$The$bark$contains$anumber$of$compounds$including$fatty$acids$and$phytosterols$(e.g.,$beta-sitosterol).$The$bark$isprocessed$and$purified$as$an$extract.

Laboratory$studies$and$animal$studies$have$shown$that$two$substances$in$bark$extract$from$P.africanum$are$active$in$blocking$cells$from$taking$up$androgen.$The$antiandrogen$activity$found$inP. africanum$is$at$a$markedly$lower$concentration$than$the$antiandrogen$activity$found$influtamide$(an$anticancer$drug).

Beta-Sitosterol

Beta-sitosterol$is$a$member$of$the$phytosterol$family$of$phytochemicals$and$is$widely$found$inplant$life$in$different$amounts.$It$is$found$in$African$cherry$(Pygeum africanum),$saw$palmetto(Serenoa repens),$and$various$nuts,$beans,$and$seeds.$It$is$one$of$several$phytosterols$(plantsterols)$that$have$a$chemical$structure$similar$to$cholesterol.$Phytosterols,$including$beta-sitosterol,$limit$the$amount$of$cholesterol$that$can$be$absorbed$from$the$diet$and$they$are$beingstudied$for$their$potential$to$protect$against$cardiovascular$disease.$Beta-sitosterol$is$very$poorlyabsorbed$by$the$body.

Studies$suggest$that$phytosterols$may$have$anticancer$activity,$but$their$exact$actions$areunknown.$Phytosterols$may$affect$immune$and$hormonal$systems$or$may$directly$target$cellcycles$and$cause$cell$death$in$tumors.

Laboratory$studies$have$shown$that$high$concentrations$of$beta-sitosterol$markedly$slow$thegrowth$of$human$prostate$cancer$cells$and$cause$cancer$cell$death.

Changes to This Summary (07/17/2015)The$PDQ$cancer$information$summaries$are$reviewed$regularly$and$updated$as$new$informationbecomes$available.$This$section$describes$the$latest$changes$made$to$this$summary$as$of$the$dateabove.

Editorial$changes$were$made$to$this$summary.

About This PDQ Summary

About PDQ

Physician$Data$Query$(PDQ)$is$the$National$Cancer$Institute's$(NCI's)$comprehensive$cancerinformation$database.$The$PDQ$database$contains$summaries$of$the$latest$published$informationon$cancer$prevention,$detection,$genetics,$treatment,$supportive$care,$and$complementary$andalternative$medicine.$Most$summaries$come$in$two$versions.$The$health$professional$versionshave$detailed$information$written$in$technical$language.$The$patient$versions$are$written$in$easy-to-understand,$nontechnical$language.$Both$versions$have$cancer$information$that$is$accurateand$up$to$date$and$most$versions$are$also$available$in$Spanish.

PDQ$is$a$service$of$the$NCI.$The$NCI$is$part$of$the$National$Institutes$of$Health$(NIH).$NIH$is$thefederal$government’s$center$of$biomedical$research.$The$PDQ$summaries$are$based$on$anindependent$review$of$the$medical$literature.$They$are$not$policy$statements$of$the$NCI$or$theNIH.

http://www.cancer.gov/espanol/recursos/pdq

Purpose of This Summary

This$PDQ$cancer$information$summary$has$current$information$about$the$use$of$nutrition$anddietary$supplements$for$reducing$the$risk$of$developing$prostate$cancer$or$for$treating$prostatecancer.$It$is$meant$to$inform$and$help$patients,$families,$and$caregivers.$It$does$not$give$formalguidelines$or$recommendations$for$making$decisions$about$health$care.

Reviewers and Updates

Editorial$Boards$write$the$PDQ$cancer$information$summaries$and$keep$them$up$to$date.$TheseBoards$are$made$up$of$experts$in$cancer$treatment$and$other$specialties$related$to$cancer.$Thesummaries$are$reviewed$regularly$and$changes$are$made$when$there$is$new$information.$Thedate$on$each$summary$("Date$Last$Modified")$is$the$date$of$the$most$recent$change.

The$information$in$this$patient$summary$was$taken$from$the$health$professional$version,$which$isreviewed$regularly$and$updated$as$needed,$by$the$PDQ$Cancer$Complementary$and$AlternativeMedicine$Editorial$Board.

Clinical Trial Information

A$clinical$trial$is$a$study$to$answer$a$scientific$question,$such$as$whether$one$treatment$is$betterthan$another.$Trials$are$based$on$past$studies$and$what$has$been$learned$in$the$laboratory.$Eachtrial$answers$certain$scientific$questions$in$order$to$find$new$and$better$ways$to$help$cancerpatients.$During$treatment$clinical$trials,$information$is$collected$about$the$effects$of$a$newtreatment$and$how$well$it$works.$If$a$clinical$trial$shows$that$a$new$treatment$is$better$than$onecurrently$being$used,$the$new$treatment$may$become$"standard."$Patients$may$want$to$thinkabout$taking$part$in$a$clinical$trial.$Some$clinical$trials$are$open$only$to$patients$who$have$notstarted$treatment.

Clinical$trials$are$listed$in$PDQ$and$can$be$found$online$at$NCI's$Web$site.$Many$cancer$doctorswho$take$part$in$clinical$trials$are$also$listed$in$PDQ.$For$more$information,$call$the$CancerInformation$Service$1-800-4-CANCER$(1-800-422-6237).

Permission to Use This Summary

PDQ$is$a$registered$trademark.$The$content$of$PDQ$documents$can$be$used$freely$as$text.$Itcannot$be$identified$as$an$NCI$PDQ$cancer$information$summary$unless$the$whole$summary$isshown$and$it$is$updated$regularly.$However,$a$user$would$be$allowed$to$write$a$sentence$such$as“NCI’s$PDQ$cancer$information$summary$about$breast$cancer$prevention$states$the$risks$in$the

http://www.cancer.gov/cancertopics/pdq/cancer-cam-board

http://www.cancer.gov/clinicaltrials

following$way:$[include$excerpt$from$the$summary].”

The$best$way$to$cite$this$PDQ$summary$is:

National$Cancer$Institute:$PDQ®$Prostate$Cancer,$Nutrition,$and$Dietary$Supplements.$Bethesda,MD:$National$Cancer$Institute.$Date$last$modified$<MM/DD/YYYY>.$Available$at:http://www.cancer.gov/about-cancer/treatment/cam/patient/prostate-supplements-pdq.Accessed$<MM/DD/YYYY>.

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Disclaimer

The$information$in$these$summaries$should$not$be$used$to$make$decisions$about$insurancereimbursement.$More$information$on$insurance$coverage$is$available$on$Cancer.gov$on$theManaging$Cancer$Care$page.

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General CAM InformationComplementary$and$alternative$medicine$(CAM)—also$referred$to$as$integrative$medicine—includes$a$broad$range$of$healing$philosophies,$approaches,$and$therapies.$A$therapy$is$generallycalled$complementary$when$it$is$used$in$addition$to$conventional$treatments;$it$is$often$calledalternative$when$it$is$used$instead$of$conventional$treatment.$(Conventional$treatments$are$thosethat$are$widely$accepted$and$practiced$by$the$mainstream$medical$community.)$Depending$onhow$they$are$used,$some$therapies$can$be$considered$either$complementary$or$alternative.Complementary$and$alternative$therapies$are$used$in$an$effort$to$prevent$illness,$reduce$stress,prevent$or$reduce$side$effects$and$symptoms,$or$control$or$cure$disease.

Unlike$conventional$treatments$for$cancer,$complementary$and$alternative$therapies$are$often

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not$covered$by$insurance$companies.$Patients$should$check$with$their$insurance$provider$to$findout$about$coverage$for$complementary$and$alternative$therapies.

Cancer$patients$considering$complementary$and$alternative$therapies$should$discuss$thisdecision$with$their$doctor,$nurse,$or$pharmacist$as$they$would$any$therapeutic$approach,$becausesome$complementary$and$alternative$therapies$may$interfere$with$their$standard$treatment$ormay$be$harmful$when$used$with$conventional$treatment.

Evaluation of CAM ApproachesIt$is$important$that$the$same$rigorous$scientific$evaluation$used$to$assess$conventionalapproaches$be$used$to$evaluate$CAM$therapies.$The$National$Cancer$Institute$and$the$NationalCenter$for$Complementary$and$Integrative$Health$(NCCIH)$are$sponsoring$a$number$of$clinicaltrials$(research$studies)$at$medical$centers$to$evaluate$CAM$therapies$for$cancer.

Conventional$approaches$to$cancer$treatment$have$generally$been$studied$for$safety$andeffectiveness$through$a$rigorous$scientific$process$that$includes$clinical$trials$with$large$numbersof$patients.$Less$is$known$about$the$safety$and$effectiveness$of$complementary$and$alternativemethods.$Few$CAM$therapies$have$undergone$rigorous$evaluation.$A$small$number$of$CAMtherapies$originally$considered$to$be$purely$alternative$approaches$are$finding$a$place$in$cancertreatment—not$as$cures,$but$as$complementary$therapies$that$may$help$patients$feel$better$andrecover$faster.$One$example$is$acupuncture.$According$to$a$panel$of$experts$at$a$NationalInstitutes$of$Health$(NIH)$in$November$1997,$acupuncture$has$been$found$to$be$effective$in$themanagement$of$chemotherapy-associated$nausea$and$vomiting$and$in$controlling$painassociated$with$surgery.$In$contrast,$some$approaches,$such$as$the$use$of$laetrile,$have$beenstudied$and$found$ineffective$or$potentially$harmful.

The$NCI$Best$Case$Series$Program$which$was$started$in$1991,$is$one$way$CAM$approaches$that$arebeing$used$in$practice$are$being$investigated.$The$program$is$overseen$by$the$NCI’s$Office$ofCancer$Complementary$and$Alternative$Medicine$(OCCAM).$Health$care$professionals$who$offeralternative$cancer$therapies$submit$their$patients’$medical$records$and$related$materials$toOCCAM.$OCCAM$conducts$a$critical$review$of$the$materials$and$develops$follow-up$researchstrategies$for$approaches$deemed$to$warrant$NCI-initiated$research.

Questions to Ask Your Health Care Provider AboutCAMWhen$considering$complementary$and$alternative$therapies,$patients$should$ask$their$health$care

http://cam.cancer.gov/cam/best_case_intro.html

provider$the$following$questions:

What$side$effects$can$be$expected?

What$are$the$risks$associated$with$this$therapy?

Do$the$known$benefits$outweigh$the$risks?

What$benefits$can$be$expected$from$this$therapy?

Will$the$therapy$interfere$with$conventional$treatment?

Is$this$therapy$part$of$a$clinical$trial?

If$so,$who$is$sponsoring$the$trial?

Will$the$therapy$be$covered$by$health$insurance?

To Learn More About CAMNational Center for Complementary and Integrative Health (NCCIH)

The$National$Center$for$Complementary$and$Integrative$Health$(NCCIH)$at$the$National$Institutesof$Health$(NIH)$facilitates$research$and$evaluation$of$complementary$and$alternative$practices,and$provides$information$about$a$variety$of$approaches$to$health$professionals$and$the$public.

NCCIH$Clearinghouse

Post$Office$Box$7923$Gaithersburg,$MD$20898–7923

Telephone:$1–888–644–6226$(toll$free)$301–519–3153$(for$International$callers)

TTY$(for$deaf$and$hard$of$hearing$callers):$1–866–464–3615

Fax:$1–866–464–3616

E-mail:$info@nccih.nih.gov

Web$site:$https://nccih.nih.gov/

CAM on PubMed

NCCAM$and$the$NIH$National$Library$of$Medicine$(NLM)$jointly$developed$CAM$on$PubMed,$a$freeand$easy-to-use$search$tool$for$finding$CAM-related$journal$citations.$As$a$subset$of$the$NLM'sPubMed$bibliographic$database,$CAM$on$PubMed$features$more$than$230,000$references$andabstracts$for$CAM-related$articles$from$scientific$journals.$This$database$also$provides$links$to$theWeb$sites$of$over$1,800$journals,$allowing$users$to$view$full-text$articles.$(A$subscription$or$otherfee$may$be$required$to$access$full-text$articles.)$CAM$on$PubMed$is$available$through$the$NCCIHWeb$site.$It$can$also$be$accessed$through$NLM$PubMed$bibliographic$database$by$selecting$the

••••••••

https://nccih.nih.gov/

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&orig_db=PubMed&cmd_current=Limits&pmfilter_Subsets=Complementary+Medicine

http://www.ncbi.nlm.nih.gov/PubMed

"Limits"$tab$and$choosing$"Complementary$Medicine"$as$a$subset.

Office of Cancer Complementary and Alternative Medicine

The$NCI$Office$of$Cancer$Complementary$and$Alternative$Medicine$(OCCAM)$coordinates$theactivities$of$the$NCI$in$the$area$of$complementary$and$alternative$medicine$(CAM).$OCCAMsupports$CAM$cancer$research$and$provides$information$about$cancer-related$CAM$to$healthproviders$and$the$general$public$via$the$NCI$Web$site.

National Cancer Institute (NCI) Cancer Information Service

U.S.$residents$may$call$the$NCI$Cancer$Information$Service$toll$free$at$1-800-4-CANCER$(1-800-422-6237)$Monday$through$Friday$from$8:00$am$to$8:00$pm.$A$trained$Cancer$Information$Specialist$isavailable$to$answer$your$questions.

Food and Drug Administration

The$Food$and$Drug$Administration$(FDA)$regulates$drugs$and$medical$devices$to$ensure$that$theyare$safe$and$effective.

Food$and$Drug$Administration

5600$Fishers$Lane

Rockville,$MD$20857

Telephone:$1–888–463–6332$(toll$free)

Web$site:$http://www.fda.gov/

Federal Trade Commission

The$Federal$Trade$Commission$(FTC)$enforces$consumer$protection$laws.$Publications$availablefrom$the$FTC$include:

Who Cares: Sources of Information About Health Care Products and Services

Fraudulent Health Claims: Don’t Be Fooled

Consumer$Response$Center

Federal$Trade$Commission

CRC-240

Washington,$DC$20580

Telephone:$1-877-FTC-HELP$(1-877-382-4357)$(toll$free)

TTY$(for$deaf$and$hearing$impaired$callers):$202-326-2502

••

http://www.ncbi.nlm.nih.gov/PubMed

http://www.cancer.gov/cam/

http://www.fda.gov/

http://www.ftc.gov/

Web$site:$http://www.ftc.gov/

Updated:$July$17,$2015

This text may be reproduced or reused freely. Please credit the National Cancer Institute as the source.Any graphics may be owned by the artist or publisher who created them, and permission may beneeded for their reuse.

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7/24/15, 11:47High-Dose Vitamin C - National Cancer Institute

Page 1 of 17http://www.cancer.gov/about-cancer/treatment/cam/hp/vitamin-c-pdq#section/all

High-Dose Vitamin C–for healthprofessionals (PDQ®)

OverviewThis%complementary%and%alternative%medicine%(CAM)%information%summary%provides%an%overviewof%the%use%of%high-dose%vitamin%C%(also%known%as%ascorbate%or%L-ascorbic%acid)%as%a%treatment%forpeople%with%cancer.%This%summary%includes%a%brief%history%of%early%clinical%trials%of%high-dosevitamin%C;%reviews%of%laboratory,%animal,%and%human%studies;%and%current%clinical%trials.

This%summary%contains%the%following%key%information:

Vitamin%C%is%an%essential%nutrient%with%redox%functions%at%normal%physiologic%concentrations.

High-dose%vitamin%C%has%been%studied%as%a%treatment%for%cancer%patients%since%the%1970s.

Laboratory%studies%have%reported%that%high-dose%vitamin%C%has%redox%properties%anddecreased%cell%proliferation%in%prostate,%pancreatic,%hepatocellular,%colon,%mesothelioma,%andneuroblastoma%cell%lines.

Two%studies%of%high-dose%vitamin%C%in%cancer%patients%reported%improved%quality%of%life%anddecreases%in%cancer-related%side%effects.

Studies%of%vitamin%C%combined%with%other%drugs%in%animal%models%have%shown%mixed%results.

Intravenous%vitamin%C%has%been%generally%well%tolerated%in%clinical%trials.

Many%of%the%medical%and%scientific%terms%used%in%this%summary%are%hypertext%linked%(at%first%use%ineach%section)%to%the%NCI%Dictionary%of%Cancer%Terms,%which%is%oriented%toward%nonexperts.%When%alinked%term%is%clicked,%a%definition%will%appear%in%a%separate%window.

Reference%citations%in%some%PDQ%CAM%information%summaries%may%include%links%to%external%Websites%that%are%operated%by%individuals%or%organizations%for%the%purpose%of%marketing%or%advocatingthe%use%of%specific%treatments%or%products.%These%reference%citations%are%included%forinformational%purposes%only.%Their%inclusion%should%not%be%viewed%as%an%endorsement%of%thecontent%of%the%Web%sites,%or%of%any%treatment%or%product,%by%the%PDQ%Cancer%CAM%Editorial%Boardor%the%National%Cancer%Institute.

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http://www.cancer.gov/publications/dictionaries/cancer-terms/

General InformationVitamin%C%is%an%essential%nutrient%that%has%redox%functions,%is%a%cofactor%for%several%enzymes,%andplays%an%important%role%in%the%synthesis%of%collagen.[1]%A%severe%deficiency%in%vitamin%C%results%inscurvy,%which%is%associated%with%malaise,%lethargy,%easy%bruising,%and%spontaneous%bleeding.[2]One%of%the%effects%of%scurvy%is%a%change%in%collagen%structure%to%a%thinner%consistency.%Normalconsistency%is%achieved%with%administration%of%vitamin%C.

In%the%mid-20th%century,%a%study%hypothesized%that%cancer%may%be%related%to%changes%inconnective%tissue,%which%may%be%a%consequence%of%vitamin%C%deficiency.[3]%A%review%of%evidencepublished%in%1974%suggested%that%high-dose%ascorbic%acid%may%increase%host%resistance%and%be%apotential%cancer%therapy.[4]

Vitamin%C%is%synthesized%from%D-glucose%or%D-galactose%by%many%plants%and%animals.%However,humans%lack%the%enzyme%L-gulonolactone%oxidase%required%for%ascorbic%acid%synthesis%and%mustobtain%vitamin%C%through%food%or%supplements.[1]

References

1.% Naidu%KA:%Vitamin%C%in%human%health%and%disease%is%still%a%mystery?%An%overview.%Nutr%J%2:%7,2003.%[PUBMED%Abstract]

2.% Padayatty%S,%Espey%MG,%Levine%M:%Vitamin%C.%In:%Coates%PM,%Betz%JM,%Blackman%MR,%et%al.,%eds.:Encyclopedia%of%Dietary%Supplements.%2nd%ed.%New%York,%NY:%Informa%Healthcare,%2010,%pp821-31.

3.% McCORMICK%WJ:%Cancer:%a%collagen%disease,%secondary%to%a%nutritional%deficiency.%ArchPediatr%76%(4):%166-71,%1959.%[PUBMED%Abstract]

4.% Cameron%E,%Pauling%L:%The%orthomolecular%treatment%of%cancer.%I.%The%role%of%ascorbic%acid%inhost%resistance.%Chem%Biol%Interact%9%(4):%273-83,%1974.%[PUBMED%Abstract]

HistoryThe%earliest%experience%of%using%high-dose%vitamin%C%(intravenous%[IV]%and%oral)%for%cancertreatment%was%by%a%Scottish%surgeon,%Ewan%Cameron,%and%his%colleague,%Allan%Campbell,%in%the1970s.[1]%This%work%led%to%a%collaboration%between%Cameron%and%the%Nobel%Prize–winning%chemistLinus%Pauling,%further%promoting%the%potential%of%vitamin%C%therapy%in%cancer%management.[2,3]As%a%result,%two%clinical%trials%of%oral%vitamin%C%were%conducted%in%the%late%1970s%and%early%1980s.[4,5]

(Refer%to%the%Human%Studies%section%of%this%summary%for%more%information%about%these%early

http://www.cancer.gov/about-cancer/treatment/cam/hp/vitamin-c-pdq#cit/section_2.1

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14498993&dopt=Abstract

http://www.cancer.gov/about-cancer/treatment/cam/hp/vitamin-c-pdq/#link/_16

studies.)

Pharmacokinetic%studies%later%revealed%substantial%differences%in%the%maximum%achieved%bloodconcentrations%of%vitamin%C%based%on%the%route%of%administration.%When%vitamin%C%is%taken%orally,plasma%concentrations%of%the%vitamin%are%tightly%controlled,%with%a%peak%achievable%concentrationless%than%300%µM.%However,%this%tight%control%is%bypassed%with%IV%administration%of%the%vitamin,resulting%in%very%high%levels%of%vitamin%C%plasma%concentration%(i.e.,%levels%up%to%20%mM).[6,7]Further%research%suggests%that%pharmacologic%concentrations%of%ascorbate,%such%as%thoseachieved%with%IV%administration,%may%result%in%cell%death%in%many%cancer%cell%lines.[8]

Health%care%practitioners%attending%complementary%and%alternative%medicine%conferences%in%2006and%2008%were%surveyed%about%usage%of%high-dose%IV%vitamin%C%in%patients.%Of%the%199%totalrespondents,%172%had%administered%vitamin%C%to%patients.%In%general,%IV%vitamin%C%was%commonlyused%to%treat%infections,%cancer,%and%fatigue.[9]

References

1.% Cameron%E,%Campbell%A:%The%orthomolecular%treatment%of%cancer.%II.%Clinical%trial%of%high-doseascorbic%acid%supplements%in%advanced%human%cancer.%Chem%Biol%Interact%9%(4):%285-315,1974.%[PUBMED%Abstract]

2.% Cameron%E,%Pauling%L:%Supplemental%ascorbate%in%the%supportive%treatment%of%cancer:Prolongation%of%survival%times%in%terminal%human%cancer.%Proc%Natl%Acad%Sci%U%S%A%73%(10):3685-9,%1976.%[PUBMED%Abstract]

3.% Cameron%E,%Pauling%L:%Supplemental%ascorbate%in%the%supportive%treatment%of%cancer:reevaluation%of%prolongation%of%survival%times%in%terminal%human%cancer.%Proc%Natl%Acad%Sci%US%A%75%(9):%4538-42,%1978.%[PUBMED%Abstract]

4.% Creagan%ET,%Moertel%CG,%O'Fallon%JR,%et%al.:%Failure%of%high-dose%vitamin%C%(ascorbic%acid)therapy%to%benefit%patients%with%advanced%cancer.%A%controlled%trial.%N%Engl%J%Med%301%(13):687-90,%1979.%[PUBMED%Abstract]

5.% Moertel%CG,%Fleming%TR,%Creagan%ET,%et%al.:%High-dose%vitamin%C%versus%placebo%in%thetreatment%of%patients%with%advanced%cancer%who%have%had%no%prior%chemotherapy.%Arandomized%double-blind%comparison.%N%Engl%J%Med%312%(3):%137-41,%1985.%[PUBMED%Abstract]

6.% Padayatty%SJ,%Sun%H,%Wang%Y,%et%al.:%Vitamin%C%pharmacokinetics:%implications%for%oral%andintravenous%use.%Ann%Intern%Med%140%(7):%533-7,%2004.%[PUBMED%Abstract]

7.% Hoffer%LJ,%Levine%M,%Assouline%S,%et%al.:%Phase%I%clinical%trial%of%i.v.%ascorbic%acid%in%advancedmalignancy.%Ann%Oncol%19%(11):%1969-74,%2008.%[PUBMED%Abstract]

8.% Verrax%J,%Calderon%PB:%Pharmacologic%concentrations%of%ascorbate%are%achieved%by%parenteral

http://www.cancer.gov/about-cancer/treatment/cam/hp/vitamin-c-pdq/#link/_16

administration%and%exhibit%antitumoral%effects.%Free%Radic%Biol%Med%47%(1):%32-40,2009.%[PUBMED%Abstract]

9.% Padayatty%SJ,%Sun%AY,%Chen%Q,%et%al.:%Vitamin%C:%intravenous%use%by%complementary%andalternative%medicine%practitioners%and%adverse%effects.%PLoS%One%5%(7):%e11414,2010.%[PUBMED%Abstract]

Laboratory/Animal/Preclinical Studies

In Vitro Studies

Numerous%studies%have%demonstrated%that%pharmacological%doses%of%ascorbic%acid%(0.1–100%mM)decrease%cell%proliferation%in%a%variety%of%cancer%cell%lines.[1-5]%Specifically,%decreases%in%cellproliferation%after%ascorbic%acid%treatment%have%been%reported%for%prostate,[6]%pancreatic,[7,8]hepatocellular,[9]%colon,[10]%mesothelioma,[11]%and%neuroblastoma%[12]%cell%lines.

The%potential%mechanisms%through%which%treatment%with%high-dose%ascorbic%acid%may%exert%itseffects%on%cancer%cells%have%been%extensively%investigated.%Several%studies%have%demonstrated%thatthe%in vitro direct%cytotoxic%effect%of%ascorbic%acid%on%various%types%of%cancer%cells%is%mediatedthrough%a%chemical%reaction%that%generates%hydrogen%peroxide.[1,7,13,14]%Treating%colon%cancercells%with%2%mM%to%3%mM%of%ascorbic%acid%resulted%in%downregulation%of%specificity%protein%(Sp)transcription%factors%and%Sp-regulated%genes%involved%in%cancer%progression.[10]%One%studysuggested%that%ascorbate-mediated%prostate%cancer%cell%death%may%occur%through%activation%of%anautophagy%pathway.[6]

Differences%in%chemosensitivity%to%ascorbate%treatment%in%breast%cancer%cell%lines%may%depend%onexpression%of%the%sodium%-dependent%vitamin%C%transporter%2%(SVCT-2).[15]

Research%has%suggested%that%pharmacological%doses%of%ascorbic%acid%enhance%the%effects%ofarsenic%trioxide%on%ovarian%cancer%cells,[16]%gemcitabine%on%pancreatic%cancer%cells,[8]%andcombination%treatment%of%gemcitabine%and%epigallocatechin-3-gallate%(EGCG)%on%mesotheliomacells.[17]

Findings%from%one%study%reported%in%2012%suggested%that%high-dose%ascorbate%increasesradiosensitivity%of%glioblastoma%multiforme%cells,%resulting%in%more%cell%death%than%from%radiationtherapy%alone.[18]

However,%not%all%studies%combining%vitamin%C%with%chemotherapy%have%shown%improvedoutcomes.%Treating%leukemia%and%lymphoma%cells%with%dehydroascorbic%acid%(the%oxidized%form%ofvitamin%C%that%increases%levels%of%intracellular%ascorbic%acid)%reduced%the%cytotoxic%effects%ofvarious%antineoplastic%agents%tested,%including%doxorubicin,%methotrexate,%and%cisplatin%(relative

reductions%in%cytotoxicity%ranged%from%30%%to%70%).[19]%In%another%study,%multiple%myeloma%cellswere%treated%with%bortezomib%and/or%plasma%obtained%from%healthy%volunteers%who%had%takenvitamin%C%supplements.%Cells%treated%with%a%combination%of%bortezomib%and%volunteers’%plasmaexhibited%lower%cytotoxicity%than%did%cells%treated%with%bortezomib%alone.[20]

Animal Studies

Studies%have%demonstrated%tumor%growth%inhibition%after%treatment%with%pharmacologicalascorbate%in%animal%models%of%pancreatic%cancer,[1,7,8]%liver%cancer,[3]%prostate%cancer,[21]sarcoma,[22]%mesothelioma,[11]%and%ovarian%cancer.[4]

The%effects%of%high-dose%ascorbic%acid%in%combination%with%standard%treatments%on%tumors%havebeen%investigated.%In%a%mouse%model%of%pancreatic%cancer,%the%combination%of%gemcitabine%(30%or60%mg%/kg%every%4%days)%and%ascorbate%(4%g%/kg%daily)%resulted%in%greater%decreases%in%tumorvolume%and%weight,%compared%with%gemcitabine%treatment%alone.[8]%According%to%a%studyreported%in%2012,%ascorbate%enhanced%the%cancer%cell–killing%effects%of%photodynamic%therapy%inmice%injected%with%breast%cancer%cells.[23]%A%study%of%mouse%models%of%ovarian%cancer%found%thatascorbate%enhanced%the%tumor%inhibitory%effect%of%carboplatin%and%paclitaxel,%first-linechemotherapy%used%in%ovarian%cancer.[24]

Using%N-acetylcysteine%(NAC)%and%vitamin%C,%researchers%showed%in%2007%that%these%compounds,both%thought%to%act%predominantly%as%antioxidants,%may%have%antitumorigenic%actions%in vivo bydecreasing%levels%of%hypoxia%-inducible%factor%(HIF)-1,%a%transcription%factor%that%targets%vascularendothelial%growth%factor%(VEGF)%and%plays%a%role%in%angiogenesis.[25]

There%have%also%been%reports%of%animal%studies%in%which%vitamin%C%has%interfered%with%theanticancer%activity%of%various%drugs.%In%a%study%reported%in%2008,%administration%ofdehydroascorbic%acid%to%lymphoma-xenograft%mice%prior%to%doxorubicin%treatment%resulted%insignificantly%larger%tumors%than%did%treatment%with%doxorubicin%alone.[19]%Notably,%this%studyused%dehydroascorbate,%the%oxidized%form%of%vitamin%C%that%is%known%to%be%transported%activelyinto%cells%and%then%reduced%to%vitamin%C.%Treating%multiple%myeloma%xenograft%mice%with%acombination%of%oral%vitamin%C%and%bortezomib%resulted%in%significantly%greater%tumor%volume%thandid%treatment%with%bortezomib%alone.[20]%This%increase%in%tumor%volume%was%caused%by%a%chemicalreaction%that%occurs%in%the%gastrointestinal%tract%but%does%not%appear%to%be%relevant%to%intravenousadministration.

References

1.% Chen%P,%Stone%J,%Sullivan%G,%et%al.:%Anti-cancer%effect%of%pharmacologic%ascorbate%and%itsinteraction%with%supplementary%parenteral%glutathione%in%preclinical%cancer%models.%Free

Radic%Biol%Med%51%(3):%681-7,%2011.%[PUBMED%Abstract]

2.% Chen%Q,%Espey%MG,%Krishna%MC,%et%al.:%Pharmacologic%ascorbic%acid%concentrations%selectivelykill%cancer%cells:%action%as%a%pro-drug%to%deliver%hydrogen%peroxide%to%tissues.%Proc%Natl%AcadSci%U%S%A%102%(38):%13604-9,%2005.%[PUBMED%Abstract]

3.% Verrax%J,%Calderon%PB:%Pharmacologic%concentrations%of%ascorbate%are%achieved%by%parenteraladministration%and%exhibit%antitumoral%effects.%Free%Radic%Biol%Med%47%(1):%32-40,2009.%[PUBMED%Abstract]

4.% Chen%Q,%Espey%MG,%Sun%AY,%et%al.:%Pharmacologic%doses%of%ascorbate%act%as%a%prooxidant%anddecrease%growth%of%aggressive%tumor%xenografts%in%mice.%Proc%Natl%Acad%Sci%U%S%A%105%(32):11105-9,%2008.%[PUBMED%Abstract]

5.% Frömberg%A,%Gutsch%D,%Schulze%D,%et%al.:%Ascorbate%exerts%anti-proliferative%effects%through%cellcycle%inhibition%and%sensitizes%tumor%cells%towards%cytostatic%drugs.%Cancer%ChemotherPharmacol%67%(5):%1157-66,%2011.%[PUBMED%Abstract]

6.% Chen%P,%Yu%J,%Chalmers%B,%et%al.:%Pharmacological%ascorbate%induces%cytotoxicity%in%prostatecancer%cells%through%ATP%depletion%and%induction%of%autophagy.%Anticancer%Drugs%23%(4):%437-44,%2012.%[PUBMED%Abstract]

7.% Du%J,%Martin%SM,%Levine%M,%et%al.:%Mechanisms%of%ascorbate-induced%cytotoxicity%in%pancreaticcancer.%Clin%Cancer%Res%16%(2):%509-20,%2010.%[PUBMED%Abstract]

8.% Espey%MG,%Chen%P,%Chalmers%B,%et%al.:%Pharmacologic%ascorbate%synergizes%with%gemcitabinein%preclinical%models%of%pancreatic%cancer.%Free%Radic%Biol%Med%50%(11):%1610-9,%2011.%[PUBMEDAbstract]

9.% Lin%ZY,%Chuang%WL:%Pharmacologic%concentrations%of%ascorbic%acid%cause%diverse%influence%ondifferential%expressions%of%angiogenic%chemokine%genes%in%different%hepatocellular%carcinomacell%lines.%Biomed%Pharmacother%64%(5):%348-51,%2010.%[PUBMED%Abstract]

10.% Pathi%SS,%Lei%P,%Sreevalsan%S,%et%al.:%Pharmacologic%doses%of%ascorbic%acid%repress%specificityprotein%(Sp)%transcription%factors%and%Sp-regulated%genes%in%colon%cancer%cells.%Nutr%Cancer%63(7):%1133-42,%2011.%[PUBMED%Abstract]

11.% Takemura%Y,%Satoh%M,%Satoh%K,%et%al.:%High%dose%of%ascorbic%acid%induces%cell%death%inmesothelioma%cells.%Biochem%Biophys%Res%Commun%394%(2):%249-53,%2010.%[PUBMED%Abstract]

12.% Hardaway%CM,%Badisa%RB,%Soliman%KF:%Effect%of%ascorbic%acid%and%hydrogen%peroxide%onmouse%neuroblastoma%cells.%Mol%Med%Report%5%(6):%1449-52,%2012.%[PUBMED%Abstract]

13.% Du%J,%Cullen%JJ,%Buettner%GR:%Ascorbic%acid:%chemistry,%biology%and%the%treatment%of%cancer.Biochim%Biophys%Acta%1826%(2):%443-57,%2012.%[PUBMED%Abstract]

14.% Levine%M,%Padayatty%SJ,%Espey%MG:%Vitamin%C:%a%concentration-function%approach%yieldspharmacology%and%therapeutic%discoveries.%Adv%Nutr%2%(2):%78-88,%2011.%[PUBMED%Abstract]

15.% Hong%SW,%Lee%SH,%Moon%JH,%et%al.:%SVCT-2%in%breast%cancer%acts%as%an%indicator%for%L-ascorbatetreatment.%Oncogene%32%(12):%1508-17,%2013.%[PUBMED%Abstract]

16.% Ong%PS,%Chan%SY,%Ho%PC:%Differential%augmentative%effects%of%buthionine%sulfoximine%andascorbic%acid%in%As2O3-induced%ovarian%cancer%cell%death:%oxidative%stress-independent%and%-dependent%cytotoxic%potentiation.%Int%J%Oncol%38%(6):%1731-9,%2011.%[PUBMED%Abstract]

17.% Martinotti%S,%Ranzato%E,%Burlando%B:%In%vitro%screening%of%synergistic%ascorbate-drugcombinations%for%the%treatment%of%malignant%mesothelioma.%Toxicol%In%Vitro%25%(8):%1568-74,2011.%[PUBMED%Abstract]

18.% Herst%PM,%Broadley%KW,%Harper%JL,%et%al.:%Pharmacological%concentrations%of%ascorbateradiosensitize%glioblastoma%multiforme%primary%cells%by%increasing%oxidative%DNA%damageand%inhibiting%G2/M%arrest.%Free%Radic%Biol%Med%52%(8):%1486-93,%2012.%[PUBMED%Abstract]

19.% Heaney%ML,%Gardner%JR,%Karasavvas%N,%et%al.:%Vitamin%C%antagonizes%the%cytotoxic%effects%ofantineoplastic%drugs.%Cancer%Res%68%(19):%8031-8,%2008.%[PUBMED%Abstract]

20.% Perrone%G,%Hideshima%T,%Ikeda%H,%et%al.:%Ascorbic%acid%inhibits%antitumor%activity%of%bortezomibin%vivo.%Leukemia%23%(9):%1679-86,%2009.%[PUBMED%Abstract]

21.% Pollard%HB,%Levine%MA,%Eidelman%O,%et%al.:%Pharmacological%ascorbic%acid%suppressessyngeneic%tumor%growth%and%metastases%in%hormone-refractory%prostate%cancer.%In%Vivo%24(3):%249-55,%2010%May-Jun.%[PUBMED%Abstract]

22.% Yeom%CH,%Lee%G,%Park%JH,%et%al.:%High%dose%concentration%administration%of%ascorbic%acidinhibits%tumor%growth%in%BALB/C%mice%implanted%with%sarcoma%180%cancer%cells%via%therestriction%of%angiogenesis.%J%Transl%Med%7:%70,%2009.%[PUBMED%Abstract]

23.% Wei%Y,%Song%J,%Chen%Q,%et%al.:%Enhancement%of%photodynamic%antitumor%effect%with%pro-oxidantascorbate.%Lasers%Surg%Med%44%(1):%69-75,%2012.%[PUBMED%Abstract]

24.% Ma%Y,%Chapman%J,%Levine%M,%et%al.:%High-dose%parenteral%ascorbate%enhanced%chemosensitivityof%ovarian%cancer%and%reduced%toxicity%of%chemotherapy.%Sci%Transl%Med%6%(222):%222ra18,2014.%[PUBMED%Abstract]

25.% Gao%P,%Zhang%H,%Dinavahi%R,%et%al.:%HIF-dependent%antitumorigenic%effect%of%antioxidants%invivo.%Cancer%Cell%12%(3):%230-8,%2007.%[PUBMED%Abstract]

Human/Clinical Studies

Early Ascorbate-Only Trials

In%the%early%1970s,%a%consecutive%case%series%was%conducted%in%which%50%advanced-cancer%patientswere%treated%with%large%doses%of%ascorbic%acid.[1]%These%patients%began%ascorbic%acid%treatmentafter%conventional%therapies%were%deemed%unlikely%to%be%effective.%Patients%received%intravenous(IV)%ascorbic%acid%(10%g%/day%for%10%consecutive%days;%some%patients%received%higher%doses),%oralascorbic%acid%(10%g/day),%or%both.%The%subjects%exhibited%a%wide%variety%of%responses%to%treatment,including%no%or%minimal%response,%tumor%regression,%and%tumor%hemorrhage.%However,%theauthors%noted%that%lack%of%controls%prevented%definitive%assignment%of%any%beneficial%responses%tothe%ascorbic%acid%treatment.%A%case%report%published%in%1975%detailed%one%of%the%patients%who%hadexperienced%tumor%regression.[2]%Diagnosed%with%reticulum%cell%sarcoma,%the%patient%exhibitedimprovement%in%well-being%and%resolution%of%lung%masses%after%being%treated%with%ascorbic%acid.When%the%patient's%daily%dose%of%ascorbic%acid%was%reduced,%some%of%signs%of%the%diseasereturned;%however,%remission%was%achieved%again%after%the%patient%reverted%to%the%higher%initialdose.

A%larger%case%series%of%terminal%cancer%patients%treated%with%ascorbate%was%reported%in%1976.%Inthis%study,%100%terminal%cancer%patients%(50%of%whom%were%reported%on%previously)%[1]%weretreated%with%ascorbate%(10%g/day%for%10%days%IV,%then%orally)%and%compared%with%1,000%matchedcontrols%from%the%same%hospital.%The%mean%survival%time%for%ascorbate-treated%patients%was%300days%longer%than%that%of%the%matched%controls.[3,4]

Two%studies%tried%to%reproduce%earlier%results.%These%studies%were%randomized,%placebo-controlledtrials%in%which%cancer%patients%received%either%10%g%oral%vitamin%C%or%placebo%daily%until%signs%ofcancer%progression.%At%the%end%of%each%study,%no%significant%differences%were%noted%between%thetwo%ascorbate-treated%and%placebo-treated%groups%for%symptoms,%performance%status,%or%survival.[5,6]

Recent Ascorbate-Only Trials

One%study%reported%three%case%reports%of%cancer%patients%who%received%IV%vitamin%C%as%their%maintherapy.%During%vitamin%C%therapy,%the%patients%used%additional%treatments,%including%vitamins,minerals,%and%botanicals.%According%to%the%authors,%the%cases%were%reviewed%in%accordance%withthe%NCI%Best%Case%Series%guidelines.%Histopathologic%examination%suggested%poor%prognoses%forthese%patients,%but%they%had%long%survival%times%after%being%treated%with%IV%vitamin%C.[7]%Vitamin%Cwas%given%at%doses%ranging%from%15%g%to%65%g,%initially%once%or%twice%a%week%for%several%months;two%patients%then%received%it%less%frequently%for%1%to%4%years.

Two%studies%demonstrated%that%IV%vitamin%C%treatment%resulted%in%improved%quality%of%life%anddecreases%in%cancer-related%side%effects%in%cancer%patients.[8,9]

http://cam.cancer.gov/best_case_intro.html

Studies%have%shown%that%vitamin%C%can%be%safely%administered%to%healthy%volunteers%or%cancerpatients%at%doses%up%to%1.5%g/kg%and%with%screening%to%eliminate%treating%individuals%with%riskfactors%for%toxicity%(e.g.,%glucose-6-phosphate%dehydrogenase%deficiency,%renal%diseases,%orurolithiasis).%These%studies%have%also%found%that%plasma%concentrations%of%vitamin%C%are%higherwith%IV%administration%than%with%oral%administration%and%are%maintained%for%more%than%4%hours.[10,11]

Ascorbate-Combination Trials

A%phase%I%study%published%in%2012%examined%the%safety%and%efficacy%of%combining%IV%ascorbatewith%gemcitabine%and%erlotinib%in%stage%IV%pancreatic%cancer%patients.%Fourteen%subjects%enteredthe%study%and%planned%to%receive%IV%gemcitabine%(1,000%mg%/m %over%30%minutes,%once%a%week%for7%weeks),%oral%erlotinib%(100%mg%daily%for%8%weeks),%and%IV%ascorbate%(50%g/infusion,%75%g/infusion,or%100%g/infusion%3%times%per%week%for%8%weeks).%Minimal%adverse%effects%were%reported%forascorbic%acid%treatment.%Five%subjects%received%fewer%than%18%of%the%planned%24%ascorbateinfusions%and%thus%did%not%have%follow-up%imaging%to%assess%response.%Three%of%those%patients%hadclinically%determined%progressive%disease.%All%of%the%other%nine%patients%had%repeat%imaging%toassess%tumor%size,%and%each%met%the%criteria%for%having%stable%disease.[12]

A%2013%phase%I%clinical%study%evaluated%the%safety%of%combining%pharmacological%ascorbate%withgemcitabine%in%treating%stage%IV%pancreatic%cancer%patients.%During%each%4-week%cycle,%patientsreceived%gemcitabine%weekly%for%3%weeks%(1,000%mg/m %over%30%minutes)%and%twice%weeklyascorbate%infusions%for%4%weeks%(15%g%over%30%minutes%during%the%first%week,%followed%by%weeklyescalations%in%dose%until%plasma%levels%reached%at%least%350%mg/dL%[20%mM]).%Among%nine%patients,mean%progression-free%survival%was%26%weeks%and%overall%survival%was%12%months.%Thecombination%treatment%was%well%tolerated,%and%no%significant%adverse%events%were%reported.[13]

In%2014,%a%phase%I/IIA%clinical%trial%evaluated%the%toxicities%of%combining%IV%ascorbate%withcarboplatin%and%paclitaxel%in%stage%III%/IV%ovarian%cancer.%Twenty-seven%patients%were%randomlyassigned%to%receive%either%chemotherapy%alone%or%chemotherapy%and%IV%vitamin%C%concurrently.Chemotherapy%was%given%for%6%months,%and%IV%vitamin%C%was%given%for%12%months.%The%addition%ofIV%vitamin%C%was%associated%with%reduced%chemotherapy-related%toxicities.[14]

Trials%of%high-dose%IV%vitamin%C%with%other%drugs%are%ongoing.[12,14]%A%number%of%studies%haveincluded%IV%ascorbic%acid%treatment%(1,000%mg)%with%arsenic%trioxide%regimens,%with%mixed%results.The%combination%therapies%were%well%tolerated%and%suggested%beneficial%effects%in%multiplemyeloma%patients,%although%the%specific%contribution%of%vitamin%C%could%not%be%determined.[15-18]However,%similar%combination%regimens%resulted%in%severe%side%effects%and%disease%progression%inpatients%with%acute%myeloid%leukemia,[19]%refractory%metastatic%colorectal%cancer,[20]%and

2

metastatic%melanoma.[21]

Check%NCI’s%list%of%cancer%clinical%trials%for%cancer%CAM%clinical%trials%on%ascorbic%acid%that%areactively%enrolling%patients.

General%information%about%clinical%trials%is%also%available%from%the%NCI%Web%site.

References

1.% Cameron%E,%Campbell%A:%The%orthomolecular%treatment%of%cancer.%II.%Clinical%trial%of%high-doseascorbic%acid%supplements%in%advanced%human%cancer.%Chem%Biol%Interact%9%(4):%285-315,1974.%[PUBMED%Abstract]

2.% Cameron%E,%Campbell%A,%Jack%T:%The%orthomolecular%treatment%of%cancer.%III.%Reticulum%cellsarcoma:%double%complete%regression%induced%by%high-dose%ascorbic%acid%therapy.%Chem%BiolInteract%11%(5):%387-93,%1975.%[PUBMED%Abstract]

3.% Cameron%E,%Pauling%L:%Supplemental%ascorbate%in%the%supportive%treatment%of%cancer:Prolongation%of%survival%times%in%terminal%human%cancer.%Proc%Natl%Acad%Sci%U%S%A%73%(10):3685-9,%1976.%[PUBMED%Abstract]

4.% Cameron%E,%Pauling%L:%Supplemental%ascorbate%in%the%supportive%treatment%of%cancer:reevaluation%of%prolongation%of%survival%times%in%terminal%human%cancer.%Proc%Natl%Acad%Sci%US%A%75%(9):%4538-42,%1978.%[PUBMED%Abstract]

5.% Creagan%ET,%Moertel%CG,%O'Fallon%JR,%et%al.:%Failure%of%high-dose%vitamin%C%(ascorbic%acid)therapy%to%benefit%patients%with%advanced%cancer.%A%controlled%trial.%N%Engl%J%Med%301%(13):687-90,%1979.%[PUBMED%Abstract]

6.% Moertel%CG,%Fleming%TR,%Creagan%ET,%et%al.:%High-dose%vitamin%C%versus%placebo%in%thetreatment%of%patients%with%advanced%cancer%who%have%had%no%prior%chemotherapy.%Arandomized%double-blind%comparison.%N%Engl%J%Med%312%(3):%137-41,%1985.%[PUBMED%Abstract]

7.% Padayatty%SJ,%Riordan%HD,%Hewitt%SM,%et%al.:%Intravenously%administered%vitamin%C%as%cancertherapy:%three%cases.%CMAJ%174%(7):%937-42,%2006.%[PUBMED%Abstract]

8.% Vollbracht%C,%Schneider%B,%Leendert%V,%et%al.:%Intravenous%vitamin%C%administration%improvesquality%of%life%in%breast%cancer%patients%during%chemo-/radiotherapy%and%aftercare:%results%of%aretrospective,%multicentre,%epidemiological%cohort%study%in%Germany.%In%Vivo%25%(6):%983-90,2011%Nov-Dec.%[PUBMED%Abstract]

9.% Yeom%CH,%Jung%GC,%Song%KJ:%Changes%of%terminal%cancer%patients'%health-related%quality%of%life

http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?idtype=1&id=39737&tt=0&format=2

after%high%dose%vitamin%C%administration.%J%Korean%Med%Sci%22%(1):%7-11,%2007.%[PUBMEDAbstract]

12.% Monti%DA,%Mitchell%E,%Bazzan%AJ,%et%al.:%Phase%I%evaluation%of%intravenous%ascorbic%acid%incombination%with%gemcitabine%and%erlotinib%in%patients%with%metastatic%pancreatic%cancer.PLoS%One%7%(1):%e29794,%2012.%[PUBMED%Abstract]

13.% Welsh%JL,%Wagner%BA,%van't%Erve%TJ,%et%al.:%Pharmacological%ascorbate%with%gemcitabine%for%thecontrol%of%metastatic%and%node-positive%pancreatic%cancer%(PACMAN):%results%from%a%phase%Iclinical%trial.%Cancer%Chemother%Pharmacol%71%(3):%765-75,%2013.%[PUBMED%Abstract]

15.% Abou-Jawde%RM,%Reed%J,%Kelly%M,%et%al.:%Efficacy%and%safety%results%with%the%combinationtherapy%of%arsenic%trioxide,%dexamethasone,%and%ascorbic%acid%in%multiple%myeloma%patients:%aphase%2%trial.%Med%Oncol%23%(2):%263-72,%2006.%[PUBMED%Abstract]

16.% Berenson%JR,%Matous%J,%Swift%RA,%et%al.:%A%phase%I/II%study%of%arsenictrioxide/bortezomib/ascorbic%acid%combination%therapy%for%the%treatment%of%relapsed%orrefractory%multiple%myeloma.%Clin%Cancer%Res%13%(6):%1762-8,%2007.%[PUBMED%Abstract]

17.% Qazilbash%MH,%Saliba%RM,%Nieto%Y,%et%al.:%Arsenic%trioxide%with%ascorbic%acid%and%high-dosemelphalan:%results%of%a%phase%II%randomized%trial.%Biol%Blood%Marrow%Transplant%14%(12):%1401-7,%2008.%[PUBMED%Abstract]

18.% Berenson%JR,%Boccia%R,%Siegel%D,%et%al.:%Efficacy%and%safety%of%melphalan,%arsenic%trioxide%andascorbic%acid%combination%therapy%in%patients%with%relapsed%or%refractory%multiple%myeloma:%aprospective,%multicentre,%phase%II,%single-arm%study.%Br%J%Haematol%135%(2):%174-83,2006.%[PUBMED%Abstract]

19.% Welch%JS,%Klco%JM,%Gao%F,%et%al.:%Combination%decitabine,%arsenic%trioxide,%and%ascorbic%acid%forthe%treatment%of%myelodysplastic%syndrome%and%acute%myeloid%leukemia:%a%phase%I%study.%AmJ%Hematol%86%(9):%796-800,%2011.%[PUBMED%Abstract]

20.% Subbarayan%PR,%Lima%M,%Ardalan%B:%Arsenic%trioxide/ascorbic%acid%therapy%in%patients%withrefractory%metastatic%colorectal%carcinoma:%a%clinical%experience.%Acta%Oncol%46%(4):%557-61,

2007.%[PUBMED%Abstract]

21.% Bael%TE,%Peterson%BL,%Gollob%JA:%Phase%II%trial%of%arsenic%trioxide%and%ascorbic%acid%withtemozolomide%in%patients%with%metastatic%melanoma%with%or%without%central%nervous%systemmetastases.%Melanoma%Res%18%(2):%147-51,%2008.%[PUBMED%Abstract]

Adverse EffectsIntravenous%(IV)%high-dose%ascorbic%acid%has%been%generally%well%tolerated%in%clinical%trials.[1-8]Renal%failure%following%ascorbic%acid%treatment%has%been%reported%in%patients%with%preexistingrenal%disorders.[9]

Case%reports%have%indicated%that%patients%with%glucose-6-phosphate%dehydrogenase%(G-6-PD)deficiency%should%not%receive%high%doses%of%vitamin%C%because%of%the%risk%of%developing%hemolysis.[10-12]

Vitamin%C%may%increase%bioavailability%of%iron,%and%high%doses%of%the%vitamin%are%notrecommended%for%patients%with%hemochromatosis.[13]

Drug Interactions

When%administered%in%high%doses,%vitamin%C%may%result%in%adverse%interactions%with%someanticancer%agents.%These%interactions%have%primarily%been%detected%in%preclinical%studies.%A%2013phase%I%clinical%study%evaluated%the%safety%of%combining%high-dose%IV%ascorbate%with%gemcitabinein%stage%IV%pancreatic%cancer%patients.%The%combination%therapy%was%well%tolerated%by%patients,and%no%significant%adverse%events%were%reported.[14]

In vitro and%in vivo animal%studies%have%suggested%that%combining%oral%vitamin%C%with%bortezomibinterferes%with%the%drug’s%ability%to%act%as%a%proteasome%inhibitor%and%blocks%bortezomib-initiatedapoptosis.[15-17]%This%interference%occurred%even%with%the%oral%administration%of%vitamin%C%(40%mg/kg%/day)%to%animals.%Studies%in%cell%culture%and%performed%by%adding%blood%plasma%from%healthyvolunteers%given%oral%vitamin%C%(1%g%/day)%also%showed%a%significant%decrease%in%bortezomib’sgrowth%inhibitory%effect%on%multiple%myeloma%cells.%Another%study%found%similar%results.%Plasmafrom%healthy%volunteers%who%took%1%g%of%oral%vitamin%C%per%day%was%shown%to%decreasebortezomib%growth%inhibition%in%multiple%myeloma%cells%and%to%block%its%inhibitory%effect%on%20Sproteasome%activity.[17]%However,%a%study%that%utilized%mice%harboring%human%prostate%cancer%cellxenografts%failed%to%find%any%significant%effect%of%oral%vitamin%C%(40%mg/kg/day%or%500%mg/kg/day)on%the%tumor%growth%inhibitory%action%of%bortezomib.[18]

Several%studies%have%been%performed%to%assess%the%potential%synergistic%or%inhibitory%action%ofvitamin%C%on%certain%chemotherapy%drugs,%with%variable%results.%A%series%of%studies%in%cell%culture

and%in%animals%bearing%tumors%has%shown%that%when%given%at%high%concentrations%or%dosages,dehydroascorbic%acid%(an%oxidized%form%of%vitamin%C)%can%interfere%with%the%cytotoxic%effects%ofseveral%chemotherapy%drugs.[19]%However,%dehydroascorbic%acid%is%generally%present%only%at%lowconcentrations%in%dietary%supplements%and%fresh%foods.

References

3.% Chen%Q,%Espey%MG,%Sun%AY,%et%al.:%Pharmacologic%doses%of%ascorbate%act%as%a%prooxidant%anddecrease%growth%of%aggressive%tumor%xenografts%in%mice.%Proc%Natl%Acad%Sci%U%S%A%105%(32):11105-9,%2008.%[PUBMED%Abstract]

4.% Monti%DA,%Mitchell%E,%Bazzan%AJ,%et%al.:%Phase%I%evaluation%of%intravenous%ascorbic%acid%incombination%with%gemcitabine%and%erlotinib%in%patients%with%metastatic%pancreatic%cancer.PLoS%One%7%(1):%e29794,%2012.%[PUBMED%Abstract]

5.% Abou-Jawde%RM,%Reed%J,%Kelly%M,%et%al.:%Efficacy%and%safety%results%with%the%combinationtherapy%of%arsenic%trioxide,%dexamethasone,%and%ascorbic%acid%in%multiple%myeloma%patients:%aphase%2%trial.%Med%Oncol%23%(2):%263-72,%2006.%[PUBMED%Abstract]

6.% Berenson%JR,%Matous%J,%Swift%RA,%et%al.:%A%phase%I/II%study%of%arsenictrioxide/bortezomib/ascorbic%acid%combination%therapy%for%the%treatment%of%relapsed%orrefractory%multiple%myeloma.%Clin%Cancer%Res%13%(6):%1762-8,%2007.%[PUBMED%Abstract]

7.% Qazilbash%MH,%Saliba%RM,%Nieto%Y,%et%al.:%Arsenic%trioxide%with%ascorbic%acid%and%high-dosemelphalan:%results%of%a%phase%II%randomized%trial.%Biol%Blood%Marrow%Transplant%14%(12):%1401-7,%2008.%[PUBMED%Abstract]

9.% Padayatty%SJ,%Sun%AY,%Chen%Q,%et%al.:%Vitamin%C:%intravenous%use%by%complementary%andalternative%medicine%practitioners%and%adverse%effects.%PLoS%One%5%(7):%e11414,2010.%[PUBMED%Abstract]

10.% Campbell%GD%Jr,%Steinberg%MH,%Bower%JD:%Letter:%Ascorbic%acid-induced%hemolysis%in%G-6-PDdeficiency.%Ann%Intern%Med%82%(6):%810,%1975.%[PUBMED%Abstract]

11.% Mehta%JB,%Singhal%SB,%Mehta%BC:%Ascorbic-acid-induced%haemolysis%in%G-6-PD%deficiency.Lancet%336%(8720):%944,%1990.%[PUBMED%Abstract]

12.% Rees%DC,%Kelsey%H,%Richards%JD:%Acute%haemolysis%induced%by%high%dose%ascorbic%acid%inglucose-6-phosphate%dehydrogenase%deficiency.%BMJ%306%(6881):%841-2,%1993.%[PUBMEDAbstract]

13.% Barton%JC,%McDonnell%SM,%Adams%PC,%et%al.:%Management%of%hemochromatosis.Hemochromatosis%Management%Working%Group.%Ann%Intern%Med%129%(11):%932-9,1998.%[PUBMED%Abstract]

14.% Welsh%JL,%Wagner%BA,%van't%Erve%TJ,%et%al.:%Pharmacological%ascorbate%with%gemcitabine%for%thecontrol%of%metastatic%and%node-positive%pancreatic%cancer%(PACMAN):%results%from%a%phase%Iclinical%trial.%Cancer%Chemother%Pharmacol%71%(3):%765-75,%2013.%[PUBMED%Abstract]

15.% Zou%W,%Yue%P,%Lin%N,%et%al.:%Vitamin%C%inactivates%the%proteasome%inhibitor%PS-341%in%humancancer%cells.%Clin%Cancer%Res%12%(1):%273-80,%2006.%[PUBMED%Abstract]

16.% Llobet%D,%Eritja%N,%Encinas%M,%et%al.:%Antioxidants%block%proteasome%inhibitor%function%inendometrial%carcinoma%cells.%Anticancer%Drugs%19%(2):%115-24,%2008.%[PUBMED%Abstract]

17.% Perrone%G,%Hideshima%T,%Ikeda%H,%et%al.:%Ascorbic%acid%inhibits%antitumor%activity%of%bortezomibin%vivo.%Leukemia%23%(9):%1679-86,%2009.%[PUBMED%Abstract]

18.% Bannerman%B,%Xu%L,%Jones%M,%et%al.:%Preclinical%evaluation%of%the%antitumor%activity%ofbortezomib%in%combination%with%vitamin%C%or%with%epigallocatechin%gallate,%a%component%ofgreen%tea.%Cancer%Chemother%Pharmacol%68%(5):%1145-54,%2011.%[PUBMED%Abstract]

19.% Heaney%ML,%Gardner%JR,%Karasavvas%N,%et%al.:%Vitamin%C%antagonizes%the%cytotoxic%effects%ofantineoplastic%drugs.%Cancer%Res%68%(19):%8031-8,%2008.%[PUBMED%Abstract]

Changes to This Summary (06/29/2015)The%PDQ%cancer%information%summaries%are%reviewed%regularly%and%updated%as%new%informationbecomes%available.%This%section%describes%the%latest%changes%made%to%this%summary%as%of%the%dateabove.

Editorial%changes%were%made%to%this%summary.

This%summary%is%written%and%maintained%by%the%PDQ%Cancer%Complementary%and%AlternativeMedicine%Editorial%Board,%which%is%editorially%independent%of%NCI.%The%summary%reflects%anindependent%review%of%the%literature%and%does%not%represent%a%policy%statement%of%NCI%or%NIH.More%information%about%summary%policies%and%the%role%of%the%PDQ%Editorial%Boards%in%maintainingthe%PDQ%summaries%can%be%found%on%the%About%This%PDQ%Summary%and%PDQ%NCI's

http://www.cancer.gov/about-cancer/treatment/cam/hp/vitamin-c-pdq/#link/_AboutThis_1

http://www.cancer.gov/cancertopics/pdq

Comprehensive%Cancer%Database%pages.

This%PDQ%cancer%information%summary%for%health%professionals%provides%comprehensive,%peer-reviewed,%evidence-based%information%about%the%use%of%high-dose%vitamin%C%in%the%treatment%ofpeople%with%cancer.%It%is%intended%as%a%resource%to%inform%and%assist%clinicians%who%care%for%cancerpatients.%It%does%not%provide%formal%guidelines%or%recommendations%for%making%health%caredecisions.

This%summary%is%reviewed%regularly%and%updated%as%necessary%by%the%PDQ%Cancer%Complementaryand%Alternative%Medicine%Editorial%Board,%which%is%editorially%independent%of%the%National%CancerInstitute%(NCI).%The%summary%reflects%an%independent%review%of%the%literature%and%does%notrepresent%a%policy%statement%of%NCI%or%the%National%Institutes%of%Health%(NIH).

Board%members%review%recently%published%articles%each%month%to%determine%whether%an%articleshould:

be%discussed%at%a%meeting,

be%cited%with%text,%or

replace%or%update%an%existing%article%that%is%already%cited.

Changes%to%the%summaries%are%made%through%a%consensus%process%in%which%Board%membersevaluate%the%strength%of%the%evidence%in%the%published%articles%and%determine%how%the%articleshould%be%included%in%the%summary.

The%lead%reviewer%for%High-Dose%Vitamin%C%is:

Jeffrey%D.%White,%MD%(National%Cancer%Institute)

Any%comments%or%questions%about%the%summary%content%should%be%submitted%to%Cancer.govthrough%the%Web%site's%Contact%Form.%Do%not%contact%the%individual%Board%Members%withquestions%or%comments%about%the%summaries.%Board%members%will%not%respond%to%individualinquiries.

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http://www.cancer.gov/about-cancer/treatment/cam/hp/vitamin-c-pdq/#link/_AboutThis_1

http://www.cancer.gov/contact

Levels of Evidence

Some%of%the%reference%citations%in%this%summary%are%accompanied%by%a%level-of-evidencedesignation.%These%designations%are%intended%to%help%readers%assess%the%strength%of%the%evidencesupporting%the%use%of%specific%interventions%or%approaches.%The%PDQ%Cancer%Complementary%andAlternative%Medicine%Editorial%Board%uses%a%formal%evidence%ranking%system%in%developing%its%level-of-evidence%designations.

PDQ%is%a%registered%trademark.%Although%the%content%of%PDQ%documents%can%be%used%freely%astext,%it%cannot%be%identified%as%an%NCI%PDQ%cancer%information%summary%unless%it%is%presented%inits%entirety%and%is%regularly%updated.%However,%an%author%would%be%permitted%to%write%a%sentencesuch%as%“NCI’s%PDQ%cancer%information%summary%about%breast%cancer%prevention%states%the%riskssuccinctly:%[include%excerpt%from%the%summary].”

The%preferred%citation%for%this%PDQ%summary%is:

National%Cancer%Institute:%PDQ®%High-Dose%Vitamin%C.%Bethesda,%MD:%National%Cancer%Institute.Date%last%modified%<MM/DD/YYYY>.%Available%at:%http://www.cancer.gov/about-cancer/treatment/cam/hp/vitamin-c-pdq.%Accessed%<MM/DD/YYYY>.

Images%in%this%summary%are%used%with%permission%of%the%author(s),%artist,%and/or%publisher%for%usewithin%the%PDQ%summaries%only.%Permission%to%use%images%outside%the%context%of%PDQinformation%must%be%obtained%from%the%owner(s)%and%cannot%be%granted%by%the%National%CancerInstitute.%Information%about%using%the%illustrations%in%this%summary,%along%with%many%othercancer-related%images,%is%available%in%Visuals%Online,%a%collection%of%over%2,000%scientific%images.

Disclaimer

The%information%in%these%summaries%should%not%be%used%as%a%basis%for%insurance%reimbursementdeterminations.%More%information%on%insurance%coverage%is%available%on%Cancer.gov%on%theCoping%with%Cancer:%Financial,%Insurance,%and%Legal%Information%page.

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http://www.cancer.gov/publications/pdq/levels-evidence/cam

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Updated:%June%29,%2015

7/24/15, 12:03Cannabis and Cannabinoids - National Cancer Institute

Page 1 of 28http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#section/all

Cannabis and Cannabinoids–for healthprofessionals (PDQ®)

OverviewThis%complementary%and%alternative%medicine%(CAM)%information%summary%provides%an%overviewof%the%use%of%Cannabis and%its%components%as%a%treatment%for%people%with%cancer%-relatedsymptoms%caused%by%the%disease%itself%or%its%treatment.

Cannabis%has%been%used%for%medicinal%purposes%for%thousands%of%years.

By%federal%law,%the%possession%of%Cannabis,%also%known%as%marijuana,%is%illegal%in%the%UnitedStates;%however,%a%growing%number%of%states%and%the%District%of%Columbia%have%enacted%lawsto%legalize%its%medical%use.

The%U.S.%Food%and%Drug%Administration%has%not%approved%Cannabis%as%a%treatment%for%canceror%any%other%medical%condition.

Chemical%components%of%Cannabis,%called%cannabinoids,%activate%specific%receptors%foundthroughout%the%body%to%produce%pharmacologic%effects,%particularly%in%the%central%nervoussystem%and%the%immune%system.

Commercially%available%cannabinoids,%such%as%dronabinol%and%nabilone,%are%approved%drugsfor%the%treatment%of%cancer-related%side%effects.

Cannabinoids%may%have%benefits%in%the%treatment%of%cancer-related%side%effects.

Many%of%the%medical%and%scientific%terms%used%in%this%summary%are%hypertext%linked%(at%first%use%ineach%section)%to%the%NCI%Dictionary%of%Cancer%Terms,%which%is%oriented%toward%nonexperts.%When%alinked%term%is%clicked,%a%definition%will%appear%in%a%separate%window.

Reference%citations%in%some%PDQ%CAM%information%summaries%may%include%links%to%external%Websites%that%are%operated%by%individuals%or%organizations%for%the%purpose%of%marketing%or%advocatingthe%use%of%specific%treatments%or%products.%These%reference%citations%are%included%forinformational%purposes%only.%Their%inclusion%should%not%be%viewed%as%an%endorsement%of%thecontent%of%the%Web%sites,%or%of%any%treatment%or%product,%by%the%PDQ%Cancer%CAM%Editorial%Board

•

http://www.cancer.gov/dictionary/

or%the%National%Cancer%Institute.

General InformationCannabis ,%also%known%as%marijuana,%originated%in%Central%Asia%but%is%grown%worldwide%today.%Inthe%United%States,%it%is%a%controlled%substance%and%is%classified%as%a%Schedule%I%agent%(a%drug%withincreased%potential%for%abuse%and%no%known%medical%use).%The%Cannabis%plant%produces%a%resincontaining%psychoactive%compounds%called%cannabinoids.%The%highest%concentration%ofcannabinoids%is%found%in%the%female%flowers%of%the%plant.[1]%Clinical%trials%conducted%on%medicinalCannabis%are%limited.%The%U.S.%Food%and%Drug%Administration%(FDA)%has%not%approved%the%use%ofCannabis%as%a%treatment%for%any%medical%condition.%To%conduct%clinical%drug%research%in%the%UnitedStates,%researchers%must%file%an%Investigational%New%Drug%(IND)%application%with%the%FDA.

The%potential%benefits%of%medicinal%Cannabis%for%people%living%with%cancer%include%antiemeticeffects,%appetite%stimulation,%pain%relief,%and%improved%sleep.%Although%few%relevant%surveys%ofpractice%patterns%exist,%it%appears%that%physicians%caring%for%cancer%patients%in%the%United%Stateswho%recommend%medicinal%Cannabis%predominantly%do%so%for%symptom%management.[2]%Agrowing%number%of%pediatric%patients%are%seeking%symptom%relief%with%Cannabis%or%cannabinoidtreatment,%although%studies%are%limited.

Cannabinoids%are%a%group%of%terpenophenolic%compounds%found%in%Cannabis%species%(e.g.,Cannabis sativa L.).%This%summary%will%review%the%role%of%Cannabis%and%the%cannabinoids%in%thetreatment%of%people%with%cancer%and%disease-related%or%treatment-related%side%effects.

References

1.% Adams%IB,%Martin%BR:%Cannabis:%pharmacology%and%toxicology%in%animals%and%humans.Addiction%91%(11):%1585-614,%1996.%[PUBMED%Abstract]

2.% Doblin%RE,%Kleiman%MA:%Marijuana%as%antiemetic%medicine:%a%survey%of%oncologists'experiences%and%attitudes.%J%Clin%Oncol%9%(7):%1314-9,%1991.%[PUBMED%Abstract]

HistoryCannabis use%for%medicinal%purposes%dates%back%at%least%3,000%years.[1-5]%It%was%introduced%intoWestern%medicine%in%the%1840s%by%W.B.%O’Shaughnessy,%a%surgeon%who%learned%of%its%medicinalproperties%while%working%in%India%for%the%British%East%Indies%Company.%Its%use%was%promoted%forreported%analgesic,%sedative,%anti-inflammatory,%antispasmodic,%and%anticonvulsant%effects.

In%1937,%the%U.S.%Treasury%Department%introduced%the%Marihuana%Tax%Act.%This%Act%imposed%a%levy

http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_2.1

of%$1%per%ounce%for%medicinal%use%of%Cannabis%and%$100%per%ounce%for%recreational%use.%Physiciansin%the%United%States%were%the%principal%opponents%of%the%Act.%The%American%Medical%Association(AMA)%opposed%the%Act%because%physicians%were%required%to%pay%a%special%tax%for%prescribingCannabis,%use%special%order%forms%to%procure%it,%and%keep%special%records%concerning%itsprofessional%use.%In%addition,%the%AMA%believed%that%objective%evidence%that%Cannabis%was%harmfulwas%lacking%and%that%passage%of%the%Act%would%impede%further%research%into%its%medicinal%worth.[6]%In%1942,%Cannabis%was%removed%from%the%U.S.%Pharmacopoeia%because%of%persistent%concernsabout%its%potential%to%cause%harm.[2,3]

In%1951,%Congress%passed%the%Boggs%Act,%which%for%the%first%time,%included%Cannabis%with%narcoticdrugs.%In%1970,%with%the%passage%of%the%Controlled%Substances%Act,%marijuana%was%classified%as%aSchedule%I%drug.%Drugs%in%this%category%are%distinguished%as%having%no%accepted%medicinal%use.Other%Schedule%I%substances%include%heroin,%LSD,%mescaline,%and%methaqualone.

Despite%its%designation%as%having%no%medicinal%use,%Cannabis%was%distributed%to%patients%by%theU.S.%government%on%a%case-by-case%basis%under%the%Compassionate%Use%Investigational%New%Drugprogram%established%in%1978.%Distribution%of%Cannabis%through%this%program%was%discontinued%in1992.[1-4]%Although%federal%law%prohibits%the%use%of%Cannabis,%the%table%below%lists%the%localitiesthat%permit%its%use%for%certain%medical%conditions.

List of Localities That Permit Use of Cannabis for Certain MedicalConditions

Alaska%(AK)

Arizona%(AZ)

California%(CA)

Colorado%(CO)

Connecticut%(CT)

Delaware%(DE)

District%of%Columbia%(DC)

Hawaii%(HI)

Illinois%(IL)

Maine%(ME)

Maryland%(MD)

Massachusetts%(MA)

Michigan%(MI)

Minnesota%(MN)

Montana%(MT)

Nevada%(NV)

New%Hampshire%(NH)

New%Jersey%(NJ)

New%Mexico%(NM)

New%York%(NY)

The%main%psychoactive%constituent%of%Cannabis%was%identified%as%delta-9-tetrahydrocannabinol(THC).%In%1986,%synthetic%delta-9-THC%in%sesame%oil%was%licensed%and%approved%for%the%treatmentof%chemotherapy%-associated%nausea%and%vomiting%under%the%generic%name%dronabinol.%Clinicaltrials%determined%that%dronabinol%was%as%effective%as%or%better%than%other%antiemetic%agentsavailable%at%the%time.[7]%Dronabinol%was%also%studied%for%its%ability%to%stimulate%weight%gain%inpatients%with%AIDS%in%the%late%1980s.%Thus,%the%indications%were%expanded%to%include%treatment%ofanorexia%associated%with%human%immunodeficiency%virus%infection%in%1992.%Clinical%trial%resultsshowed%no%statistically%significant%weight%gain,%although%patients%reported%an%improvement%inappetite.[8,9]

Within%the%past%20%years,%the%neurobiology%of%cannabinoids%has%been%analyzed.[10-13]%The%firstcannabinoid%receptor,%CB1,%was%identified%in%the%brain%in%1988.%A%second%cannabinoid%receptor,CB2,%was%identified%in%1993.%The%highest%expression%of%CB2%receptors%is%located%on%B%lymphocytesand%natural%killer%cells,%suggesting%a%possible%role%in%immunity.%Endogenous%cannabinoids(endocannabinoids)%have%been%identified%and%appear%to%have%a%role%in,%for%example,%painmodulation,%control%of%movement,%feeding%behavior,%and%memory.[11]

Spasticity%is%a%common%symptom%of%multiple%sclerosis%for%which%existing%therapy%is%unsatisfactoryand%may%include%muscle%stiffness,%reduced%mobility,%and%pain.%In%Canada,%New%Zealand,%and%somecountries%in%Europe,%nabiximols%(a%THC:cannabidiol%extract)%is%approved%for%the%treatment%ofspasticity%associated%with%multiple%sclerosis%via%oromucosal%administration.[14,15]%Nabiximols%isalso%approved%in%Canada%(under%the%Notice%of%Compliance%with%Conditions)%for%symptomatic%reliefof%pain%in%multiple%sclerosis%and%advanced%cancer.[15]

References

1.% Abel%EL:%Marihuana,%The%First%Twelve%Thousand%Years.%New%York:%Plenum%Press,%1980.%Alsoavailable%online .%Last%accessed%July%16,%2015.

Oregon%(OR)

Rhode%Island%(RI)

Vermont%(VT)

Washington%(WA)

http://www.druglibrary.org/Schaffer/hemp/history/first12000/abel.htm

2.% Joy%JE,%Watson%SJ,%Benson%JA,%eds.:%Marijuana%and%Medicine:%Assessing%the%Science%Base.Washington,%DC:%National%Academy%Press,%1999.%Also%available%online .%Last%accessed%July%16,2015.

3.% Mack%A,%Joy%J:%Marijuana%As%Medicine?%The%Science%Beyond%the%Controversy.%Washington,%DC:National%Academy%Press,%2001.%Also%available%online .%Last%accessed%July%16,%2015.

4.% Booth%M:%Cannabis:%A%History.%New%York,%NY:%St%Martin's%Press,%2003.

5.% Russo%EB,%Jiang%HE,%Li%X,%et%al.:%Phytochemical%and%genetic%analyses%of%ancient%cannabis%fromCentral%Asia.%J%Exp%Bot%59%(15):%4171-82,%2008.%[PUBMED%Abstract]

6.% Schaffer%Library%of%Drug%Policy:%The%Marihuana%Tax%Act%of%1937:%Taxation%of%Marihuana.Washington,%DC:%House%of%Representatives,%Committee%on%Ways%and%Means,%1937.%Availableonline .%Last%accessed%July%16,%2015.

7.% Sallan%SE,%Zinberg%NE,%Frei%E%3rd:%Antiemetic%effect%of%delta-9-tetrahydrocannabinol%in%patientsreceiving%cancer%chemotherapy.%N%Engl%J%Med%293%(16):%795-7,%1975.%[PUBMED%Abstract]

8.% Gorter%R,%Seefried%M,%Volberding%P:%Dronabinol%effects%on%weight%in%patients%with%HIVinfection.%AIDS%6%(1):%127,%1992.%[PUBMED%Abstract]

9.% Beal%JE,%Olson%R,%Laubenstein%L,%et%al.:%Dronabinol%as%a%treatment%for%anorexia%associated%withweight%loss%in%patients%with%AIDS.%J%Pain%Symptom%Manage%10%(2):%89-97,%1995.%[PUBMEDAbstract]

10.% Devane%WA,%Dysarz%FA%3rd,%Johnson%MR,%et%al.:%Determination%and%characterization%of%acannabinoid%receptor%in%rat%brain.%Mol%Pharmacol%34%(5):%605-13,%1988.%[PUBMED%Abstract]

11.% Devane%WA,%Hanus%L,%Breuer%A,%et%al.:%Isolation%and%structure%of%a%brain%constituent%that%bindsto%the%cannabinoid%receptor.%Science%258%(5090):%1946-9,%1992.%[PUBMED%Abstract]

12.% Pertwee%RG,%Howlett%AC,%Abood%ME,%et%al.:%International%Union%of%Basic%and%ClinicalPharmacology.%LXXIX.%Cannabinoid%receptors%and%their%ligands:%beyond%CB₁%and%CB₂.Pharmacol%Rev%62%(4):%588-631,%2010.%[PUBMED%Abstract]

13.% Felder%CC,%Glass%M:%Cannabinoid%receptors%and%their%endogenous%agonists.%Annu%RevPharmacol%Toxicol%38:%179-200,%1998.%[PUBMED%Abstract]

14.% Zajicek%JP,%Apostu%VI:%Role%of%cannabinoids%in%multiple%sclerosis.%CNS%Drugs%25%(3):%187-201,2011.%[PUBMED%Abstract]

15.% Howard%P,%Twycross%R,%Shuster%J,%et%al.:%Cannabinoids.%J%Pain%Symptom%Manage%46%(1):%142-9,2013.%[PUBMED%Abstract]

http://books.nap.edu/openbook.php?isbn=0309071550

http://books.nap.edu/openbook.php?isbn=0309065313#

http://www.druglibrary.org/schaffer/hemp/taxact/woodward.htm

Laboratory/Animal/Preclinical StudiesCannabinoids%are%a%group%of%21-carbon–containing%terpenophenolic%compounds%produceduniquely%by%Cannabis species%(e.g.,%Cannabis sativa%L.)%.[1,2]%These%plant-derived%compounds%maybe%referred%to%as%phytocannabinoids.%Although%delta-9-tetrahydrocannabinol%(THC)%is%the%primarypsychoactive%ingredient,%other%known%compounds%with%biologic%activity%are%cannabinol,cannabidiol%(CBD),%cannabichromene,%cannabigerol,%tetrahydrocannabivarin,%and%delta-8-THC.CBD,%in%particular,%is%thought%to%have%significant%analgesic%and%anti-inflammatory%activity%withoutthe%psychoactive%effect%(high)%of%delta-9-THC.

Antitumor Effects

One%study%in%mice%and%rats%suggested%that%cannabinoids%may%have%a%protective%effect%against%thedevelopment%of%certain%types%of%tumors.[3]%During%this%2-year%study,%groups%of%mice%and%rats%weregiven%various%doses%of%THC%by%gavage.%A%dose-related%decrease%in%the%incidence%of%hepaticadenoma%tumors%and%hepatocellular%carcinoma%(HCC)%was%observed%in%the%mice.%Decreasedincidences%of%benign%tumors%(polyps%and%adenomas)%in%other%organs%(mammary%gland,%uterus,pituitary,%testis,%and%pancreas)%were%also%noted%in%the%rats.%In%another%study,%delta-9-THC,%delta-8-THC,%and%cannabinol%were%found%to%inhibit%the%growth%of%Lewis%lung%adenocarcinoma%cells%in vitroand%in vivo .[4]%In%addition,%other%tumors%have%been%shown%to%be%sensitive%to%cannabinoid-inducedgrowth%inhibition.[5-8]

Cannabinoids%may%cause%antitumor%effects%by%various%mechanisms,%including%induction%of%celldeath,%inhibition%of%cell%growth,%and%inhibition%of%tumor%angiogenesis%invasion%and%metastasis.[9-12]%Two%reviews%summarize%the%molecular%mechanisms%of%action%of%cannabinoids%as%antitumoragents.[13,14]%Cannabinoids%appear%to%kill%tumor%cells%but%do%not%affect%their%nontransformedcounterparts%and%may%even%protect%them%from%cell%death.%For%example,%these%compounds%havebeen%shown%to%induce%apoptosis%in%glioma%cells%in%culture%and%induce%regression%of%glioma%tumorsin%mice%and%rats,%while%they%protect%normal%glial%cells%of%astroglial%and%oligodendroglial%lineagesfrom%apoptosis%mediated%by%the%CB1%receptor.[9]

The%effects%of%delta-9-THC%and%a%synthetic%agonist%of%the%CB2%receptor%were%investigated%in%HCC.[15]%Both%agents%reduced%the%viability%of%HCC%cells%in vitro%and%demonstrated%antitumor%effects%inHCC%subcutaneous%xenografts%in%nude%mice.%The%investigations%documented%that%the%anti-HCCeffects%are%mediated%by%way%of%the%CB2%receptor.%Similar%to%findings%in%glioma%cells,%thecannabinoids%were%shown%to%trigger%cell%death%through%stimulation%of%an%endoplasmic%reticulumstress%pathway%that%activates%autophagy%and%promotes%apoptosis.%Other%investigations%haveconfirmed%that%CB1%and%CB2%receptors%may%be%potential%targets%in%non-small%cell%lung%carcinoma[16]%and%breast%cancer.[17]

An%in vitro%study%of%the%effect%of%CBD%on%programmed%cell%death%in%breast%cancer%cell%lines%foundthat%CBD%induced%programmed%cell%death,%independent%of%the%CB1,%CB2,%or%vanilloid%receptors.CBD%inhibited%the%survival%of%both%estrogen%receptor–positive%and%estrogen%receptor–negativebreast%cancer%cell%lines,%inducing%apoptosis%in%a%concentration-dependent%manner%while%havinglittle%effect%on%nontumorigenic%mammary%cells.[18]%Other%studies%have%also%shown%the%antitumoreffect%of%cannabinoids%(i.e.,%CBD%and%THC)%in%preclinical%models%of%breast%cancer.[19,20]

CBD%has%also%been%demonstrated%to%exert%a%chemopreventive%effect%in%a%mouse%model%of%coloncancer.[21]%In%this%experimental%system,%azoxymethane%increased%premalignant%and%malignantlesions%in%the%mouse%colon.%Animals%treated%with%azoxymethane%and%CBD%concurrently%wereprotected%from%developing%premalignant%and%malignant%lesions.%In%in vitro%experiments%involvingcolorectal%cancer%cell%lines,%the%investigators%found%that%CBD%protected%DNA%from%oxidativedamage,%increased%endocannabinoid%levels,%and%reduced%cell%proliferation.%In%a%subsequent%study,the%investigators%found%that%the%antiproliferative%effect%of%CBD%was%counteracted%by%selective%CB1but%not%CB2%receptor%antagonists,%suggesting%an%involvement%of%CB1%receptors.[22]

Another%investigation%into%the%antitumor%effects%of%CBD%examined%the%role%of%intercellularadhesion%molecule-1%(ICAM-1).[12]%ICAM-1%expression%has%been%reported%to%be%negativelycorrelated%with%cancer%metastasis.%In%lung%cancer%cell%lines,%CBD%upregulated%ICAM-1,%leading%todecreased%cancer%cell%invasiveness.

In%an%in vivo%model%using%severe%combined%immunodeficient%mice,%subcutaneous%tumors%weregenerated%by%inoculating%the%animals%with%cells%from%human%non-small%cell%lung%carcinoma%celllines.[23]%Tumor%growth%was%inhibited%by%60%%in%THC-treated%mice%compared%with%vehicle-treatedcontrol%mice.%Tumor%specimens%revealed%that%THC%had%antiangiogenic%and%antiproliferativeeffects.%However,%research%with%immunocompetent%murine%tumor%models%has%demonstratedimmunosuppression%and%enhanced%tumor%growth%in%mice%treated%with%THC.[24,25]

In%addition,%both%plant-derived%and%endogenous%cannabinoids%have%been%studied%for%anti-inflammatory%effects.%A%mouse%study%demonstrated%that%endogenous%cannabinoid%systemsignaling%is%likely%to%provide%intrinsic%protection%against%colonic%inflammation.[26]%As%a%result,%ahypothesis%that%phytocannabinoids%and%endocannabinoids%may%be%useful%in%the%risk%reductionand%treatment%of%colorectal%cancer%has%been%developed.[27-30]

CBD%may%also%enhance%uptake%of%cytotoxic%drugs%into%malignant%cells.%Activation%of%the%transientreceptor%potential%vanilloid%type%2%(TRPV2)%has%been%shown%to%inhibit%proliferation%of%humanglioblastoma%multiforme%cells%and%overcome%resistance%to%the%chemotherapy%agent%carmustine.[31]%In%an%in vitro%model,%CBD%increased%TRPV2%activation%and%increased%uptake%of%cytotoxic%drugs,leading%to%apoptosis%of%glioma%cells%without%affecting%normal%human%astrocytes.%This%suggeststhat%coadministration%of%CBD%with%cytotoxic%agents%may%increase%drug%uptake%and%potentiate%cell

death%in%human%glioma%cells.%Also,%CBD%together%with%THC%may%enhance%the%antitumor%activity%ofclassic%chemotherapeutic%drugs%such%as%temozolomide%in%some%mouse%models%of%cancer.[13,32]

Appetite Stimulation

Many%animal%studies%have%previously%demonstrated%that%delta-9-THC%and%other%cannabinoidshave%a%stimulatory%effect%on%appetite%and%increase%food%intake.%It%is%believed%that%the%endogenouscannabinoid%system%may%serve%as%a%regulator%of%feeding%behavior.%The%endogenous%cannabinoidanandamide%potently%enhances%appetite%in%mice.[33]%Moreover,%CB1%receptors%in%thehypothalamus%may%be%involved%in%the%motivational%or%reward%aspects%of%eating.[34]

Analgesia

Understanding%the%mechanism%of%cannabinoid-induced%analgesia%has%been%increased%through%thestudy%of%cannabinoid%receptors,%endocannabinoids,%and%synthetic%agonists%and%antagonists.%TheCB1%receptor%is%found%in%both%the%central%nervous%system%(CNS)%and%in%peripheral%nerve%terminals.Similar%to%opioid%receptors,%increased%levels%of%the%CB1%receptor%are%found%in%regions%of%the%brainthat%regulate%nociceptive%processing.[35]%CB2%receptors,%located%predominantly%in%peripheraltissue,%exist%at%very%low%levels%in%the%CNS.%With%the%development%of%receptor-specific%antagonists,additional%information%about%the%roles%of%the%receptors%and%endogenous%cannabinoids%in%themodulation%of%pain%has%been%obtained.[36,37]

Cannabinoids%may%also%contribute%to%pain%modulation%through%an%anti-inflammatory%mechanism;a%CB2%effect%with%cannabinoids%acting%on%mast%cell%receptors%to%attenuate%the%release%ofinflammatory%agents,%such%as%histamine%and%serotonin,%and%on%keratinocytes%to%enhance%therelease%of%analgesic%opioids%has%been%described.[38-40]%One%study%reported%that%the%efficacy%ofsynthetic%CB1-%and%CB2-receptor%agonists%were%comparable%with%the%efficacy%of%morphine%in%amurine%model%of%tumor%pain.[41]

References

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13.% Velasco%G,%Sánchez%C,%Guzmán%M:%Towards%the%use%of%cannabinoids%as%antitumour%agents.%NatRev%Cancer%12%(6):%436-44,%2012.%[PUBMED%Abstract]

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15.% Vara%D,%Salazar%M,%Olea-Herrero%N,%et%al.:%Anti-tumoral%action%of%cannabinoids%onhepatocellular%carcinoma:%role%of%AMPK-dependent%activation%of%autophagy.%Cell%Death%Differ18%(7):%1099-111,%2011.%[PUBMED%Abstract]

16.% Preet%A,%Qamri%Z,%Nasser%MW,%et%al.:%Cannabinoid%receptors,%CB1%and%CB2,%as%novel%targets%forinhibition%of%non-small%cell%lung%cancer%growth%and%metastasis.%Cancer%Prev%Res%(Phila)%4%(1):65-75,%2011.%[PUBMED%Abstract]

17.% Nasser%MW,%Qamri%Z,%Deol%YS,%et%al.:%Crosstalk%between%chemokine%receptor%CXCR4%andcannabinoid%receptor%CB2%in%modulating%breast%cancer%growth%and%invasion.%PLoS%One%6%(9):e23901,%2011.%[PUBMED%Abstract]

18.% Shrivastava%A,%Kuzontkoski%PM,%Groopman%JE,%et%al.:%Cannabidiol%induces%programmed%celldeath%in%breast%cancer%cells%by%coordinating%the%cross-talk%between%apoptosis%and%autophagy.Mol%Cancer%Ther%10%(7):%1161-72,%2011.%[PUBMED%Abstract]

19.% Caffarel%MM,%Andradas%C,%Mira%E,%et%al.:%Cannabinoids%reduce%ErbB2-driven%breast%cancerprogression%through%Akt%inhibition.%Mol%Cancer%9:%196,%2010.%[PUBMED%Abstract]

20.% McAllister%SD,%Murase%R,%Christian%RT,%et%al.:%Pathways%mediating%the%effects%of%cannabidiol%onthe%reduction%of%breast%cancer%cell%proliferation,%invasion,%and%metastasis.%Breast%Cancer%ResTreat%129%(1):%37-47,%2011.%[PUBMED%Abstract]

21.% Aviello%G,%Romano%B,%Borrelli%F,%et%al.:%Chemopreventive%effect%of%the%non-psychotropicphytocannabinoid%cannabidiol%on%experimental%colon%cancer.%J%Mol%Med%(Berl)%90%(8):%925-34,2012.%[PUBMED%Abstract]

22.% Romano%B,%Borrelli%F,%Pagano%E,%et%al.:%Inhibition%of%colon%carcinogenesis%by%a%standardizedCannabis%sativa%extract%with%high%content%of%cannabidiol.%Phytomedicine%21%(5):%631-9,2014.%[PUBMED%Abstract]

23.% Preet%A,%Ganju%RK,%Groopman%JE:%Delta9-Tetrahydrocannabinol%inhibits%epithelial%growthfactor-induced%lung%cancer%cell%migration%in%vitro%as%well%as%its%growth%and%metastasis%in%vivo.Oncogene%27%(3):%339-46,%2008.%[PUBMED%Abstract]

24.% Zhu%LX,%Sharma%S,%Stolina%M,%et%al.:%Delta-9-tetrahydrocannabinol%inhibits%antitumor%immunityby%a%CB2%receptor-mediated,%cytokine-dependent%pathway.%J%Immunol%165%(1):%373-80,2000.%[PUBMED%Abstract]

25.% McKallip%RJ,%Nagarkatti%M,%Nagarkatti%PS:%Delta-9-tetrahydrocannabinol%enhances%breastcancer%growth%and%metastasis%by%suppression%of%the%antitumor%immune%response.%J%Immunol174%(6):%3281-9,%2005.%[PUBMED%Abstract]

26.% Massa%F,%Marsicano%G,%Hermann%H,%et%al.:%The%endogenous%cannabinoid%system%protectsagainst%colonic%inflammation.%J%Clin%Invest%113%(8):%1202-9,%2004.%[PUBMED%Abstract]

27.% Patsos%HA,%Hicks%DJ,%Greenhough%A,%et%al.:%Cannabinoids%and%cancer:%potential%for%colorectalcancer%therapy.%Biochem%Soc%Trans%33%(Pt%4):%712-4,%2005.%[PUBMED%Abstract]

28.% Liu%WM,%Fowler%DW,%Dalgleish%AG:%Cannabis-derived%substances%in%cancer%therapy--anemerging%anti-inflammatory%role%for%the%cannabinoids.%Curr%Clin%Pharmacol%5%(4):%281-7,2010.%[PUBMED%Abstract]

29.% Malfitano%AM,%Ciaglia%E,%Gangemi%G,%et%al.:%Update%on%the%endocannabinoid%system%as%ananticancer%target.%Expert%Opin%Ther%Targets%15%(3):%297-308,%2011.%[PUBMED%Abstract]

30.% Sarfaraz%S,%Adhami%VM,%Syed%DN,%et%al.:%Cannabinoids%for%cancer%treatment:%progress%andpromise.%Cancer%Res%68%(2):%339-42,%2008.%[PUBMED%Abstract]

31.% Nabissi%M,%Morelli%MB,%Santoni%M,%et%al.:%Triggering%of%the%TRPV2%channel%by%cannabidiolsensitizes%glioblastoma%cells%to%cytotoxic%chemotherapeutic%agents.%Carcinogenesis%34%(1):%48-57,%2013.%[PUBMED%Abstract]

32.% Torres%S,%Lorente%M,%Rodríguez-Fornés%F,%et%al.:%A%combined%preclinical%therapy%ofcannabinoids%and%temozolomide%against%glioma.%Mol%Cancer%Ther%10%(1):%90-103,2011.%[PUBMED%Abstract]

33.% Mechoulam%R,%Berry%EM,%Avraham%Y,%et%al.:%Endocannabinoids,%feeding%and%suckling--from%ourperspective.%Int%J%Obes%(Lond)%30%(Suppl%1):%S24-8,%2006.%[PUBMED%Abstract]

34.% Fride%E,%Bregman%T,%Kirkham%TC:%Endocannabinoids%and%food%intake:%newborn%suckling%andappetite%regulation%in%adulthood.%Exp%Biol%Med%(Maywood)%230%(4):%225-34,%2005.%[PUBMEDAbstract]

35.% Walker%JM,%Hohmann%AG,%Martin%WJ,%et%al.:%The%neurobiology%of%cannabinoid%analgesia.%Life%Sci65%(6-7):%665-73,%1999.%[PUBMED%Abstract]

36.% Meng%ID,%Manning%BH,%Martin%WJ,%et%al.:%An%analgesia%circuit%activated%by%cannabinoids.Nature%395%(6700):%381-3,%1998.%[PUBMED%Abstract]

37.% Walker%JM,%Huang%SM,%Strangman%NM,%et%al.:%Pain%modulation%by%release%of%the%endogenouscannabinoid%anandamide.%Proc%Natl%Acad%Sci%U%S%A%96%(21):%12198-203,%1999.%[PUBMEDAbstract]

38.% Facci%L,%Dal%Toso%R,%Romanello%S,%et%al.:%Mast%cells%express%a%peripheral%cannabinoid%receptorwith%differential%sensitivity%to%anandamide%and%palmitoylethanolamide.%Proc%Natl%Acad%Sci%U%SA%92%(8):%3376-80,%1995.%[PUBMED%Abstract]

39.% Ibrahim%MM,%Porreca%F,%Lai%J,%et%al.:%CB2%cannabinoid%receptor%activation%producesantinociception%by%stimulating%peripheral%release%of%endogenous%opioids.%Proc%Natl%Acad%Sci%US%A%102%(8):%3093-8,%2005.%[PUBMED%Abstract]

40.% Richardson%JD,%Kilo%S,%Hargreaves%KM:%Cannabinoids%reduce%hyperalgesia%and%inflammationvia%interaction%with%peripheral%CB1%receptors.%Pain%75%(1):%111-9,%1998.%[PUBMED%Abstract]

41.% Khasabova%IA,%Gielissen%J,%Chandiramani%A,%et%al.:%CB1%and%CB2%receptor%agonists%promoteanalgesia%through%synergy%in%a%murine%model%of%tumor%pain.%Behav%Pharmacol%22%(5-6):%607-16,%2011.%[PUBMED%Abstract]

Human/Clinical Studies

Cannabis Pharmacology

When%Cannabis is%ingested%by%mouth,%there%is%a%low%(6%–20%)%and%variable%oral%bioavailability.[1,2]Peak%plasma%concentrations%of%delta-9-tetrahydrocannabinol%(THC)%occur%after%1%to%6%hours%andremain%elevated%with%a%terminal%half-life%of%20%to%30%hours.%Taken%by%mouth,%delta-9-THC%is%initiallymetabolized%in%the%liver%to%11-OH-THC,%a%potent%psychoactive%metabolite.%When%inhaled,cannabinoids%are%rapidly%absorbed%into%the%bloodstream%with%a%peak%concentration%in%2%to%10minutes,%declining%rapidly%for%a%period%of%30%minutes%and%with%less%generation%of%the%psychoactive11-OH%metabolite.

Cannabinoids%are%known%to%interact%with%the%hepatic%cytochrome%P450%enzyme%system.[3,4]%In%onestudy,%24%cancer%patients%were%treated%with%intravenous%irinotecan%(600%mg,%n%=%12)%or%docetaxel(180%mg,%n%=%12),%followed%3%weeks%later%by%the%same%drugs%concomitant%with%medicinal%Cannabistaken%in%the%form%of%an%herbal%tea%for%15%consecutive%days,%starting%12%days%before%the%secondtreatment.[4]%The%administration%of%Cannabis%did%not%significantly%influence%exposure%to%andclearance%of%irinotecan%or%docetaxel,%although%the%herbal%tea%route%of%administration%may%notreproduce%the%effects%of%inhalation%or%oral%ingestion%of%fat-soluble%cannabinoids.

Cancer Risk

A%number%of%studies%have%yielded%conflicting%evidence%regarding%the%risks%of%various%cancersassociated%with%Cannabis%use.

A%pooled%analysis%of%three%case-cohort%studies%of%men%in%northwestern%Africa%(430%cases%and%778controls)%showed%a%significantly%increased%risk%of%lung%cancer%among%tobacco%smokers%who%alsoinhaled%Cannabis.[5]

A%large,%retrospective%cohort%study%of%64,855%men%aged%15%to%49%years%from%the%United%Statesfound%that%Cannabis%use%was%not%associated%with%tobacco-related%cancers%and%a%number%of%othercommon%malignancies.%However,%the%study%did%find%that,%among%nonsmokers%of%tobacco,%everhaving%used%Cannabis%was%associated%with%an%increased%risk%of%prostate%cancer.[6]

A%population-based%case-control%study%of%611%lung%cancer%patients%revealed%that%chronic%lowCannabis%exposure%was%not%associated%with%an%increased%risk%of%lung%cancer%or%other%upperaerodigestive%tract%cancers%and%found%no%positive%associations%with%any%cancer%type%(oral,pharyngeal,%laryngeal,%lung,%or%esophagus)%when%adjusting%for%several%confounders,%includingcigarette%smoking.[7]

A%systematic%review%assessing%19%studies%that%evaluated%premalignant%or%malignant%lung%lesions%inpersons%18%years%or%older%who%inhaled%marijuana%concluded%that%observational%studies%failed%todemonstrate%statistically%significant%associations%between%marijuana%inhalation%and%lung%cancerafter%adjusting%for%tobacco%use.[8]

Epidemiologic%studies%examining%one%association%of%Cannabis%use%with%head%and%neck%squamouscell%carcinomas%have%also%been%inconsistent%in%their%findings.%A%pooled%analysis%of%nine%case-control%studies%from%the%U.S./Latin%American%International%Head%and%Neck%Cancer%Epidemiology(INHANCE)%Consortium%included%information%from%1,921%oropharyngeal%cases,%356%tongue%cases,and%7,639%controls.%Compared%with%those%who%never%smoked%Cannabis,%Cannabis%smokers%had%anelevated%risk%of%oropharyngeal%cancers%and%a%reduced%risk%of%tongue%cancer.%These%study%resultsboth%reflect%the%inconsistent%effects%of%cannabinoids%on%cancer%incidence%noted%in%previousstudies%and%suggest%that%more%work%needs%to%be%done%to%understand%the%potential%role%of%humanpapillomavirus%infection.[9]

With%a%hypothesis%that%chronic%marijuana%use%produces%adverse%effects%on%the%human%endocrineand%reproductive%systems,%the%association%between%marijuana%use%and%incidence%of%testiculargerm%cell%tumors%(TGCTs)%has%been%examined.[10-12]%Three%population-based%case-controlstudies%report%an%association%between%marijuana%use%and%elevated%risk%of%TGCTs,%especiallynonseminoma%or%mixed-histology%tumors.[10-12]%However,%the%sample%sizes%in%these%studies%wereinadequate%to%address%marijuana%dose%by%addressing%associations%with%respect%to%recency,frequency,%and%duration%of%use.%These%early%reports%of%marijuana%use%and%TGCTs%establish%theneed%for%larger,%well-powered,%prospective%studies,%especially%studies%evaluating%the%role%ofendocannabinoid%signaling%and%cannabinoid%receptors%in%TGCTs.

An%analysis%of%84,170%participants%in%the%California%Men’s%Health%Study%was%performed%toinvestigate%the%association%between%Cannabis%use%and%the%incidence%of%bladder%cancer.%During%16years%of%follow-up,%89%Cannabis%users%(0.3%)%developed%bladder%cancer%compared%with%190%(0.4%)of%the%men%who%did%not%report%Cannabis%use%(P%<%.001).%After%adjusting%for%age,%race,%ethnicity,%andbody%mass%index,%Cannabis%use%was%associated%with%a%45%%reduction%in%bladder%cancer%incidence(hazard%ratio,%0.55;%95%%confidence%interval,%0.33–1.00).[13]

A%comprehensive%Health%Canada%monograph%on%marijuana%concluded%that%while%there%are%manycellular%and%molecular%studies%that%provide%strong%evidence%that%inhaled%marijuana%iscarcinogenic,%the%epidemiologic%evidence%of%a%link%between%marijuana%use%and%cancer%is%stillinconclusive.[14]

Cancer Treatment

No%clinical%trials%of%Cannabis%as%a%treatment%for%cancer%in%humans%were%identified%in%a%PubMed

search;%however,%a%single,%small%study%of%intratumoral%injection%of%delta-9-THC%in%patients%withrecurrent%glioblastoma%multiforme%reported%potential%antitumoral%activity.[15,16]

Antiemetic Effect

Cannabinoids

Despite%advances%in%pharmacologic%and%nonpharmacologic%management,%nausea%and%vomiting(N/V)%remain%distressing%side%effects%for%cancer%patients%and%their%families.%Dronabinol,%asynthetically%produced%delta-9-THC,%was%approved%in%the%United%States%in%1986%as%an%antiemetic%tobe%used%in%cancer%chemotherapy.%Nabilone,%a%synthetic%derivative%of%delta-9-THC,%was%firstapproved%in%Canada%in%1982%and%is%now%also%available%in%the%United%States.[17]%Both%dronabinoland%nabilone%have%been%approved%by%the%U.S.%Food%and%Drug%Administration%for%the%treatment%ofN/V%associated%with%cancer%chemotherapy%in%patients%who%have%failed%to%respond%to%conventionalantiemetic%therapy.%Numerous%clinical%trials%and%meta-analyses%have%shown%that%dronabinol%andnabilone%are%effective%in%the%treatment%of%N/V%induced%by%chemotherapy.[18-21]%The%NationalComprehensive%Cancer%Network%Guidelines %recommend%cannabinoids%as%breakthroughtreatment%for%chemotherapy-related%N/V.

One%systematic%review%studied%30%randomized%comparisons%of%delta-9-THC%preparations%withplacebo%or%other%antiemetics%from%which%data%on%efficacy%and%harm%were%available.[22]%Oralnabilone,%oral%dronabinol,%and%intramuscular%levonantradol%(a%synthetic%analog%of%dronabinol)were%tested.%Inhaled%Cannabis%trials%were%not%included.%Among%all%1,366%patients%included%in%thereview,%cannabinoids%were%found%to%be%more%effective%than%the%conventional%antiemeticsprochlorperazine,%metoclopramide,%chlorpromazine,%thiethylperazine,%haloperidol,%domperidone,and%alizapride.%Cannabinoids,%however,%were%not%more%effective%for%patients%receiving%very%low%orvery%high%emetogenic%chemotherapy.%Side%effects%included%a%feeling%of%being%high,%euphoria,sedation%or%drowsiness,%dizziness,%dysphoria%or%depression,%hallucinations,%paranoia,%andhypotension.[22]%Newer%antiemetics%(e.g.,%5-HT3%receptor%antagonists)%have%not%been%directlycompared%with%Cannabis%or%cannabinoids%in%cancer%patients.

Another%analysis%of%15%controlled%studies%compared%nabilone%with%placebo%or%available%antiemeticdrugs.[23]%Among%600%cancer%patients,%nabilone%was%found%to%be%superior%to%prochlorperazine,domperidone,%and%alizapride,%with%nabilone%favored%for%continuous%use.

(Refer%to%the%Cannabis%section%in%the%PDQ%summary%on%Nausea%and%Vomiting%for%moreinformation.)

Cannabis

https://subscriptions.nccn.org/login.aspx?ReturnURL=http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf

http://www.cancer.gov/about-cancer/treatment/side-effects/nausea/nausea-hp-pdq

Three%trials%have%evaluated%the%efficacy%of%inhaled%marijuana%in%chemotherapy-induced%N/V.[24-26]%In%two%of%the%studies,%inhaled%Cannabis%was%made%available%only%after%dronabinol%failure.%In%thefirst%trial,%no%antiemetic%effect%was%achieved%with%marijuana%in%patients%receivingcyclophosphamide%or%doxorubicin,[24]%but%in%the%second%trial,%a%statistically%significant%superiorantiemetic%effect%of%inhaled%Cannabis%versus%placebo%was%found%among%patients%receiving%high-dose%methotrexate.[25]%The%third%trial%was%a%randomized,%double-blind,%placebo-controlled,%cross-over%trial%involving%20%adults%in%which%both%inhaled%marijuana%and%oral%THC%were%evaluated.%One-quarter%of%the%patients%reported%a%favorable%antiemetic%response%to%the%cannabinoid%therapies.This%latter%study%was%reported%in%abstract%form%in%1984.%A%full%report,%detailing%the%methods%andoutcomes%apparently%has%not%been%published,%which%limits%a%thorough%interpretation%of%thesignificance%of%these%findings.[26]

Appetite Stimulation

Anorexia,%early%satiety,%weight%loss,%and%cachexia%are%problems%experienced%by%cancer%patients.Such%patients%are%faced%not%only%with%the%disfigurement%associated%with%wasting%but%also%with%aninability%to%engage%in%the%social%interaction%of%meals.

Cannabinoids

Three%controlled%trials%demonstrated%that%oral%THC%has%variable%effects%on%appetite%stimulationand%weight%loss%in%patients%with%advanced%malignancies%and%human%immunodeficiency%virus%(HIV)infection.[23]%One%study%evaluated%whether%dronabinol%alone%or%with%megestrol%acetate%wasgreater,%less,%or%equal%in%efficacy%to%megestrol%acetate%alone%for%managing%cancer-associatedanorexia.[27]%In%this%randomized,%double-blind%study%of%469%adults%with%advanced%cancer%andweight%loss,%patients%received%2.5%mg%of%oral%THC%twice%daily,%800%mg%of%oral%megestrol%daily,%orboth.%Appetite%increased%by%75%%in%the%megestrol%group%and%weight%increased%by%11%,%comparedwith%a%49%%increase%in%appetite%and%a%3%%increase%in%weight%in%the%oral%THC%group%after%8%to%11weeks%of%treatment.%These%two%differences%were%statistically%significant.%Furthermore,%thecombined%therapy%did%not%offer%additional%benefits%beyond%those%provided%by%megestrol%acetatealone.%The%authors%concluded%that%dronabinol%did%little%to%promote%appetite%or%weight%gain%inadvanced%cancer%patients%compared%with%megestrol%acetate.%However,%a%smaller,%placebo-controlled%trial%of%dronabinol%in%cancer%patients%demonstrated%improved%and%enhancedchemosensory%perception%in%the%cannabinoid%group—food%tasted%better,%appetite%increased,%andthe%proportion%of%calories%consumed%as%protein%was%greater%than%in%the%placebo%recipients.[28]

In%a%randomized%clinical%trial,%researchers%compared%the%safety%and%effectiveness%of%orallyadministered%Cannabis%extract%(2.5%mg%THC%and%1%mg%cannabidinol),%THC%(2.5%mg),%or%placebo%forthe%treatment%of%cancer-related%anorexia-cachexia%in%243%patients%with%advanced%cancer%who

received%treatment%twice%daily%for%6%weeks.%Results%demonstrated%that%although%these%agentswere%well%tolerated%by%these%patients,%no%differences%were%observed%in%patient%appetite%or%qualityof%life%among%the%three%groups%at%this%dose%level%and%duration%of%intervention.[29]

Another%clinical%trial%that%involved%139%patients%with%HIV%or%AIDS%and%weight%loss%found%that,compared%with%placebo,%oral%dronabinol%was%associated%with%a%statistically%significant%increase%inappetite%after%4%to%6%weeks%of%treatment.%Patients%receiving%dronabinol%tended%to%have%weightstabilization,%whereas%patients%receiving%placebo%continued%to%lose%weight.[30]

Cannabis

In%trials%conducted%in%the%1980s%that%involved%healthy%control%subjects,%inhaling%Cannabis%led%to%anincrease%in%caloric%intake,%mainly%in%the%form%of%between-meal%snacks,%with%increased%intakes%offatty%and%sweet%foods.[31,32]%No%published%studies%have%explored%the%effect%of%inhaled%Cannabison%appetite%in%cancer%patients.

Analgesia

Cannabinoids

Pain%management%improves%a%patient’s%quality%of%life%throughout%all%stages%of%cancer.%Throughthe%study%of%cannabinoid%receptors,%endocannabinoids,%and%synthetic%agonists%and%antagonists,the%mechanisms%of%cannabinoid-induced%analgesia%have%been%analyzed.%The%CB1%receptor%isfound%in%the%central%nervous%system%(CNS)%and%in%peripheral%nerve%terminals.[33]%CB2%receptorsare%located%mainly%in%peripheral%tissue%and%are%expressed%in%only%low%amounts%in%the%CNS.Whereas%only%CB1%agonists%exert%analgesic%activity%in%the%CNS,%both%CB1%and%CB2%agonists%haveanalgesic%activity%in%peripheral%tissue.[34,35]

Cancer%pain%results%from%inflammation,%invasion%of%bone%or%other%pain-sensitive%structures,%ornerve%injury.%When%cancer%pain%is%severe%and%persistent,%it%is%often%resistant%to%treatment%withopioids.

Two%studies%examined%the%effects%of%oral%delta-9-THC%on%cancer%pain.%The%first,%a%double-blindplacebo-controlled%study%involving%ten%patients,%measured%both%pain%intensity%and%pain%relief.[36]It%was%reported%that%15%mg%and%20%mg%doses%of%the%cannabinoid%delta-9-THC%were%associated%withsubstantial%analgesic%effects,%with%antiemetic%effects%and%appetite%stimulation.

In%a%follow-up,%single-dose%study%involving%36%patients,%it%was%reported%that%10%mg%doses%of%delta-9-THC%produced%analgesic%effects%during%a%7-hour%observation%period%that%were%comparable%to%60mg%doses%of%codeine,%and%20%mg%doses%of%delta-9-THC%induced%effects%equivalent%to%120%mg%dosesof%codeine.[37]%Higher%doses%of%THC%were%found%to%be%more%sedative%than%codeine.

Another%study%examined%the%effects%of%a%whole-plant%extract%with%controlled%cannabinoid%contentin%an%oromucosal%spray.%In%a%multicenter,%double-blind,%placebo-controlled%study,%theTHC:cannabidiol%nabiximols%(THC:CBD)%extract%and%THC%extract%alone%were%compared%in%theanalgesic%management%of%patients%with%advanced%cancer%and%with%moderate-to-severe%cancer-related%pain.%Patients%were%assigned%to%one%of%three%treatment%groups:%THC:CBD%extract,%THCextract,%or%placebo.%The%researchers%concluded%that%the%THC:CBD%extract%was%efficacious%for%painrelief%in%advanced%cancer%patients%whose%pain%was%not%fully%relieved%by%strong%opioids.[38]%In%arandomized,%placebo-controlled,%graded-dose%trial,%opioid-treated%cancer%patients%with%poorlycontrolled%chronic%pain%demonstrated%significantly%better%control%of%pain%and%sleep%disruptionwith%THC:CBD%oromucosal%spray%at%lower%doses%(1–4%and%6–10%sprays/day),%compared%withplacebo.%Adverse%events%were%dose%related,%with%only%the%high-dose%group%(11–16%sprays/day)comparing%unfavorably%with%the%placebo%arm.%These%studies%provide%promising%evidence%of%an“adjuvant%analgesic”%effect%of%THC:CBD%in%this%opioid-refractory%patient%population%and%mayprovide%an%opportunity%to%address%this%significant%clinical%challenge.[39]%An%open-label%extensionstudy%of%43%patients%who%had%participated%in%the%randomized%trial%found%that%some%patientscontinued%to%obtain%relief%of%their%cancer-related%pain%with%long-term%use%of%the%THC:CBDoromucosal%spray%without%increasing%their%dose%of%the%spray%or%the%dose%of%their%other%analgesics.[40]

A%randomized,%placebo-controlled,%crossover%pilot%study%of%nabiximols%in%16%patients%withchemotherapy-induced%neuropathic%pain%showed%no%significant%difference%between%the%treatmentand%placebo%groups.%A%responder%analysis,%however,%demonstrated%that%five%patients%reported%areduction%in%their%pain%of%at%least%2%points,%suggesting%that%a%larger%follow-up%study%may%bewarranted.[41]

An%observational%study%assessed%the%effectiveness%of%nabilone%in%advanced%cancer%patients%whowere%experiencing%pain%and%other%symptoms%(anorexia,%depression,%and%anxiety).%The%researchersreported%that%patients%who%used%nabilone%experienced%improved%management%of%pain,%nausea,anxiety,%and%distress%when%compared%with%untreated%patients.%Nabilone%was%also%associated%witha%decreased%use%of%opioids,%nonsteroidal%anti-inflammatory%drugs,%tricyclic%antidepressants,gabapentin,%dexamethasone,%metoclopramide,%and%ondansetron.[42]

Cannabis

Animal%studies%have%suggested%a%synergistic%analgesic%effect%when%cannabinoids%are%combinedwith%opioids.%The%results%from%one%pharmacokinetic%interaction%study%have%been%reported.%In%thisstudy,%21%patients%with%chronic%pain%were%administered%vaporized%Cannabis%along%with%sustained-release%morphine%or%oxycodone%for%5%days.[43]%The%patients%who%received%vaporized%Cannabis%andsustained-release%morphine%had%a%statistically%significant%decrease%in%their%mean%pain%score%over

the%5-day%period;%those%who%received%vaporized%Cannabis%and%oxycodone%did%not.%These%findingsshould%be%verified%by%further%studies%before%recommendations%favoring%such%an%approach%arewarranted%in%general%clinical%practice.

Neuropathic%pain%is%a%symptom%cancer%patients%may%experience,%especially%if%treated%withplatinum-based%chemotherapy%or%taxanes.%To%date,%no%clinical%trial%has%examined%the%effectivenessof%cannabinoid%preparations%in%the%treatment%of%chemotherapy-induced%neuropathic%pain.

Two%randomized%controlled%trials%of%inhaled%Cannabis%in%patients%with%peripheral%neuropathy%orneuropathic%pain%of%various%etiologies%found%that%pain%was%reduced%in%patients%who%receivedinhaled%Cannabis,%compared%with%those%who%received%placebo.[44,45]%Two%additional%trials%ofinhaled%Cannabis%have%also%demonstrated%the%benefit%of%Cannabis%over%placebo%in%HIV-associatedneuropathic%pain.[46,47]

Anxiety and Sleep

Cannabis

Patients%often%experience%mood%elevation%after%exposure%to%Cannabis,%depending%on%their%priorexperience.%In%a%five-patient%case%series%of%inhaled%marijuana%that%examined%the%analgesic%effectsof%THC,%it%was%reported%that%patients%administered%THC%had%improved%mood,%improved%sense%ofwell-being,%and%less%anxiety.[48]

Another%common%effect%of%Cannabis%is%sleepiness.%In%a%trial%of%a%sublingual%spray,%a%Cannabis-based%mixture%was%able%to%improve%sleep%quality.[49]%A%small%placebo-controlled%study%ofdronabinol%in%cancer%patients%with%altered%chemosensory%perception%also%noted%increased%qualityof%sleep%and%relaxation%in%THC-treated%patients.[28]

Check%NCI’s%list%of%cancer%clinical%trials%for%cancer%CAM%clinical%trials%on%dronabinol,%marijuana,nabiximols,%nabilone%and%cannabidiol%that%are%actively%enrolling%patients.

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Adverse Effects

Cannabis and Cannabinoids

Because%cannabinoid%receptors,%unlike%opioid%receptors,%are%not%located%in%the%brainstem%areascontrolling%respiration,%lethal%overdoses%from%Cannabis and%cannabinoids%do%not%occur.[1-4]However,%cannabinoid%receptors%are%present%in%other%tissues%throughout%the%body,%not%just%in%thecentral%nervous%system,%and%adverse%effects%include%tachycardia,%hypotension,%conjunctivalinjection,%bronchodilation,%muscle%relaxation,%and%decreased%gastrointestinal%motility.

Although%cannabinoids%are%considered%by%some%to%be%addictive%drugs,%their%addictive%potential%isconsiderably%lower%than%that%of%other%prescribed%agents%or%substances%of%abuse.[2,4]%The%braindevelops%a%tolerance%to%cannabinoids.

Withdrawal%symptoms%such%as%irritability,%insomnia%with%sleep%electroencephalogram%disturbance,restlessness,%hot%flashes,%and,%rarely,%nausea%and%cramping%have%been%observed.%However,%thesesymptoms%appear%to%be%mild%compared%with%withdrawal%symptoms%associated%with%opiates%orbenzodiazepines,%and%the%symptoms%usually%dissipate%after%a%few%days.

Unlike%other%commonly%used%drugs,%cannabinoids%are%stored%in%adipose%tissue%and%excreted%at%alow%rate%(half-life%1–3%days),%so%even%abrupt%cessation%of%cannabinoid%intake%is%not%associated%withrapid%declines%in%plasma%concentrations%that%would%precipitate%severe%or%abrupt%withdrawalsymptoms%or%drug%cravings.

Since%Cannabis%smoke%contains%many%of%the%same%components%as%tobacco%smoke,%there%are%validconcerns%about%the%adverse%pulmonary%effects%of%inhaled%Cannabis.%A%longitudinal%study%in%anoncancer%population%evaluated%repeated%measurements%of%pulmonary%function%over%20%years%in5,115%men%and%women%whose%smoking%histories%were%known.[5]%While%tobacco%exposure%wasassociated%with%decreased%pulmonary%function,%the%investigators%concluded%that%occasional%andlow-cumulative%Cannabis%use%was%not%associated%with%adverse%effects%on%pulmonary%function(forced%expiratory%volume%in%the%first%second%of%expiration%[FEV1]%and%forced%vital%capacity%[FVC]).

References

2.% Grotenhermen%F,%Russo%E,%eds.:%Cannabis%and%Cannabinoids:%Pharmacology,%Toxicology,%andTherapeutic%Potential.%Binghamton,%NY:%The%Haworth%Press,%2002.

3.% Sutton%IR,%Daeninck%P:%Cannabinoids%in%the%management%of%intractable%chemotherapy-induced%nausea%and%vomiting%and%cancer-related%pain.%J%Support%Oncol%4%(10):%531-5,%2006Nov-Dec.%[PUBMED%Abstract]

4.% Guzmán%M:%Cannabinoids:%potential%anticancer%agents.%Nat%Rev%Cancer%3%(10):%745-55,2003.%[PUBMED%Abstract]

5.% Pletcher%MJ,%Vittinghoff%E,%Kalhan%R,%et%al.:%Association%between%marijuana%exposure%andpulmonary%function%over%20%years.%JAMA%307%(2):%173-81,%2012.%[PUBMED%Abstract]

Summary of the Evidence for Cannabis andCannabinoidsTo%assist%readers%in%evaluating%the%results%of%human%studies%of%complementary%and%alternativemedicine%(CAM)%treatments%for%people%with%cancer,%the%strength%of%the%evidence%(i.e.,%the%levels%ofevidence)%associated%with%each%type%of%treatment%is%provided%whenever%possible.%To%qualify%for%alevel%of%evidence%analysis,%a%study%must:

Be%published%in%a%peer-reviewed%scientific%journal.

Report%on%therapeutic%outcome%or%outcomes,%such%as%tumor%response,%improvement%insurvival,%or%measured%improvement%in%quality%of%life.

Describe%clinical%findings%in%sufficient%detail%for%a%meaningful%evaluation%to%be%made.

Separate%levels%of%evidence%scores%are%assigned%to%qualifying%human%studies%on%the%basis%ofstatistical%strength%of%the%study%design%and%scientific%strength%of%the%treatment%outcomes%(i.e.,endpoints)%measured.%The%resulting%two%scores%are%then%combined%to%produce%an%overall%score.An%overall%level%of%evidence%score%cannot%be%assigned%to%cannabinoids%because%there%has%beeninsufficient%clinical%research%to%date.%For%an%explanation%of%possible%scores%and%additionalinformation%about%levels%of%evidence%analysis%of%CAM%treatments%for%people%with%cancer,%refer%toLevels%of%Evidence%for%Human%Studies%of%Cancer%Complementary%and%Alternative%Medicine.

Cannabinoids

Several%controlled%clinical%trials%have%been%performed,%and%meta-analyses%of%these%support%abeneficial%effect%of%cannabinoids%(dronabinol%and%nabilone)%on%chemotherapy%-inducednausea%and%vomiting%(N/V)%compared%with%placebo.%Both%dronabinol%and%nabilone%areapproved%by%the%U.S.%Food%and%Drug%Administration%for%the%prevention%or%treatment%ofchemotherapy-induced%N/V%in%cancer%patients%but%not%for%other%symptom%management%oroff-label%use.

Cannabis

There%have%been%only%three%small%clinical%trials%on%the%use%of%Cannabis%in%cancer%patients.%Allthree%studies%assessed%antiemetic%activity%but%each%explored%a%different%patient%populationand%chemotherapy%regimen.%One%study%demonstrated%no%effect,%the%second%study%showed%apositive%effect%versus%placebo,%and%the%report%of%the%third%study%did%not%provide%enough

•

information%to%characterize%the%overall%outcome%as%positive%or%neutral.%Consequently,%thereare%insufficient%data%to%provide%an%overall%level%of%evidence%assessment%for%the%use%ofCannabis%for%chemotherapy-induced%N/V.%Apparently,%there%are%no%published%data%on%the%useof%Cannabis%for%other%cancer-related%or%cancer%treatment–related%symptoms.

An%increasing%number%of%trials%are%evaluating%the%oromucosal%administration%of%wholeCannabis%plant%extract%with%fixed%concentrations%of%cannabinoid%components.

At%present,%there%is%insufficient%evidence%to%recommend%inhaling%Cannabis%as%a%treatment%forcancer-related%symptoms%or%cancer%treatment–related%side%effects.

Human/Clinical+Studies

Added%text%about%an%analysis%of%84,170%participants%in%the%California%Men's%Health%Study%thatinvestigated%the%association%between%Cannabis%use%and%the%incidence%of%bladder%cancer;%afteradjusting%for%age,%race,%ethnicity,%and%body%mass%index,%Cannabis%use%was%associated%with%a%45%reduction%in%bladder%cancer%incidence%(cited%Thomas%et%al.%as%reference%13).

This%summary%is%written%and%maintained%by%the%PDQ%Cancer%Complementary%and%AlternativeMedicine%Editorial%Board,%which%is%editorially%independent%of%NCI.%The%summary%reflects%anindependent%review%of%the%literature%and%does%not%represent%a%policy%statement%of%NCI%or%NIH.More%information%about%summary%policies%and%the%role%of%the%PDQ%Editorial%Boards%in%maintainingthe%PDQ%summaries%can%be%found%on%the%About%This%PDQ%Summary%and%PDQ%NCI'sComprehensive%Cancer%Database%pages.

This%PDQ%cancer%information%summary%for%health%professionals%provides%comprehensive,%peer-reviewed,%evidence-based%information%about%the%use%of%Cannabis%and%cannabinoids%in%thetreatment%of%people%with%cancer.%It%is%intended%as%a%resource%to%inform%and%assist%clinicians%whocare%for%cancer%patients.%It%does%not%provide%formal%guidelines%or%recommendations%for%makinghealth%care%decisions.

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http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq/#link/_9

http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq/#link/_226

http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq/#link/_AboutThis_1

The%lead%reviewers%for%Cannabis%and%Cannabinoids%are:

Donald%I.%Abrams,%MD%(UCSF%Osher%Center%for%Integrative%Medicine)

Nagi%B.%Kumar,%PhD,%RD,%FADA%(Fellow%of%the%American%Dietetic%Association)

Levels of Evidence

Some%of%the%reference%citations%in%this%summary%are%accompanied%by%a%level-of-evidencedesignation.%These%designations%are%intended%to%help%readers%assess%the%strength%of%the%evidencesupporting%the%use%of%specific%interventions%or%approaches.%The%PDQ%Cancer%Complementary%andAlternative%Medicine%Editorial%Board%uses%a%formal%evidence%ranking%system%in%developing%itslevel-of-evidence%designations.

PDQ%is%a%registered%trademark.%Although%the%content%of%PDQ%documents%can%be%used%freely%astext,%it%cannot%be%identified%as%an%NCI%PDQ%cancer%information%summary%unless%it%is%presented%in

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its%entirety%and%is%regularly%updated.%However,%an%author%would%be%permitted%to%write%a%sentencesuch%as%“NCI’s%PDQ%cancer%information%summary%about%breast%cancer%prevention%states%the%riskssuccinctly:%[include%excerpt%from%the%summary].”

National%Cancer%Institute:%PDQ®%Cannabis%and%Cannabinoids.%Bethesda,%MD:%National%CancerInstitute.%Date%last%modified%<MM/DD/YYYY>.%Available%at:%http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq.%Accessed%<MM/DD/YYYY>.

Disclaimer

Contact Us

Updated:%July%16,%2015

http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq

7/24/15, 12:10Cartilage (Bovine and Shark) - National Cancer Institute

Page 1 of 31http://www.cancer.gov/about-cancer/treatment/cam/hp/cartilage-pdq#section/all

Cartilage (Bovine and Shark)–for healthprofessionals (PDQ®)

OverviewNOTE:&The&information&in&this&summary&is&no&longer&being&updated&and&is&provided&forreference&purposes&only.

This%complementary%and%alternative%medicine%(CAM)%information%summary%provides%an%overview

of%the%use%of%cartilage%as%a%treatment%for%people%with%cancer.%The%summary%includes%a%brief

history%of%cartilage%research,%the%results%of%clinical%studies,%and%possible%side%effects%of%cartilage

use.

Bovine%(cow)%cartilage%and%shark%cartilage%have%been%studied%as%treatments%for%people%with

cancer%and%other%medical%conditions%for%more%than%30%years.

Numerous%cartilage%products%are%sold%commercially%in%the%United%States%as%dietary

supplements.

Three%principal%mechanisms%of%action%have%been%proposed%to%explain%the%antitumor%potential

of%cartilage:%(1)%it%kills%cancer%cells%directly;%(2)%it%stimulates%the%immune%system;%and%(3)%it

blocks%the%formation%of%new%blood%vessels%(angiogenesis),%which%tumors%need%for

unrestricted%growth.

At%least%three%different%inhibitors%of%angiogenesis%have%been%identified%in%bovine%cartilage,

and%two%angiogenesis%inhibitors%have%been%purified%from%shark%cartilage.

Few%human%studies%of%cartilage%as%a%treatment%for%people%with%cancer%have%been%reported%to

date,%and%the%results%are%inconclusive.

Additional%clinical%trials%of%cartilage%as%a%treatment%for%people%with%cancer%are%now%being

conducted.

Many%of%the%medical%and%scientific%terms%used%in%this%summary%are%hypertext%linked%(at%first%use%in

each%section)%to%the%NCI%Dictionary%of%Cancer%Terms,%which%is%oriented%toward%nonexperts.%When

a%linked%term%is%clicked,%a%definition%will%appear%in%a%separate%window.

•

http://cancer.gov/dictionary/

Reference%citations%in%some%PDQ%CAM%information%summaries%may%include%links%to%external%Web

sites%that%are%operated%by%individuals%or%organizations%for%the%purpose%of%marketing%or%advocating

the%use%of%specific%treatments%or%products.%These%reference%citations%are%included%for

informational%purposes%only.%Their%inclusion%should%not%be%viewed%as%an%endorsement%of%the

content%of%the%Web%sites,%or%of%any%treatment%or%product,%by%the%PDQ%Cancer%CAM%Editorial%Board

or%the%National%Cancer%Institute.

General InformationBovine%(cow)%cartilage%and%shark%cartilage%have%been%investigated%as%treatments%for%people%with

cancer,%psoriasis,%arthritis,%and%a%number%of%other%medical%conditions%for%more%than%30%years.[1-

19]%At%least%some%of%the%interest%in%cartilage%as%a%treatment%for%people%with%cancer%arose%from%the

mistaken%belief%that%sharks,%whose%skeletons%are%made%primarily%of%cartilage,%are%not%affected%by

this%disease.[16,20,21]%Although%reports%of%malignant%tumors%in%sharks%are%rare,%a%variety%of

cancers%have%been%detected%in%these%animals.[20-23]%Nonetheless,%several%substances%that%have

antitumor%activity%have%been%identified%in%cartilage.[2-4,7,15-19,24-49]%More%than%half%a%dozen

clinical%studies%of%cartilage%as%a%treatment%for%people%with%cancer%have%already%been%conducted.[2-

4,6-9,15-18,49,50]%Additional%clinical%studies,%MDA-ID-99303%and%AETERNA-AE-MM-00-02%have%been

completed.[6,15,50]

The%absence%of%blood%vessels%in%cartilage%led%to%the%hypothesis%that%cartilage%cells%(also%known%as

chondrocytes)%produce%one%or%more%substances%that%inhibit%blood%vessel%formation.[27-

30,35,36,48]%The%formation%of%new%blood%vessels%or%angiogenesis%is%necessary%for%tumors%to%grow

larger%than%a%few%millimeters%in%diameter%(i.e.,%larger%than%approximately%100,000%to%1,000,000

cells)%because%tumors,%like%normal%tissues,%must%obtain%most%of%their%oxygen%and%nutrients%from

blood.[33,34,41,51-54]%A%developing%tumor,%therefore,%cannot%continue%to%grow%unless%it

establishes%connections%to%the%circulatory%system%of%its%host.%It%has%been%reported%that%tumors%can

initiate%the%process%of%angiogenesis%when%they%contain%as%few%as%100%cells.[53]%Inhibition%of

angiogenesis%at%this%early%stage%may,%in%some%instances,%lead%to%complete%tumor%regression.[53]

The%possibility%that%cartilage%could%be%a%source%of%one%or%more%types%of%angiogenesis%inhibitors%for

the%treatment%of%cancer%has%prompted%much%research.

The%major%structural%components%of%cartilage%include%several%types%of%the%protein%collagen%and

several%types%of%glycosaminoglycans,%which%are%polysaccharides.[19,29,30,39,48,54,55]%Chondroitin

sulfate%is%the%major%glycosaminoglycan%in%cartilage.[39,54]%Although%there%is%no%evidence%that%the

collagens%in%cartilage,%or%their%breakdown%products,%can%inhibit%angiogenesis,%there%is%evidence

that%shark%cartilage%contains%at%least%one%angiogenesis%inhibitor%that%has%a%glycosaminoglycan

component%(refer%to%the%Laboratory/Animal/Preclinical%Studies%section%of%this%summary%for%more

http://www.cancer.gov/about-cancer/treatment/cam/hp/cartilage-pdq#cit/section_2.1

http://www.cancer.gov/clinicaltrials/NCT00005838

http://www.cancer.gov/about-cancer/treatment/cam/hp/cartilage-pdq/#link/_23

information).[46]%Other%data%indicate%that%most%of%the%antiangiogenic%activity%in%cartilage%is%not

associated%with%the%major%structural%components.[26,30,48]

Some%glycosaminoglycans%in%cartilage%reportedly%have%anti-inflammatory%and%immune-system%-

stimulating%properties,[1,2,14,16,56,57]%and%it%has%been%suggested%that%either%they%or%some%of

their%breakdown%products%are%toxic%to%tumor%cells.[2,3,24]%Thus,%the%antitumor%potential%of

cartilage%may%involve%more%than%one%mechanism%of%action.

Cartilage%products%are%sold%commercially%in%the%United%States%as%dietary%supplements.%More%than

40%different%brand%names%of%shark%cartilage%alone%are%available%to%consumers.[17]%In%the%United

States,%dietary%supplements%are%regulated%as%foods,%not%drugs.%Therefore,%premarket%evaluation

and%approval%by%the%U.S.%Food%and%Drug%Administration%(FDA)%are%not%required%unless%specific

disease%prevention%or%treatment%claims%are%made.%Because%manufacturers%of%cartilage%products

are%not%required%to%show%evidence%of%anticancer%or%other%biologic%effects,%it%is%unclear%whether%any

of%these%products%have%therapeutic%potential.%In%addition,%individual%products%may%vary

considerably%from%lot%to%lot%because%standard%manufacturing%processes%do%not%exist,%and%binding

agents%and%fillers%may%be%added%during%production.[17]%The%FDA%has%not%approved%the%use%of

cartilage%as%a%treatment%for%people%with%cancer%or%any%other%medical%condition.%The%FDA%is

notifying%consumers%of%a%refund%program%for%purchasers%of%Lane%Labs-USA,%Inc.'s%shark%cartilage

product,%BeneFin.%Consumers%are%eligible%for%a%partial%refund%of%the%purchase%price%and%any

shipping%and%handling%costs%if%this%product%was%purchased%between%September%22,%1999%and%July

12,%2004.

To%conduct%clinical%drug%research%in%the%United%States,%researchers%must%file%an%Investigational

New%Drug%(IND)%application%with%the%FDA.%To%date,%IND%status%has%been%granted%to%at%least%four

groups%of%investigators,%one%of%which%was%the%MDA-ID-99303%trial,%that%is%now%closed,%to%study

cartilage%as%a%treatment%for%people%with%cancer.[7,18,58]%Because%the%IND%application%process%is

confidential%and%because%the%existence%of%an%IND%can%be%disclosed%only%by%the%applicants,%it%is%not

known%whether%other%applications%have%been%made.

In%animal%studies,%cartilage%products%have%been%administered%in%a%variety%of%ways.%In%some

studies,%oral%administration%of%either%liquid%or%powdered%forms%has%been%used.

[19,39,40,43,44,59,15,47]%In%other%studies,%cartilage%products%have%been%given%by%injection

(intravenous%or%intraperitoneal),%applied%topically,%or%placed%in%slow-release%plastic%pellets%that

were%surgically%implanted.[26-28,32,33,35,38,40,42,44,46,48]%Most%of%the%latter%studies%investigated

the%effects%of%cartilage%products%on%the%development%of%blood%vessels%in%the%chorioallantoic

membrane%of%chicken%embryos,%the%cornea%of%rabbits,%or%the%conjunctiva%of%mice.[26-

28,32,35,38,40,42,44,46,48]

In%human%studies%(MDA-ID-99303,%AETERNA-AE-MM-00-02,%and%NCCTG-971151),%cartilage%products

have%been%administered%topically%or%orally,%or%they%have%been%given%by%enema%or%subcutaneous

injection.[2-4,7-9]AETERNA-AE-RC-99-02,[6,15,16,18,60]%For%oral%administration,%liquid,%powdered,

and%pill%forms%have%been%used%as%described%in%the%following%closed%trials,%MDA-ID-99303,%NCCTG-

971151,%and%AETERNA-AE-MM-00-02.[2-4,6-9,15,16,18]%The%dose%and%duration%of%cartilage

treatment%have%varied%in%human%studies,%in%part%because%different%types%of%products%have%been

tested.

In%this%summary,%the%brand%name%(i.e.,%registered%or%trademarked%name)%of%the%cartilage

product(s)%used%in%individual%studies%will%be%identified%wherever%possible.

References

1.% Prudden%JF,%Balassa%LL:%The%biological%activity%of%bovine%cartilage%preparations.%Clinical

demonstration%of%their%potent%anti-inflammatory%capacity%with%supplementary%notes%on

certain%relevant%fundamental%supportive%studies.%Semin%Arthritis%Rheum%3%(4):%287-321,%1974

Summer.%[PUBMED%Abstract]

2.% Prudden%JF:%The%treatment%of%human%cancer%with%agents%prepared%from%bovine%cartilage.%J

Biol%Response%Mod%4%(6):%551-84,%1985.%[PUBMED%Abstract]

3.% Romano%CF,%Lipton%A,%Harvey%HA,%et%al.:%A%phase%II%study%of%Catrix-S%in%solid%tumors.%J%Biol

Response%Mod%4%(6):%585-9,%1985.%[PUBMED%Abstract]

4.% Puccio%C,%Mittelman%A,%Chun%P,%et%al.:%Treatment%of%metastatic%renal%cell%carcinoma%with%Catrix.

[Abstract]%Proceedings%of%the%American%Society%of%Clinical%Oncology%13:%A-769,%246,%1994.

5.% Dupont%E,%Savard%PE,%Jourdain%C,%et%al.:%Antiangiogenic%properties%of%a%novel%shark%cartilage

extract:%potential%role%in%the%treatment%of%psoriasis.%J%Cutan%Med%Surg%2%(3):%146-52,

6.% Falardeau%P,%Champagne%P,%Poyet%P,%et%al.:%Neovastat,%a%naturally%occurring%multifunctional

antiangiogenic%drug,%in%phase%III%clinical%trials.%Semin%Oncol%28%(6):%620-5,%2001.%[PUBMED

Abstract]

7.% Miller%DR,%Anderson%GT,%Stark%JJ,%et%al.:%Phase%I/II%trial%of%the%safety%and%efficacy%of%shark

cartilage%in%the%treatment%of%advanced%cancer.%J%Clin%Oncol%16%(11):%3649-55,%1998.%[PUBMED

Abstract]

8.% Leitner%SP,%Rothkopf%MM,%Haverstick%L,%et%al.:%Two%phase%II%studies%of%oral%dry%shark%cartilage

powder%(SCP)%with%either%metastatic%breast%or%prostate%cancer%refractory%to%standard

treatment.%[Abstract]%Proceedings%of%the%American%Society%of%Clinical%Oncology%17:%A-240,

1998.

9.% Rosenbluth%RJ,%Jennis%AA,%Cantwell%S,%et%al.:%Oral%shark%cartilage%in%the%treatment%of%patients

with%advanced%primary%brain%tumors.%[Abstract]%Proceedings%of%the%American%Society%of

Clinical%Oncology%18:%A-554,%1999.

10.% Iandoli%R:%Shark%cartilage%in%the%treatment%of%psoriasis.%Dermatologia%Clinica%21%(part%1):%39-

42,%2001.

11.% Milner%M:%A%guide%to%the%use%of%shark%cartilage%in%the%treatment%of%arthritis%and%other

inflammatory%joint%diseases.%American%Chiropractor%21%(4):%40-2,%1999.

12.% Himmel%PB,%Seligman%TM:%Treatment%of%systemic%sclerosis%with%shark%cartilage%extract.%Journal

of%Orthomolecular%Medicine%14%(2):%73-7,%1999.%Also%available%online .%Last%accessed%May%21,

2015.

13.% Sorbera%LA,%Castañer%RM,%Leeson%PA:%AE-941.%Oncolytic,%antipsoriatic,%treatment%of%age-

related%macular%degeneration,%angiogenesis%inhibitor.%Drugs%Future%25%(6):%551-7,%2000.

14.% Prudden%JF,%Migel%P,%Hanson%P,%et%al.:%The%discovery%of%a%potent%pure%chemical%wound-healing

accelerator.%Am%J%Surg%119%(5):%560-4,%1970.%[PUBMED%Abstract]

15.% AE%941--Neovastat.%Drugs%R%D%1%(2):%135-6,%1999.%[PUBMED%Abstract]

16.% Cassileth%BR:%Shark%and%bovine%cartilage%therapies.%In:%Cassileth%BR,%ed.:%The%Alternative

Medicine%Handbook:%The%Complete%Reference%Guide%to%Alternative%and%Complementary

Therapies.%New%York,%NY:%WW%Norton%&%Company,%1998,%pp%197-200.

17.% Holt%S:%Shark%cartilage%and%nutriceutical%update.%Altern%Complement%Ther%1%(6):%414-16,%1995.

18.% Hunt%TJ,%Connelly%JF:%Shark%cartilage%for%cancer%treatment.%Am%J%Health%Syst%Pharm%52%(16):

1756,%1760,%1995.%[PUBMED%Abstract]

19.% Fontenele%JB,%Araújo%GB,%de%Alencar%JW,%et%al.:%The%analgesic%and%anti-inflammatory%effects%of

shark%cartilage%are%due%to%a%peptide%molecule%and%are%nitric%oxide%(NO)%system%dependent.

Biol%Pharm%Bull%20%(11):%1151-4,%1997.%[PUBMED%Abstract]

20.% Ostrander%GK,%Cheng%KC,%Wolf%JC,%et%al.:%Shark%cartilage,%cancer%and%the%growing%threat%of

pseudoscience.%Cancer%Res%64%(23):%8485-91,%2004.%[PUBMED%Abstract]

21.% Finkelstein%JB:%Sharks%do%get%cancer:%few%surprises%in%cartilage%research.%J%Natl%Cancer%Inst%97

(21):%1562-3,%2005.%[PUBMED%Abstract]

22.% Schlumberger%HG,%Lucke%B:%Tumors%of%fishes,%amphibians,%and%reptiles.%Cancer%Res%8%(12):

657-754,%1948.

23.% Wellings%SR:%Neoplasia%and%primitive%vertebrate%phylogeny:%echinoderms,%prevertebrates,%and

fishes--A%review.%Natl%Cancer%Inst%Monogr%31:%59-128,%1969.%[PUBMED%Abstract]

24.% Durie%BG,%Soehnlen%B,%Prudden%JF:%Antitumor%activity%of%bovine%cartilage%extract%(Catrix-S)%in

http://orthomolecular.org/library/jom/1999/pdf/1999-v14n02-p073.pdf

the%human%tumor%stem%cell%assay.%J%Biol%Response%Mod%4%(6):%590-5,%1985.%[PUBMED%Abstract]

25.% Murray%JB,%Allison%K,%Sudhalter%J,%et%al.:%Purification%and%partial%amino%acid%sequence%of%a

bovine%cartilage-derived%collagenase%inhibitor.%J%Biol%Chem%261%(9):%4154-9,%1986.%[PUBMED

Abstract]

26.% Moses%MA,%Sudhalter%J,%Langer%R:%Identification%of%an%inhibitor%of%neovascularization%from

cartilage.%Science%248%(4961):%1408-10,%1990.%[PUBMED%Abstract]

27.% Moses%MA,%Sudhalter%J,%Langer%R:%Isolation%and%characterization%of%an%inhibitor%of

neovascularization%from%scapular%chondrocytes.%J%Cell%Biol%119%(2):%475-82,%1992.%[PUBMED

Abstract]

28.% Moses%MA:%A%cartilage-derived%inhibitor%of%neovascularization%and%metalloproteinases.%Clin

Exp%Rheumatol%11%(Suppl%8):%S67-9,%1993%Mar-Apr.%[PUBMED%Abstract]

29.% Takigawa%M,%Pan%HO,%Enomoto%M,%et%al.:%A%clonal%human%chondrosarcoma%cell%line%produces

an%anti-angiogenic%antitumor%factor.%Anticancer%Res%10%(2A):%311-5,%1990%Mar-Apr.%[PUBMED

Abstract]

30.% Ohba%Y,%Goto%Y,%Kimura%Y,%et%al.:%Purification%of%an%angiogenesis%inhibitor%from%culture

medium%conditioned%by%a%human%chondrosarcoma-derived%chondrocytic%cell%line,%HCS-2/8.

Biochim%Biophys%Acta%1245%(1):%1-8,%1995.%[PUBMED%Abstract]

31.% Sadove%AM,%Kuettner%KE:%Inhibition%of%mammary%carcinoma%invasiveness%with%cartilage-

derived%inhibitor.%Surg%Forum%28:%499-501,%1977.%[PUBMED%Abstract]

32.% Langer%R,%Brem%H,%Falterman%K,%et%al.:%Isolations%of%a%cartilage%factor%that%inhibits%tumor

neovascularization.%Science%193%(4247):%70-2,%1976.%[PUBMED%Abstract]

33.% Langer%R,%Conn%H,%Vacanti%J,%et%al.:%Control%of%tumor%growth%in%animals%by%infusion%of%an

angiogenesis%inhibitor.%Proc%Natl%Acad%Sci%U%S%A%77%(7):%4331-5,%1980.%[PUBMED%Abstract]

34.% Takigawa%M,%Shirai%E,%Enomoto%M,%et%al.:%Cartilage-derived%anti-tumor%factor%(CATF)%inhibits

the%proliferation%of%endothelial%cells%in%culture.%Cell%Biol%Int%Rep%9%(7):%619-25,%1985.%[PUBMED

Abstract]

35.% Takigawa%M,%Shirai%E,%Enomoto%M,%et%al.:%A%factor%in%conditioned%medium%of%rabbit%costal

chondrocytes%inhibits%the%proliferation%of%cultured%endothelial%cells%and%angiogenesis%induced

by%B16%melanoma:%its%relation%with%cartilage-derived%anti-tumor%factor%(CATF).%Biochem%Int%14

(2):%357-63,%1987.%[PUBMED%Abstract]

36.% Hiraki%Y,%Inoue%H,%Iyama%K,%et%al.:%Identification%of%chondromodulin%I%as%a%novel%endothelial%cell

growth%inhibitor.%Purification%and%its%localization%in%the%avascular%zone%of%epiphyseal%cartilage.

J%Biol%Chem%272%(51):%32419-26,%1997.%[PUBMED%Abstract]

37.% Pauli%BU,%Memoli%VA,%Kuettner%KE:%Regulation%of%tumor%invasion%by%cartilage-derived%anti-

invasion%factor%in%vitro.%J%Natl%Cancer%Inst%67%(1):%65-73,%1981.%[PUBMED%Abstract]

38.% Lee%A,%Langer%R:%Shark%cartilage%contains%inhibitors%of%tumor%angiogenesis.%Science%221

(4616):%1185-7,%1983.%[PUBMED%Abstract]

39.% Davis%PF,%He%Y,%Furneaux%RH,%et%al.:%Inhibition%of%angiogenesis%by%oral%ingestion%of%powdered

shark%cartilage%in%a%rat%model.%Microvasc%Res%54%(2):%178-82,%1997.%[PUBMED%Abstract]

40.% Sheu%JR,%Fu%CC,%Tsai%ML,%et%al.:%Effect%of%U-995,%a%potent%shark%cartilage-derived%angiogenesis

inhibitor,%on%anti-angiogenesis%and%anti-tumor%activities.%Anticancer%Res%18%(6A):%4435-41,

1998%Nov-Dec.%[PUBMED%Abstract]

41.% McGuire%TR,%Kazakoff%PW,%Hoie%EB,%et%al.:%Antiproliferative%activity%of%shark%cartilage%with%and

without%tumor%necrosis%factor-alpha%in%human%umbilical%vein%endothelium.%Pharmacotherapy

16%(2):%237-44,%1996%Mar-Apr.%[PUBMED%Abstract]

42.% Oikawa%T,%Ashino-Fuse%H,%Shimamura%M,%et%al.:%A%novel%angiogenic%inhibitor%derived%from

Japanese%shark%cartilage%(I).%Extraction%and%estimation%of%inhibitory%activities%toward%tumor

and%embryonic%angiogenesis.%Cancer%Lett%51%(3):%181-6,%1990.%[PUBMED%Abstract]

43.% Morris%GM,%Coderre%JA,%Micca%PL,%et%al.:%Boron%neutron%capture%therapy%of%the%rat%9L

gliosarcoma:%evaluation%of%the%effects%of%shark%cartilage.%Br%J%Radiol%73%(868):%429-34,

44.% Dupont%E,%Falardeau%P,%Mousa%SA,%et%al.:%Antiangiogenic%and%antimetastatic%properties%of

Neovastat%(AE-941),%an%orally%active%extract%derived%from%cartilage%tissue.%Clin%Exp%Metastasis

19%(2):%145-53,%2002.%[PUBMED%Abstract]

45.% Béliveau%R,%Gingras%D,%Kruger%EA,%et%al.:%The%antiangiogenic%agent%neovastat%(AE-941)%inhibits

vascular%endothelial%growth%factor-mediated%biological%effects.%Clin%Cancer%Res%8%(4):%1242-50,

46.% Liang%JH,%Wong%KP:%The%characterization%of%angiogenesis%inhibitor%from%shark%cartilage.%Adv

Exp%Med%Biol%476:%209-23,%2000.%[PUBMED%Abstract]

47.% Wojtowicz-Praga%S:%Clinical%potential%of%matrix%metalloprotease%inhibitors.%Drugs%R%D%1%(2):

48.% Suzuki%F:%Cartilage-derived%growth%factor%and%antitumor%factor:%past,%present,%and%future

studies.%Biochem%Biophys%Res%Commun%259%(1):%1-7,%1999.%[PUBMED%Abstract]

49.% Batist%G,%Champagne%P,%Hariton%C,%et%al.:%Dose-survival%relationship%in%a%phase%II%study%of

Neovastat%in%refractory%renal%cell%carcinoma%patients.%[Abstract]%Proceedings%of%the%American

Society%of%Clinical%Oncology%21:%A-1907,%2002.

50.% Loprinzi%CL,%Levitt%R,%Barton%DL,%et%al.:%Evaluation%of%shark%cartilage%in%patients%with%advanced

cancer:%a%North%Central%Cancer%Treatment%Group%trial.%Cancer%104%(1):%176-82,%2005.%[PUBMED

Abstract]

51.% Folkman%J:%The%role%of%angiogenesis%in%tumor%growth.%Semin%Cancer%Biol%3%(2):%65-71,

52.% Sipos%EP,%Tamargo%RJ,%Weingart%JD,%et%al.:%Inhibition%of%tumor%angiogenesis.%Ann%N%Y%Acad%Sci

732:%263-72,%1994.%[PUBMED%Abstract]

53.% Li%CY,%Shan%S,%Huang%Q,%et%al.:%Initial%stages%of%tumor%cell-induced%angiogenesis:%evaluation%via

skin%window%chambers%in%rodent%models.%J%Natl%Cancer%Inst%92%(2):%143-7,%2000.%[PUBMED

Abstract]

54.% Alberts%B,%Bray%D,%Lewis%J,%et%al.:%Molecular%Biology%of%the%Cell.%3rd%ed.%New%York,%NY:%Garland

Publishing,%1994.

55.% Cremer%MA,%Rosloniec%EF,%Kang%AH:%The%cartilage%collagens:%a%review%of%their%structure,

organization,%and%role%in%the%pathogenesis%of%experimental%arthritis%in%animals%and%in%human

rheumatic%disease.%J%Mol%Med%76%(3-4):%275-88,%1998.%[PUBMED%Abstract]

56.% Rosen%J,%Sherman%WT,%Prudden%JF,%et%al.:%Immunoregulatory%effects%of%catrix.%J%Biol%Response

Mod%7%(5):%498-512,%1988.%[PUBMED%Abstract]

57.% Houck%JC,%Jacob%RA,%Deangelo%L,%et%al.:%The%inhibition%of%inflammation%and%the%acceleration%of

tissue%repair%by%cartilage%powder.%Surgery%51:%632-8,%1962.%[PUBMED%Abstract]

58.% Simone%CB,%Simone%NL,%Simone%CB%2nd:%Shark%cartilage%for%cancer.%Lancet%351%(9113):%1440,

59.% Horsman%MR,%Alsner%J,%Overgaard%J:%The%effect%of%shark%cartilage%extracts%on%the%growth%and

metastatic%spread%of%the%SCCVII%carcinoma.%Acta%Oncol%37%(5):%441-5,%1998.%[PUBMED%Abstract]

60.% Gingras%D,%Batist%G,%Béliveau%R:%AE-941%(Neovastat):%a%novel%multifunctional%antiangiogenic

compound.%Expert%Rev%Anticancer%Ther%1%(3):%341-7,%2001.%[PUBMED%Abstract]

HistoryThe%therapeutic%potential%of%cartilage%has%been%investigated%for%more%than%30%years.%As%noted

previously%(refer%to%the%General%Information%section%of%this%summary%for%more%information),

cartilage%products%have%been%tested%as%treatments%for%people%with%cancer,%psoriasis,%and%arthritis.

Cartilage%products%have%also%been%studied%as%enhancers%of%wound%repair%and%as%treatments%for

people%with%osteoporosis,%ulcerative%colitis,%regional%enteritis,%acne,%scleroderma,%hemorrhoids,

severe%anal%itching,%and%the%dermatitis%caused%by%poison%oak%and%poison%ivy.[1-5]

Early%studies%of%cartilage’s%therapeutic%potential%utilized%extracts%of%bovine%(cow)%cartilage.%The

ability%of%these%extracts%to%suppress%inflammation%was%first%described%in%the%early%1960s.[1]%The

first%report%that%bovine%cartilage%contains%at%least%one%angiogenesis%inhibitor%was%published%in%the

mid-1970s.[6]%The%use%of%bovine%cartilage%extracts%to%treat%patients%with%cancer%and%the%ability%of

these%extracts%to%kill%cancer%cells%directly%and%to%stimulate%animal%immune%systems%were%first

described%in%the%mid-%to%late-1980s.[7-10]

The%first%report%that%shark%cartilage%contains%at%least%one%angiogenesis%inhibitor%was%published%in

the%early%1980s,[11]%and%the%only%published%report%to%date%of%a%clinical%trial%of%shark%cartilage%as%a

treatment%for%people%with%cancer%appeared%in%the%late%1990s.[12]%The%more%recent%interest%in

shark%cartilage%is%due,%in%part,%to%the%greater%abundance%of%cartilage%in%this%animal%and%its

apparently%higher%level%of%antiangiogenic%activity.%Approximately%6%%of%the%body%weight%of%a%shark

is%composed%of%cartilage,%compared%with%less%than%1%%of%the%body%weight%of%a%cow.[13]%In

addition,%on%a%weight-for-weight%basis,%shark%cartilage%contains%approximately%1,000%times%more

antiangiogenic%activity%than%bovine%cartilage.[11]

As%indicated%previously%(refer%to%the%Overview%and%General%Information%sections%of%this%summary

for%more%information),%at%least%three%different%mechanisms%of%action%have%been%proposed%to

explain%the%anticancer%potential%of%cartilage:%1)%it%is%toxic%to%cancer%cells;%2)%it%stimulates%the

immune%system;%and%3)%it%inhibits%angiogenesis.%Only%limited%evidence%is%available%to%support%the

first%two%mechanisms%of%action;%however,%the%evidence%in%favor%of%the%third%mechanism%is%more

substantial%(refer%to%the%Laboratory/Animal/Preclinical%Studies%section%of%this%summary%for%more

information).

The%process%of%angiogenesis%requires%at%least%four%coordinated%steps,%each%of%which%may%be%a

target%for%inhibition.%First,%tumors%must%communicate%with%the%endothelial%cells%that%line%the%inside

of%nearby%blood%vessels.%This%communication%takes%place,%in%part,%through%the%secretion%of

angiogenesis%factors%such%as%vascular%endothelial%growth%factor.[14-18]%Second,%the%activated

endothelial%cells%must%divide%to%produce%new%endothelial%cells,%which%will%be%used%to%make%the%new

blood%vessels.[15,17-20]%Third,%the%dividing%endothelial%cells%must%migrate%toward%the%tumor.[15-

20]%To%accomplish%this,%they%must%produce%enzymes%called%matrix%metalloproteinases,%which%will

help%them%carve%a%pathway%through%the%tissue%elements%that%separate%them%from%the%tumor.[18-

22]%Fourth,%the%new%endothelial%cells%must%form%the%hollow%tubes%that%will%become%the%new%blood

vessels.[17,18]%Some%angiogenesis%inhibitors%may%be%able%to%block%more%than%one%step%in%this

process.

Cartilage%is%relatively%resistant%to%invasion%by%tumor%cells,[23-30]%and%tumor%cells%use%matrix

metalloproteinases%when%they%migrate%during%the%process%of%metastasis.[21,25,31,32]%Therefore,%if

the%angiogenesis%inhibitors%in%cartilage%are%also%inhibitors%of%matrix%metalloproteinases,%then%the

same%molecules%may%be%able%to%block%both%angiogenesis%and%metastasis.%Shark%tissues%other%than

cartilage%have%also%been%reported%to%produce%antitumor%substances.[33-36]

References

1.% Houck%JC,%Jacob%RA,%Deangelo%L,%et%al.:%The%inhibition%of%inflammation%and%the%acceleration%of

tissue%repair%by%cartilage%powder.%Surgery%51:%632-8,%1962.%[PUBMED%Abstract]

2.% Prudden%JF,%Balassa%LL:%The%biological%activity%of%bovine%cartilage%preparations.%Clinical

demonstration%of%their%potent%anti-inflammatory%capacity%with%supplementary%notes%on

certain%relevant%fundamental%supportive%studies.%Semin%Arthritis%Rheum%3%(4):%287-321,%1974

Summer.%[PUBMED%Abstract]

3.% Prudden%JF,%Migel%P,%Hanson%P,%et%al.:%The%discovery%of%a%potent%pure%chemical%wound-healing

accelerator.%Am%J%Surg%119%(5):%560-4,%1970.%[PUBMED%Abstract]

5.% Fontenele%JB,%Araújo%GB,%de%Alencar%JW,%et%al.:%The%analgesic%and%anti-inflammatory%effects%of

shark%cartilage%are%due%to%a%peptide%molecule%and%are%nitric%oxide%(NO)%system%dependent.

Biol%Pharm%Bull%20%(11):%1151-4,%1997.%[PUBMED%Abstract]

(4616):%1185-7,%1983.%[PUBMED%Abstract]

Abstract]

14.% Folkman%J:%The%role%of%angiogenesis%in%tumor%growth.%Semin%Cancer%Biol%3%(2):%65-71,

15.% Sipos%EP,%Tamargo%RJ,%Weingart%JD,%et%al.:%Inhibition%of%tumor%angiogenesis.%Ann%N%Y%Acad%Sci

732:%263-72,%1994.%[PUBMED%Abstract]

16.% Li%CY,%Shan%S,%Huang%Q,%et%al.:%Initial%stages%of%tumor%cell-induced%angiogenesis:%evaluation%via

skin%window%chambers%in%rodent%models.%J%Natl%Cancer%Inst%92%(2):%143-7,%2000.%[PUBMED

Abstract]

Publishing,%1994.

18.% Moses%MA:%The%regulation%of%neovascularization%of%matrix%metalloproteinases%and%their

inhibitors.%Stem%Cells%15%(3):%180-9,%1997.%[PUBMED%Abstract]

19.% Stetler-Stevenson%WG:%Matrix%metalloproteinases%in%angiogenesis:%a%moving%target%for

therapeutic%intervention.%J%Clin%Invest%103%(9):%1237-41,%1999.%[PUBMED%Abstract]

20.% Haas%TL,%Madri%JA:%Extracellular%matrix-driven%matrix%metalloproteinase%production%in

endothelial%cells:%implications%for%angiogenesis.%Trends%Cardiovasc%Med%9%(3-4):%70-7,%1999

Apr-May.%[PUBMED%Abstract]

21.% McCawley%LJ,%Matrisian%LM:%Matrix%metalloproteinases:%multifunctional%contributors%to%tumor

progression.%Mol%Med%Today%6%(4):%149-56,%2000.%[PUBMED%Abstract]

22.% Mandal%M,%Mandal%A,%Das%S,%et%al.:%Clinical%implications%of%matrix%metalloproteinases.%Mol%Cell

Biochem%252%(1-2):%305-29,%2003.%[PUBMED%Abstract]

Abstract]

25.% Sadove%AM,%Kuettner%KE:%Inhibition%of%mammary%carcinoma%invasiveness%with%cartilage-

derived%inhibitor.%Surg%Forum%28:%499-501,%1977.%[PUBMED%Abstract]

Abstract]

(2):%357-63,%1987.%[PUBMED%Abstract]

28.% Pauli%BU,%Memoli%VA,%Kuettner%KE:%Regulation%of%tumor%invasion%by%cartilage-derived%anti-

invasion%factor%in%vitro.%J%Natl%Cancer%Inst%67%(1):%65-73,%1981.%[PUBMED%Abstract]

Abstract]

33.% Pettit%GR,%Ode%RH:%Antineoplastic%agents%L:%isolation%and%characterization%of%sphyrnastatins%1

and%2%from%the%hammerhead%shark%Sphyrna%lewini.%J%Pharm%Sci%66%(5):%757-8,%1977.%[PUBMED

Abstract]

34.% Sigel%MM,%Fugmann%RA:%Studies%on%immunoglobulins%reactive%with%tumor%cells%and%antigens.

Cancer%Res%28%(7):%1457-9,%1968.%[PUBMED%Abstract]

35.% Snodgrass%MJ,%Burke%JD,%Meetz%GD:%Inhibitory%effect%of%shark%serum%on%the%Lewis%lung

carcinoma.%J%Natl%Cancer%Inst%56%(5):%981-4,%1976.%[PUBMED%Abstract]

36.% Pugliese%PT,%Heinerman%J:%Devour%Disease%with%Shark%Liver%Oil.%Green%Bay,%Wis:%Impakt

Communications,%1999.

Laboratory/Animal/Preclinical StudiesThe%antitumor%potential%of%cartilage%has%been%investigated%extensively%in%laboratory%and%animal

studies.%Some%of%these%studies%have%assessed%the%toxicity%of%cartilage%products%toward%cancer%cells

in vitro .[1-5]

Powdered Cartilage Products

In%one%study,%cells%from%22%freshly%isolated%human%tumors%(nine%ovary,%three%lung,%two%brain,%two

breast,%and%one%each%of%sarcoma,%melanoma,%colon,%pancreas,%cervix,%and%testis)%and%three%human

cultured%cell%lines%(breast%cancer,%colon%cancer,%and%myeloma)%were%treated%with%Catrix,%which%is%a

commercially%available%powdered%preparation%of%bovine%(cow)%cartilage.[1,3,4]%In%the%study,%the

growth%of%all%three%cultured%cell%lines%and%cells%from%approximately%70%%of%the%tumor%specimens

were%inhibited%by%50%%or%more%when%Catrix%was%used%at%high%concentrations%(1–5%mg%/mL%of

culture%fluid).%However,%it%is%unclear%whether%the%inhibitory%effect%of%Catrix%in%this%study%was

specific%to%the%growth%of%cancer%cells%because%the%preparation’s%effect%on%the%growth%of%normal

cells%was%not%tested.%In%addition,%the%cytotoxic%component%of%Catrix%has%not%been%identified,%and%it

has%not%been%shown%that%equivalent%inhibitory%concentrations%of%this%component%can%be%achieved

in%the%bloodstreams%of%patients%who%may%be%treated%with%either%injected%or%oral%formulations%of

this%product.%(Refer%to%the%Human/Clinical%Studies%section%of%this%summary%for%more%information.)

A%commercially%available%preparation%of%powdered%shark%cartilage%(no%brand%name%given)%was

reported%to%have%no%effect%on%the%growth%of%human%astrocytoma%cells%in vitro.[2]%The%sharkcartilage%product%tested%in%this%study,%however,%was%examined%at%only%one%concentration%(0.75

mg/mL).[2]

The%immune%system%–stimulating%potential%of%cartilage%has%also%been%investigated%in%laboratory

and%animal%studies.[6]%In%one%study,%Catrix%was%shown%to%stimulate%the%production%of%antibodies

by%mouse%B%cells%(B%lymphocytes)%both%in vitro%and%in vivo .%However,%increased%antibodyproduction%in vivo%was%observed%only%when%Catrix%was%administered%by%intraperitoneal%or

intravenous%injection.%It%was%not%observed%when%oral%formulations%of%Catrix%were%used.[6]%In%most

experiments,%the%proliferation%of%mouse%B%cells%(i.e.,%normal,%nonmalignant%cells)%in vitro%wasincreasingly%inhibited%as%the%concentration%of%Catrix%was%increased%(tested%concentration%range,

1–20%mg/mL).%Catrix%has%also%been%reported%to%stimulate%the%activity%of%mouse%macrophages%invivo,[3]%but%results%demonstrating%this%effect%have%not%been%published.

The%effects%of%shark%cartilage%on%the%immune%system%were%also%reported%in%two%studies%that%used

the%same%purified%protein%fraction%that%had%exhibited%the%most%immunostimulatory%effects%when

tested.[7,8]%One%study%explored%the%effects%of%this%fraction%on%tumor%immune%response%by

observing%the%infiltration%of%this%fraction%on%CD4%and%CD8%lymphocytes%in%a%murine%tumor%model.

An%increase%in%the%ratio%of%CD4/CD8%lymphocytes%was%seen%in%tumor-infiltrating%lymphocytes%but

not%in%peripheral%blood%lymphocytes.[8]%The%second%study%exploring%immune%system%response

measured%antibody%response,%cytotoxic%assay,%lymphocyte%transformation,%and%intratumor%T-cell

ratio%in%mice.%The%fraction%exhibited%the%ability%to%augment%delayed-type%hypersensitivity%response

against%sheep%red%blood%cells%in%mice%and%to%decrease%the%cytotoxic%activity%of%natural%killer%cells.

In%addition,%this%fraction%showed%a%strong%inhibitory%effect%on%human%brain%microvascular

endothelial%cell%proliferation%and%migration%in%the%fibrin%matrix.[7]

Additional%in vivo%studies%of%the%antitumor%potential%of%shark%cartilage%have%been%published%in%the

peer-reviewed%scientific%literature.[9-11]%In%one%study,%oral%administration%of%powdered%shark

cartilage%(no%brand%name%given)%was%shown%to%inhibit%chemically%induced%angiogenesis%in%the

mesenteric%membrane%of%rats.[9]%In%another%study,%oral%administration%of%powdered%shark

cartilage%(no%brand%name%given)%was%shown%to%reduce%the%growth%of%GS-9L%gliosarcomas%in%rats.

[10]%It%was%reported%in%a%third%study%that%oral%administration%of%two%powdered%shark%cartilage

products,%Sharkilage%and%MIA%Shark%Powder,%did%not%inhibit%the%growth%or%the%metastasis%of

SCCVII%squamous%cell%carcinomas%in%mice.[11]

A%large%number%of%laboratory%and%animal%studies%concerning%the%antiangiogenic%potential%of

cartilage%have%been%published.[2,9,12-32]%Overall,%these%studies%have%revealed%the%presence%of%at

least%three%angiogenesis%inhibitors%in%bovine%cartilage%[13,14,16-18,21,23,33]%and%at%least%two%in

shark%cartilage.[2,9,25,26]

Aqueous Extracts of Cartilage

A%liquid%(i.e.,%aqueous)%extract%of%shark%cartilage%called%AE-941/Neovastat%has%also%been%reported

to%inhibit%the%growth%of%a%variety%of%cancer%cell%types%in vitro.[5]%These%results%have%not%beenpublished%in%a%peer-reviewed%scientific%journal%and%are%not%consistent%with%other%results%obtained

by%the%same%group%of%investigators.[27,34]

Three%angiogenesis%inhibitors%in%bovine%cartilage%have%been%very%well%characterized.[13,14,16-

18,21,23,33]%They%are%relatively%small%proteins%with%molecular%masses%that%range%from%23,000%to

28,000.[13,14,16,23]%These%proteins,%called%cartilage-derived%inhibitor%(CDI),%cartilage-derived

antitumor%factor%(CATF),%and%cartilage-derived%collagenase%inhibitor%(CDCI)%by%the%researchers

who%purified%them,[13,14,21]%have%been%shown%to%block%endothelial%cell%proliferation%in vitro%andnew%blood%vessel%formation%in%the%chorioallantoic%membrane%of%chicken%embryos.[14,16-

18,21,23,33]%Two%of%the%proteins%(CDI%and%CDCI)%have%been%shown%to%inhibit%matrix

metalloproteinase%activity%in vitro,[13,14,16,18]%and%one%(CDI)%has%been%shown%to%inhibitendothelial%cell%migration%in vitro.[14,16]%These%proteins%do%not%block%the%proliferation%of%normal

cells%or%of%tumor%cells%in vitro.[14,16,17,21,33]%When%the%amino%acid%sequences%of%CDI,%CATF,%and

CDCI%were%determined,%it%was%discovered%that%they%were%the%same%as%those%of%proteins%known

otherwise%as%tissue%inhibitor%of%matrix%metalloproteinases%1%(TIMP-1),%chondromodulin%I,%and

TIMP-2,%respectively.[13,14,18,23,33]

A%possible%fourth%angiogenesis%inhibitor%in%bovine%cartilage%has%been%purified%not%from%cartilage

but%from%the%culture%fluid%of%bovine%chondrocytes%grown%in%the%laboratory.[15]%This%inhibitor,

which%has%been%named%chondrocyte-derived%inhibitor%(ChDI),%is%a%protein%that%has%a%molecular

mass%of%approximately%36,000.%It%has%been%reported%that%ChDI%and%CDI/TIMP-1%have%similar

antiangiogenic%activities,[15,16,33]%but%the%relationship%between%these%proteins%is%unclear%because

amino%acid%sequence%information%for%ChDI%is%not%available.%Thus,%whether%CDI/TIMP-1%is%a

breakdown%product%of%ChDI%or%whether%ChDI%is%truly%the%fourth%angiogenesis%inhibitor%identified

in%bovine%cartilage%is%unknown.

As%indicated%previously,%shark%cartilage,%like%bovine%cartilage,%contains%more%than%one%type%of

angiogenesis%inhibitor.%One%shark%cartilage%inhibitor,%named%U-995,%reportedly%contains%two%small

proteins,%one%with%a%molecular%mass%of%approximately%14,000%and%the%other%with%a%molecular%mass

of%approximately%10,000.[25]%Both%proteins%have%shown%antiangiogenic%activity%when%tested

individually.%The%exact%relationship%between%these%two%proteins%and%their%relationship%to%the

larger%bovine%angiogenesis%inhibitors%are%not%known%because%amino%acid%sequence%information

for%U-995%is%not%available.%U-995%has%been%reported%to%inhibit%endothelial%cell%proliferation,

endothelial%cell%migration,%matrix%metalloproteinase%activity%in vitro,%and%the%formation%of%new

blood%vessels%in%the%chorioallantoic%membrane%of%chicken%embryos.[25]%It%does%not%appear%to

inhibit%the%proliferation%of%other%types%of%normal%cells%or%of%cancer%cells%in vitro.%Intraperitoneal%butnot%oral%administration%of%U-995%has%been%shown%to%inhibit%the%growth%of%mouse%sarcoma-180

tumors%implanted%subcutaneously%on%the%backs%of%mice%and%the%formation%of%lung%metastases%of

mouse%B16-F10%melanoma%cells%injected%into%the%tail%veins%of%mice.[25]

The%second%angiogenesis%inhibitor%identified%in%shark%cartilage%appears%to%have%been%studied

independently%by%three%groups%of%investigators.[2,26,35]%This%inhibitor,%which%was%named%SCF2%by

one%of%the%groups,[35]%is%a%proteoglycan%that%has%a%molecular%mass%of%about%10,000.

Proteoglycans%are%combinations%of%glycosaminoglycans%and%protein.[30]%The%principal

glycosaminoglycan%in%SCF2%is%keratan%sulfate.[35]%SCF2%has%been%shown%to%block%endothelial%cell

proliferation%in vitro,[2,26,35]%the%formation%of%new%blood%vessels%in%the%chorioallantoic%membrane

of%chicken%embryos,[2,26]%and%tumor-induced%angiogenesis%in%the%corneas%of%rabbits.[2,26]

Other%studies%have%demonstrated%that%AE-941/Neovastat,%the%previously%mentioned%aqueous

extract%of%shark%cartilage,%has%antiangiogenic%activity,[12,27,28,34,36-39]%but%the%molecular%basis

for%this%activity%has%not%been%defined.%Therefore,%whether%AE-941/Neovastat%contains%U-995

and/or%SCF2%or%some%other%angiogenesis%inhibitor%is%not%known.%It%has%been%reported%that%AE-

941/Neovastat%inhibits%endothelial%cell%proliferation%and%matrix%metalloproteinase%activity%in vitroand%the%formation%of%new%blood%vessels%in%the%chorioallantoic%membrane%of%chicken%embryos.

[12,27,31]%In%addition,%AE-941/Neovastat%has%been%shown%to%induce%endothelial%cell%apoptosis%by

activating%caspases,%enzymes%important%in%the%promotion%and%regulation%of%apoptosis.[32,34,38]%It

also%appears%to%inhibit%the%action%of%vascular%endothelial%growth%factor,%thus%interfering%with%the

communication%between%tumor%cells%and%nearby%blood%vessels.[28,34,37,38]%AE-941/Neovastat

may%also%inhibit%angiogenesis%through%promotion%of%tissue%plasminogen%activator%(tPA)%activity.

Neovastat%stimulates%tPA%expression%in%endothelial%cells%through%an%increase%in%the%transcription

of%the%tPA%gene.[40]%This%transcriptional%activation%is%associated%with%activation%of%c-Jun%N-terminal

kinase%(JNK)%and%nuclear%factor-kappa%B%(NF-kappa%B)%signaling%pathways%to%an%extent%similar%to

tumor%necrosis%factor-alpha%(TNF-alpha).[40]%Furthermore,%AE-941/Neovastat%has%been%reported

to%inhibit%the%growth%of%DA3%mammary%adenocarcinoma%cells%and%the%metastasis%of%Lewis%lung

carcinoma%cells%in vivo%in%mice.[5,27,34,41]%In%the%Lewis%lung%carcinoma%experiments,%AE-

941/Neovastat%enhanced%the%antimetastatic%effect%of%the%chemotherapy%drug%cisplatin.[5,27,34,41]

All%the%aspects%of%preclinical%development%have%been%reviewed.[42]

The%cartilage-derived%antiangiogenic%substance%troponin%I%(TnI)%has%been%isolated%from%human

cartilage%and%has%been%produced%by%the%cloning%and%expression%of%cDNA%of%human%cartilage.%It

has%been%shown%to%specifically%inhibit%angiogenesis%in vivo%and%in vitro%and%tumor%metastasis%invivo.[43]%The%active%site%of%Tnl%has%been%located%in%the%amino%acid%residues%of%96%to%116.%The

synthetic%peptide%Glu94-Leu123%(pTnl)%has%been%shown%to%be%a%potent%inhibitor%of%endothelial%cell

tube%formation%and%endothelial%cell%division%and%to%inhibit%pancreatic%cancer%metastases%in%an%invivo%liver%metastases%model.[44]

References

2.% McGuire%TR,%Kazakoff%PW,%Hoie%EB,%et%al.:%Antiproliferative%activity%of%shark%cartilage%with%and

without%tumor%necrosis%factor-alpha%in%human%umbilical%vein%endothelium.%Pharmacotherapy

16%(2):%237-44,%1996%Mar-Apr.%[PUBMED%Abstract]

7.% Hassan%ZM,%Feyzi%R,%Sheikhian%A,%et%al.:%Low%molecular%weight%fraction%of%shark%cartilage%can

modulate%immune%responses%and%abolish%angiogenesis.%Int%Immunopharmacol%5%(6):%961-70,

8.% Feyzi%R,%Hassan%ZM,%Mostafaie%A:%Modulation%of%CD(4)(+)%and%CD(8)(+)%tumor%infiltrating

lymphocytes%by%a%fraction%isolated%from%shark%cartilage:%shark%cartilage%modulates%anti-tumor

immunity.%Int%Immunopharmacol%3%(7):%921-6,%2003.%[PUBMED%Abstract]

9.% Davis%PF,%He%Y,%Furneaux%RH,%et%al.:%Inhibition%of%angiogenesis%by%oral%ingestion%of%powdered

shark%cartilage%in%a%rat%model.%Microvasc%Res%54%(2):%178-82,%1997.%[PUBMED%Abstract]

10.% Morris%GM,%Coderre%JA,%Micca%PL,%et%al.:%Boron%neutron%capture%therapy%of%the%rat%9L

gliosarcoma:%evaluation%of%the%effects%of%shark%cartilage.%Br%J%Radiol%73%(868):%429-34,

11.% Horsman%MR,%Alsner%J,%Overgaard%J:%The%effect%of%shark%cartilage%extracts%on%the%growth%and

metastatic%spread%of%the%SCCVII%carcinoma.%Acta%Oncol%37%(5):%441-5,%1998.%[PUBMED%Abstract]

12.% Dupont%E,%Savard%PE,%Jourdain%C,%et%al.:%Antiangiogenic%properties%of%a%novel%shark%cartilage

extract:%potential%role%in%the%treatment%of%psoriasis.%J%Cutan%Med%Surg%2%(3):%146-52,

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14.% Moses%MA,%Sudhalter%J,%Langer%R:%Identification%of%an%inhibitor%of%neovascularization%from

cartilage.%Science%248%(4961):%1408-10,%1990.%[PUBMED%Abstract]

15.% Moses%MA,%Sudhalter%J,%Langer%R:%Isolation%and%characterization%of%an%inhibitor%of

neovascularization%from%scapular%chondrocytes.%J%Cell%Biol%119%(2):%475-82,%1992.%[PUBMED

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16.% Moses%MA:%A%cartilage-derived%inhibitor%of%neovascularization%and%metalloproteinases.%Clin

Exp%Rheumatol%11%(Suppl%8):%S67-9,%1993%Mar-Apr.%[PUBMED%Abstract]

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20.% Langer%R,%Conn%H,%Vacanti%J,%et%al.:%Control%of%tumor%growth%in%animals%by%infusion%of%an

angiogenesis%inhibitor.%Proc%Natl%Acad%Sci%U%S%A%77%(7):%4331-5,%1980.%[PUBMED%Abstract]

Abstract]

(2):%357-63,%1987.%[PUBMED%Abstract]

23.% Hiraki%Y,%Inoue%H,%Iyama%K,%et%al.:%Identification%of%chondromodulin%I%as%a%novel%endothelial%cell

growth%inhibitor.%Purification%and%its%localization%in%the%avascular%zone%of%epiphyseal%cartilage.

J%Biol%Chem%272%(51):%32419-26,%1997.%[PUBMED%Abstract]

(4616):%1185-7,%1983.%[PUBMED%Abstract]

25.% Sheu%JR,%Fu%CC,%Tsai%ML,%et%al.:%Effect%of%U-995,%a%potent%shark%cartilage-derived%angiogenesis

inhibitor,%on%anti-angiogenesis%and%anti-tumor%activities.%Anticancer%Res%18%(6A):%4435-41,

1998%Nov-Dec.%[PUBMED%Abstract]

26.% Oikawa%T,%Ashino-Fuse%H,%Shimamura%M,%et%al.:%A%novel%angiogenic%inhibitor%derived%from

Japanese%shark%cartilage%(I).%Extraction%and%estimation%of%inhibitory%activities%toward%tumor

and%embryonic%angiogenesis.%Cancer%Lett%51%(3):%181-6,%1990.%[PUBMED%Abstract]

27.% Dupont%E,%Falardeau%P,%Mousa%SA,%et%al.:%Antiangiogenic%and%antimetastatic%properties%of

Neovastat%(AE-941),%an%orally%active%extract%derived%from%cartilage%tissue.%Clin%Exp%Metastasis

19%(2):%145-53,%2002.%[PUBMED%Abstract]

28.% Béliveau%R,%Gingras%D,%Kruger%EA,%et%al.:%The%antiangiogenic%agent%neovastat%(AE-941)%inhibits

vascular%endothelial%growth%factor-mediated%biological%effects.%Clin%Cancer%Res%8%(4):%1242-50,

29.% Cho%J,%Kim%Y:%Sharks:%a%potential%source%of%antiangiogenic%factors%and%tumor%treatments.%Mar

Biotechnol%(NY)%4%(6):%521-5,%2002.%[PUBMED%Abstract]

Publishing,%1994.

31.% Gingras%D,%Renaud%A,%Mousseau%N,%et%al.:%Matrix%proteinase%inhibition%by%AE-941,%a

multifunctional%antiangiogenic%compound.%Anticancer%Res%21%(1A):%145-55,%2001%Jan-

Feb.%[PUBMED%Abstract]

32.% Boivin%D,%Gendron%S,%Beaulieu%E,%et%al.:%The%antiangiogenic%agent%Neovastat%(AE-941)%induces

endothelial%cell%apoptosis.%Mol%Cancer%Ther%1%(10):%795-802,%2002.%[PUBMED%Abstract]

Abstract]

36.% Bukowski%RM:%AE-941,%a%multifunctional%antiangiogenic%compound:%trials%in%renal%cell

carcinoma.%Expert%Opin%Investig%Drugs%12%(8):%1403-11,%2003.%[PUBMED%Abstract]

37.% Gingras%D,%Batist%G,%Béliveau%R:%AE-941%(Neovastat):%a%novel%multifunctional%antiangiogenic

compound.%Expert%Rev%Anticancer%Ther%1%(3):%341-7,%2001.%[PUBMED%Abstract]

38.% Gingras%D,%Boivin%D,%Deckers%C,%et%al.:%Neovastat--a%novel%antiangiogenic%drug%for%cancer

therapy.%Anticancer%Drugs%14%(2):%91-6,%2003.%[PUBMED%Abstract]

39.% Ryoo%JJ,%Cole%CE,%Anderson%KC:%Novel%therapies%for%multiple%myeloma.%Blood%Rev%16%(3):%167-

74,%2002.%[PUBMED%Abstract]

40.% Gingras%D,%Nyalendo%C,%Di%Tomasso%G,%et%al.:%Activation%of%tissue%plasminogen%activator%gene

transcription%by%Neovastat,%a%multifunctional%antiangiogenic%agent.%Biochem%Biophys%Res

Commun%320%(1):%205-12,%2004.%[PUBMED%Abstract]

42.% Dredge%K:%AE-941%(AEterna).%Curr%Opin%Investig%Drugs%5%(6):%668-77,%2004.%[PUBMED%Abstract]

43.% Moses%MA,%Wiederschain%D,%Wu%I,%et%al.:%Troponin%I%is%present%in%human%cartilage%and%inhibits

angiogenesis.%Proc%Natl%Acad%Sci%U%S%A%96%(6):%2645-50,%1999.%[PUBMED%Abstract]

44.% Kern%BE,%Balcom%JH,%Antoniu%BA,%et%al.:%Troponin%I%peptide%(Glu94-Leu123),%a%cartilage-derived

angiogenesis%inhibitor:%in%vitro%and%in%vivo%effects%on%human%endothelial%cells%and%on

pancreatic%cancer.%J%Gastrointest%Surg%7%(8):%961-8;%discussion%969,%2003.%[PUBMED%Abstract]

Human/Clinical StudiesSince%the%early%1970s,%at%least%a%dozen%clinical%trials%(MDA-ID-99303,%NCCTG-971151,%and%AETERNA-

AE-MM-00-02)%of%cartilage%as%a%treatment%for%people%with%cancer%have%been%(or%are%being)

conducted;[1-15]%(refer%to%the%table%at%the%end%of%this%section)%however,%results%from%only%seven

studies%have%been%published%in%peer-reviewed%scientific%journals.[1,2,4,8,9,16]%It%is%not%clear

whether%any%of%the%patients%in%these%studies%were%children.

In%the%first%randomized%trial%published%in%a%peer-reviewed%scientific%journal,%83%incurable%breast

cancer%and%colorectal%cancer%patients%were%randomly%assigned%to%receive%either%shark%cartilage%or

placebo,%in%addition%to%standard%care.%No%difference%was%observed%in%survival%or%quality%of%life

between%those%receiving%shark%cartilage%and%those%receiving%placebo.[8]%Additional%clinical%studies

are%under%way;%however,%the%cumulative%evidence%to%date%is%inconclusive%regarding%the

effectiveness%of%cartilage%as%a%treatment%for%people%with%cancer.

Powdered Cartilage Products

Two%of%the%three%published%clinical%studies%evaluated%the%use%of%Catrix,%the%previously%mentioned

(refer%to%the%Laboratory/Animal/Preclinical%Studies%section%of%this%summary%for%more%information)

powdered%preparation%of%bovine%(cow)%cartilage,%as%a%treatment%for%various%solid%tumors.[1,2]%One

of%these%studies%was%a%case%series%that%included%31%patients;[1]%the%other%was%a%phase%II%clinical

trial%that%included%9%patients.[2]

In%the%case%series,[1]%all%patients%were%treated%with%subcutaneously%injected%and/or%oral%Catrix;

however,%three%patients%(one%with%squamous%cell%carcinoma%of%the%skin%and%two%with%basal%cell

carcinoma%of%the%skin)%were%also%treated%with%topical%preparations.%The%individual%dose,%the%total

dose,%and%the%duration%of%Catrix%treatment%in%this%series%varied%from%patient%to%patient;%however,

the%minimum%treatment%duration%was%7%months,%and%the%maximum%duration%was%more%than%10

years.%Eighteen%patients%had%been%treated%with%conventional%therapy%(surgery,%chemotherapy,

radiation%therapy,%hormonal%therapy)%within%1%year%of%the%start%of%Catrix%treatment;%nine%patients

received%conventional%therapy%concurrently%with%Catrix%treatment;%and%seven%patients%received

conventional%therapy%both%prior%to%and%during%Catrix%treatment.%It%was%reported%that%19%patients

had%a%complete%response,%10%patients%had%a%partial%response,%and%1%patient%had%stable%disease

following%Catrix%treatment.%The%remaining%patient%did%not%respond%to%cartilage%therapy.%Eight%of

the%patients%with%a%complete%response%received%no%prior%or%concurrent%conventional%therapy.

Approximately%half%of%the%patients%with%a%complete%response%eventually%experienced%recurrent

cancer.

This%clinical%study%had%several%weaknesses%that%could%have%affected%its%outcome,%including%the

absence%of%a%control%group%and%the%receipt%of%prior%and/or%concurrent%conventional%therapy%by

most%patients.

Partial%results%of%a%third%clinical%study%of%Catrix%are%described%in%an%abstract%submitted%for

presentation%at%a%scientific%conference,[3]%but%complete%results%of%this%study%have%not%been

published%in%a%peer-reviewed%scientific%journal.%In%the%study,%35%patients%with%metastatic%renal%cell

carcinoma%were%divided%into%four%groups,%and%the%individuals%in%each%group%were%treated%with

identical%doses%of%subcutaneously%injected%and/or%oral%Catrix.%Three%partial%responses%and%no

complete%responses%were%observed%among%22%evaluable%patients%who%were%treated%with%Catrix%for

more%than%3%months.%Following%Catrix%therapy,%2%of%the%22%evaluable%patients%were%reported%to

have%stable%disease,%and%17%were%reported%to%have%progressive%disease.%No%relationship%between

Catrix%dose%and%tumor%response%could%be%established%in%this%study.

The%third%published%study%of%cartilage%as%a%treatment%for%people%with%cancer%was%a%phase%I/II%trial

that%tested%the%safety%and%the%efficacy%of%orally%administered%Cartilade,%a%commercially%available

powdered%preparation%of%shark%cartilage,%in%60%patients%with%various%types%of%advanced%solid

tumors.[4]%All%but%one%patient%in%this%trial%had%been%treated%previously%with%conventional%therapy.

According%to%the%design%of%the%study,%no%additional%anticancer%treatment%could%be%given

concurrently%with%Cartilade%therapy.%No%complete%responses%or%partial%responses%were%observed

among%50%evaluable%patients%who%were%treated%with%Cartilade%for%at%least%6%weeks.%However,

stable%disease%that%lasted%12%weeks%or%more%was%reported%for%10%of%the%50%patients.%All%ten%of%these

patients%eventually%experienced%progressive%disease.

Partial%results%of%three%other%clinical%studies%of%powdered%shark%cartilage%are%described%in%two

abstracts%submitted%for%presentation%at%scientific%conferences,[5,6]%but%complete%results%of%these

studies%have%not%been%published%in%peer-reviewed%scientific%journals.%All%three%studies%were%phase

II%clinical%trials%that%involved%patients%with%advanced%disease;%two%of%the%studies%were%conducted

by%the%same%group%of%investigators.[5]%These%three%studies%enrolled%20%patients%with%breast

cancer,[5]%12%patients%with%prostate%cancer,[5]%and%12%patients%with%primary%brain%tumors.[6]%All

patients%had%been%treated%previously%with%conventional%therapy.%No%other%anticancer%treatment

was%allowed%concurrently%with%cartilage%therapy.%In%two%of%the%studies,[5]%the%name%of%the

cartilage%product%was%not%identified;%however,%in%the%third%study,[6]%the%commercially%available

product%BeneFin%was%used.%Ten%patients%in%each%study%completed%at%least%8%weeks%of%treatment

and%therefore%were%considered%evaluable%for%response.%No%complete%responses%or%partial

responses%were%observed%in%any%of%the%studies.%Two%evaluable%patients%in%the%breast%cancer%study

were%reported%to%have%stable%disease%that%lasted%8%weeks%or%more;%two%evaluable%patients%in%the

brain%tumor%study%had%stable%disease%that%lasted%20%weeks%or%more;%and%three%evaluable%patients

in%the%prostate%cancer%study%had%stable%disease%that%also%lasted%20%weeks%or%more.

Aqueous Extracts of Cartilage

In%the%phase%II%trial,[2]%Catrix%was%administered%by%subcutaneous%injection%only.%All%patients%in%this

trial%had%progressive%disease%following%radiation%therapy%and/or%chemotherapy.%Identical

individual%doses%of%Catrix%were%administered%to%each%patient,%but%the%duration%of%treatment%and

the%total%delivered%dose%varied%because%of%disease%progression%or%death.%The%minimum%duration

of%Catrix%treatment%in%this%study%was%4%weeks.%One%patient%(with%metastatic%renal%cell%carcinoma)

reportedly%had%a%complete%response%that%lasted%more%than%39%weeks.%The%remaining%eight

patients%did%not%respond%to%Catrix%treatment.%The%researchers%in%this%trial%also%investigated

whether%Catrix%had%an%effect%on%immune%system%function%in%these%patients.%No%consistent%trend%or

change%in%the%numbers,%percentages,%or%ratios%of%white%blood%cells%(i.e.,%total%lymphocyte%counts,

total%T%cell%counts,%total%B%cell%counts,%percentage%of%T%cells,%percentage%of%B%cells,%and%ratio%of

helper%T%cells%to%cytotoxic%T%cells)%was%observed,%though%increased%numbers%of%T%cells%were%found

in%three%patients.

The%safety%and%the%efficacy%of%AE-941/Neovastat,%the%previously%mentioned%aqueous%extract%of

shark%cartilage,%has%also%been%examined%in%clinical%studies.[9-11,15,17]%It%has%been%reported%that

AE-941/Neovastat%has%little%toxicity.[10,11,15]%In%addition,%there%is%evidence%from%a%randomized

clinical%trial%that%examined%the%effect%of%AE-941/Neovastat%on%angiogenesis%associated%with

surgical%wound%repair%that%this%product%contains%at%least%one%antiangiogenic%component%that%is

orally%bioavailable.[17]

AE-941/Neovastat%was%administered%to%331%patients%with%advanced%solid%tumors%(including%lung,

prostate,%breast,%and%kidney%tumors)%in%two%phase%I/II%trials.[10]%The%results%of%these%trials,

however,%have%not%been%fully%reported.%A%retrospective%analysis%involving%a%subgroup%of%patients

with%advanced%non-small%cell%lung%cancer%(NSCLC)%suggests%that%AE-941/Neovastat%is%able%to

lengthen%the%survival%of%patients%with%this%disease.[10]%Furthermore,%in%a%prospective%analysis

involving%22%patients%with%refractory%renal%cell%carcinoma,%survival%was%longer%in%patients%treated

with%240%mL%/day%AE-941/Neovastat%than%in%patients%treated%with%only%60%mL/day.[7,10,16]

In%2003,%the%results%of%a%phase%I/II%trial%of%AE-941/Neovastat%in%80%patients%with%advanced%NSCLC

reported%that%there%was%a%significant%survival%advantage%for%patients%receiving%the%highest%doses

(2.6%mL/kg/day)%of%AE-941/Neovastat.%A%survival%analysis%of%48%patients%with%unresectable%stage

IIIA,%IIIB,%or%IV%NSCLC%showed%a%median%survival%advantage%of%P%=%.0026%in%patients%receiving%thehighest%doses.%The%trial%was%principally%conducted%to%explore%the%safety%and%efficacy%of%orally

administered%AE-941/Neovastat%when%administered%in%escalating%doses%(30,%60,%120,%and%240

mL/day).%No%dose-limiting%toxicity%was%found,%and%no%tumor%response%was%observed.[9]

In%2001,%a%phase%II%trial%(AETERNA-AE-MM-00-02)%of%AE-941/Neovastat%was%initiated%in%patients

with%relapsed%or%refractory%multiple%myeloma.%This%trial%closed%approximately%1%year%later,%and%no

results%have%been%reported.[18]

Two%randomized%phase%III%trials%of%AE-941/Neovastat%in%patients%with%advanced%cancer%have%been

approved%by%the%U.S.%Food%and%Drug%Administration%(FDA).%In%one%trial%(MDA-ID-99303),%which%is

completed,%treatment%with%oral%AE-941/Neovastat%plus%chemotherapy%and%radiation%therapy%was

compared%with%treatment%with%placebo%plus%the%same%chemotherapy%and%radiation%therapy%in

patients%with%stage%III%NSCLC.%In%the%second%trial,%which%closed%to%patient%recruitment%in%2002,

treatment%with%oral%AE-941/Neovastat%was%compared%with%treatment%with%placebo%in%patients%with

metastatic%renal%cell%carcinoma.%Results%from%this%second%phase%III%trial%have%not%been%reported%in

the%peer-reviewed%scientific%literature.[19]%Despite%AE-941/Neovastat%being%granted%orphan%drug

status%by%the%FDA%in%2002%for%use%in%the%treatment%of%renal%cell%carcinoma,%the%company%that

produces%AE-941/Neovastat,%Aeterna%Laboratories,%announced%in%early%2004%that%this%application

would%be%discontinued%in%favor%of%a%focus%on%the%treatment%of%NSCLC.[19,20]

In%2010,%the%results%of%a%randomized,%double-blind,%placebo-controlled%phase%III%trial%aimed%at

assessing%the%effect%of%adding%AE-941%to%chemotherapy%and%radiation%therapy%on%the%overall

survival%of%patients%with%nonresectable%stage%III%NSCLC%were%reported.%A%total%of%379%eligible

patients%received%induction%chemotherapy%followed%by%concurrent%chemotherapy%with%chest

radiation%therapy;%participating%centers%used%one%of%two%chemotherapy%regimens,%either

carboplatin%and%paclitaxel,%or%cisplatin%and%vinorelbine.%No%statistically%significant%difference%in

overall%survival%was%observed%between%the%group%(n%=%188)%receiving%chemotherapy%and%radiation

therapy%plus%AE-941%(120%mL%administered%orally%twice%daily)%and%the%group%receiving

chemotherapy%and%radiation%therapy%plus%placebo%(n%=%191).%Both%AE-941%and%placebo%were%well

tolerated.[21]

Cartilage Use in Cancer Treatment: Clinical Studies WithTherapeutic Endpointsa,b

Reference&Citation(s) Type&of&Study Type(s)&of&Cancer Cartilage&

[8] Phase%III%randomized,

placebo-controlled,

double-blind%trial%(2%arms)

Breast%and%colorectal BeneFin%(shark)

[21] Randomized%controlled

phase%III%trial

NSCLC AE-941%(shark)

[1] Nonconsecutive%case

series

Various%advanced%or

recurrent

Catrix%(bovine)

[2] Phase%II%trial Various%metastatic Catrix%(bovine)

[3] Phase%II%trial Metastatic%renal%cell Catrix%(bovine)

[10,16] Two%phase%I/II%trials Various%advanced,

refractory%solid%tumors

AE-941/%Neovastat%(shark)

[9] Phase%I/II%trial Advanced%non-small%cell

lung%cancer

AT-941/Neovastat%(shark)

[4] Phase%I/II%trial Various%advanced%solid

tumors

Cartilade%(shark)

[5] Phase%II%trial Metastatic,%refractory

breast

Unknown%(shark)

[5] Phase%II%trial Metastatic,%hormone-

refractory%prostate

Unknown%(shark)

g

References

Abstract]

1998.

No.%=%number;%NSCLC%=%non-small%cell%lung%cancer;%wk%=%week.

See%text%and%the%NCI%Dictionary%of%Cancer%Terms%for%additional%information%and%definition%of%terms.

Other%clinical%studies%have%been%conducted,%but%no%results%have%been%reported.

Strongest%evidence%reported%that%the%treatment%under%study%has%anticancer%activity%or%otherwise%improves%the%well-being%of%cancer%patients.

Chemotherapy,%radiation%therapy,%hormonal%therapy,%or%cytokine%therapy%given/allowed%at%the%same%time%as%cartilage%therapy.

For%information%about%Levels%of%Evidence%analysis%and%an%explanation%of%the%level%of%evidence%scores,%see%Levels%of%Evidence%for%Human%Studies%of%Cancer%Complementary%and%Alternative%Medicine

Study%results%reported%in%review%article%or%abstract%form%only;%insufficient%information%presented%for%Level%of%Evidence%analysis.

Insufficient%information%available%to%describe%these%studies%separately.

[6] Phase%II%trial Various%advanced%brain BeneFin%(shark)

a

b

c

d

e

f

g

7.% Batist%G,%Champagne%P,%Hariton%C,%et%al.:%Dose-survival%relationship%in%a%phase%II%study%of

Neovastat%in%refractory%renal%cell%carcinoma%patients.%[Abstract]%Proceedings%of%the%American

Society%of%Clinical%Oncology%21:%A-1907,%2002.

8.% Loprinzi%CL,%Levitt%R,%Barton%DL,%et%al.:%Evaluation%of%shark%cartilage%in%patients%with%advanced

cancer:%a%North%Central%Cancer%Treatment%Group%trial.%Cancer%104%(1):%176-82,%2005.%[PUBMED

Abstract]

9.% Latreille%J,%Batist%G,%Laberge%F,%et%al.:%Phase%I/II%trial%of%the%safety%and%efficacy%of%AE-941

(Neovastat)%in%the%treatment%of%non-small-cell%lung%cancer.%Clin%Lung%Cancer%4%(4):%231-6,

Abstract]

13.% Holt%S:%Shark%cartilage%and%nutriceutical%update.%Altern%Complement%Ther%1%(6):%414-16,%1995.

15.% AE%941.%Drugs%R%D%5%(2):%83-9,%2004.%[PUBMED%Abstract]

16.% Batist%G,%Patenaude%F,%Champagne%P,%et%al.:%Neovastat%(AE-941)%in%refractory%renal%cell

carcinoma%patients:%report%of%a%phase%II%trial%with%two%dose%levels.%Ann%Oncol%13%(8):%1259-63,

17.% Berbari%P,%Thibodeau%A,%Germain%L,%et%al.:%Antiangiogenic%effects%of%the%oral%administration%of

liquid%cartilage%extract%in%humans.%J%Surg%Res%87%(1):%108-13,%1999.%[PUBMED%Abstract]

18.% Ryoo%JJ,%Cole%CE,%Anderson%KC:%Novel%therapies%for%multiple%myeloma.%Blood%Rev%16%(3):%167-

74,%2002.%[PUBMED%Abstract]

19.% Bukowski%RM:%AE-941,%a%multifunctional%antiangiogenic%compound:%trials%in%renal%cell

carcinoma.%Expert%Opin%Investig%Drugs%12%(8):%1403-11,%2003.%[PUBMED%Abstract]

20.% New%treatment%option%for%postmenopausal%women%with%early%breast%cancer.%Expert%Rev

Anticancer%Ther%2%(6):%617,%2002.%[PUBMED%Abstract]

21.% Lu%C,%Lee%JJ,%Komaki%R,%et%al.:%Chemoradiotherapy%with%or%without%AE-941%in%stage%III%non-small

cell%lung%cancer:%a%randomized%phase%III%trial.%J%Natl%Cancer%Inst%102%(12):%859-65,

Adverse EffectsThe%side%effects%associated%with%cartilage%therapy%are%generally%described%as%mild%to%moderate%in

severity.%Inflammation%at%injection%sites,%dysgeusia,%fatigue,%nausea,%dyspepsia,%fever,%dizziness,

and%edema%of%the%scrotum%have%been%reported%after%treatment%with%the%bovine%(cow)%cartilage

product%Catrix.[1-3]%Nausea,%vomiting,%abdominal%cramping%and/or%bloating,%constipation,

hypotension,%hyperglycemia,%generalized%weakness,%and%hypercalcemia%have%been%associated

with%the%use%of%powdered%shark%cartilage.[4-6]%The%high%level%of%calcium%in%shark%cartilage%may

contribute%to%the%development%of%hypercalcemia.[5,7]%In%addition,%one%case%of%hepatitis%has%been

associated%with%the%use%of%powdered%shark%cartilage.[8]%Nausea,%vomiting,%and%dyspepsia%are%the

most%commonly%reported%side%effects%following%treatment%with%AE-941/Neovastat,%the%aqueous

extract%of%shark%cartilage.[9]

References

Abstract]

1998.

7.% Jungi%WF:%Dangerous%nutrition.%Support%Care%Cancer%11%(4):%197-8,%2003.%[PUBMED%Abstract]

8.% Ashar%B,%Vargo%E:%Shark%cartilage-induced%hepatitis.%Ann%Intern%Med%125%(9):%780-1,

Abstract]

Summary of the Evidence for CartilageAlthough%at%least%a%dozen%clinical%studies%of%cartilage%as%a%treatment%for%people%with%cancer%have

been%conducted%since%the%early%1970s,%relatively%few%results%have%been%reported%in%the%peer-

reviewed%scientific%literature.%There%are%small%amounts%of%reported%data%from%phase%III%clinical

trials.%Additional%clinical%studies%are%now%under%way.%At%present,%the%use%of%cartilage%(bovine%[cow]

or%shark)%as%a%treatment%for%people%with%cancer%cannot%be%recommended%outside%the%context%of

well-designed%clinical%trials.

Separate%levels%of%evidence%scores%are%assigned%to%qualifying%human%studies%on%the%basis%of

statistical%strength%of%the%study%design%and%scientific%strength%of%the%treatment%outcomes%(i.e.,

endpoints)%measured.%The%resulting%two%scores%are%then%combined%to%produce%an%overall%score.

For%additional%information%about%levels%of%evidence%analysis,%refer%to%Levels%of%Evidence%for

Human%Studies%of%Cancer%Complementary%and%Alternative%Medicine.

Changes to This Summary (05/21/2015)The%PDQ%cancer%information%summaries%are%reviewed%regularly%and%updated%as%new%information

becomes%available.%This%section%describes%the%latest%changes%made%to%this%summary%as%of%the%date

above.

Overview

Added%text%to%note%that%the%information%in%this%summary%is%no%longer%being%updated%and%is

provided%for%reference%purposes%only.

This%summary%is%written%and%maintained%by%the%PDQ%Cancer%Complementary%and%Alternative

Medicine%Editorial%Board,%which%is%editorially%independent%of%NCI.%The%summary%reflects%an

independent%review%of%the%literature%and%does%not%represent%a%policy%statement%of%NCI%or%NIH.

More%information%about%summary%policies%and%the%role%of%the%PDQ%Editorial%Boards%in%maintaining

the%PDQ%summaries%can%be%found%on%the%About%This%PDQ%Summary%and%PDQ%NCI's

Comprehensive%Cancer%Database%pages.

http://www.cancer.gov/about-cancer/treatment/cam/hp/cartilage-pdq/#link/_AboutThis_1

This%PDQ%cancer%information%summary%for%health%professionals%provides%comprehensive,%peer-

reviewed,%evidence-based%information%about%the%use%of%cartilage%(bovine%and%shark)%in%the

treatment%of%people%with%cancer.%It%is%intended%as%a%resource%to%inform%and%assist%clinicians%who

care%for%cancer%patients.%It%does%not%provide%formal%guidelines%or%recommendations%for%making

health%care%decisions.

This%summary%is%reviewed%regularly%and%updated%as%necessary%by%the%PDQ%Cancer

Complementary%and%Alternative%Medicine%Editorial%Board,%which%is%editorially%independent%of%the

National%Cancer%Institute%(NCI).%The%summary%reflects%an%independent%review%of%the%literature%and

does%not%represent%a%policy%statement%of%NCI%or%the%National%Institutes%of%Health%(NIH).

Board%members%review%recently%published%articles%each%month%to%determine%whether%an%article

should:

Changes%to%the%summaries%are%made%through%a%consensus%process%in%which%Board%members

evaluate%the%strength%of%the%evidence%in%the%published%articles%and%determine%how%the%article

should%be%included%in%the%summary.

The%lead%reviewers%for%Cartilage%(Bovine%and%Shark)%are:

John%A.%Beutler,%PhD%(National%Cancer%Institute)

Keith%I.%Block,%MD%(Block%Center%for%Integrative%Cancer%Treatment%&%University%of%Illinois

College%of%Medicine)

Any%comments%or%questions%about%the%summary%content%should%be%submitted%to%Cancer.gov

through%the%Web%site's%Contact%Form.%Do%not%contact%the%individual%Board%Members%with

questions%or%comments%about%the%summaries.%Board%members%will%not%respond%to%individual

inquiries.

•

Levels of Evidence

Some%of%the%reference%citations%in%this%summary%are%accompanied%by%a%level-of-evidence

designation.%These%designations%are%intended%to%help%readers%assess%the%strength%of%the%evidence

supporting%the%use%of%specific%interventions%or%approaches.%The%PDQ%Cancer%Complementary%and

Alternative%Medicine%Editorial%Board%uses%a%formal%evidence%ranking%system%in%developing%its

level-of-evidence%designations.

PDQ%is%a%registered%trademark.%Although%the%content%of%PDQ%documents%can%be%used%freely%as

text,%it%cannot%be%identified%as%an%NCI%PDQ%cancer%information%summary%unless%it%is%presented%in

its%entirety%and%is%regularly%updated.%However,%an%author%would%be%permitted%to%write%a%sentence

such%as%“NCI’s%PDQ%cancer%information%summary%about%breast%cancer%prevention%states%the%risks

succinctly:%[include%excerpt%from%the%summary].”

National%Cancer%Institute:%PDQ®%Cartilage%(Bovine%and%Shark).%Bethesda,%MD:%National%Cancer

Institute.%Date%last%modified%<MM/DD/YYYY>.%Available%at:%http://www.cancer.gov/about-

cancer/treatment/cam/hp/cartilage-pdq.%Accessed%<MM/DD/YYYY>.

Images%in%this%summary%are%used%with%permission%of%the%author(s),%artist,%and/or%publisher%for

use%within%the%PDQ%summaries%only.%Permission%to%use%images%outside%the%context%of%PDQ

information%must%be%obtained%from%the%owner(s)%and%cannot%be%granted%by%the%National%Cancer

Institute.%Information%about%using%the%illustrations%in%this%summary,%along%with%many%other

cancer-related%images,%is%available%in%Visuals%Online,%a%collection%of%over%2,000%scientific%images.

Disclaimer

The%information%in%these%summaries%should%not%be%used%as%a%basis%for%insurance%reimbursement

determinations.%More%information%on%insurance%coverage%is%available%on%Cancer.gov%on%the

Coping%with%Cancer:%Financial,%Insurance,%and%Legal%Information%page.

Contact Us

More%information%about%contacting%us%or%receiving%help%with%the%Cancer.gov%Web%site%can%be

found%on%our%Contact%Us%for%Help%page.%Questions%can%also%be%submitted%to%Cancer.gov%through

the%Web%site’s%Contact%Form.

http://www.cancer.gov/about-cancer/treatment/cam/hp/cartilage-pdq

Updated:%May%21,%2015

7/24/15, 12:12Coenzyme Q10 - National Cancer Institute

Page 1 of 19http://www.cancer.gov/about-cancer/treatment/cam/hp/coenzyme-q10-pdq#section/all

Coenzyme Q10–for health professionals(PDQ®)

OverviewThis%complementary%and%alternative%medicine%(CAM)%information%summary%provides%an%overviewof%the%use%of%coenzyme%Q10%in%cancer%therapy.%The%summary%includes%a%history%of%coenzyme%Q10research,%a%review%of%laboratory%studies,%and%data%from%investigations%involving%human%subjects.Although%several%naturally%occurring%forms%of%coenzyme%Q%have%been%identified,%Q10%is%thepredominant%form%found%in%humans%and%most%mammals,%and%it%is%the%form%most%studied%fortherapeutic%potential.%Thus,%it%will%be%the%only%form%of%coenzyme%Q%discussed%in%this%summary.

Coenzyme%Q10%is%made%naturally%by%the%human%body.

Coenzyme%Q10%helps%cells%to%produce%energy,%and%it%acts%as%an%antioxidant.

Coenzyme%Q10%has%shown%an%ability%to%stimulate%the%immune%system%and%to%protect%the%heartfrom%damage%caused%by%certain%chemotherapy%drugs.

Low%blood%levels%of%coenzyme%Q10%have%been%detected%in%patients%with%some%types%of%cancer.

No%report%of%a%randomized%clinical%trial%of%coenzyme%Q10%as%a%treatment%for%cancer%has%beenpublished%in%a%peer-reviewed%scientific%journal.

Coenzyme%Q10%is%marketed%in%the%United%States%as%a%dietary%supplement.

Many%of%the%medical%and%scientific%terms%used%in%the%summary%are%hypertext%linked%(at%first%use%ineach%section)%to%the%NCI%Dictionary%of%Cancer%Terms,%which%is%oriented%toward%nonexperts.%Whena%linked%term%is%clicked,%a%definition%will%appear%in%a%separate%window.

•••

••

•

General InformationCoenzyme%Q10%(also%known%as%CoQ10,%Q10,%vitamin%Q10,%ubiquinone,%and%ubidecarenone)%is%abenzoquinone%compound%synthesized%naturally%by%the%human%body.%The%“Q”%and%the%“10”%in%thename%refer%to%the%quinone%chemical%group%and%the%10%isoprenyl%subunits%that%are%part%of%thiscompound’s%structure.%The%term%“coenzyme”%denotes%it%as%an%organic%(contains%carbon%atoms),nonprotein%molecule%necessary%for%the%proper%functioning%of%its%protein%partner%(an%enzyme%or%anenzyme%complex).%Coenzyme%Q10%is%used%by%cells%of%the%body%in%a%process%known%variously%asaerobic%respiration,%aerobic%metabolism,%oxidative%metabolism,%or%cell%respiration.%Through%thisprocess,%mitochondria%produce%energy%for%cell%growth%and%maintenance.[1-4]%Coenzyme%Q10%isalso%used%by%the%body%as%an%endogenous%antioxidant.[1,2,4-8]%An%antioxidant%is%a%substance%thatprotects%cells%from%free%radicals,%which%are%highly%reactive%chemicals,%often%containing%oxygenatoms,%capable%of%damaging%important%cellular%components%such%as%DNA%and%lipids.%In%addition,the%plasma%level%of%coenzyme%Q10%has%been%used%in%studies%as%a%measure%of%oxidative%stress.[9,10]

Coenzyme%Q10%is%present%in%most%tissues,%but%the%highest%concentrations%are%found%in%the%heart,the%liver,%the%kidneys,%and%the%pancreas.[11]%The%lowest%concentration%is%found%in%the%lungs.[11]Tissue%levels%of%this%compound%decrease%as%people%age,%due%to%increased%requirements,decreased%production,[11]%or%insufficient%intake%of%the%chemical%precursors%needed%for%synthesis.[12]%In%humans,%normal%blood%levels%of%coenzyme%Q10%have%been%defined%variably,%with%reportednormal%values%ranging%from%0.30%to%3.84%µg%/mL.[2,4,13,14]

Given%the%importance%of%coenzyme%Q10%in%optimizing%cellular%energy%production,%use%of%thiscompound%as%a%treatment%for%diseases%other%than%cancer%has%been%explored.%Most%of%theseinvestigations%have%focused%on%coenzyme%Q10%as%a%treatment%for%cardiovascular%disease.[2,4,15]In%patients%with%cancer,%coenzyme%Q10%has%been%shown%to%protect%the%heart%from%anthracycline%-induced%cardiotoxicity%(anthracyclines%are%a%family%of%chemotherapy%drugs,%including%doxorubicin,that%have%the%potential%to%damage%the%heart)[3,16-18]%and%to%stimulate%the%immune%system.[19,20]%Stimulation%of%the%immune%system%by%this%compound%has%also%been%observed%in%animalstudies%and%in%humans%without%cancer.[21-27]%In%part%because%of%its%immunostimulatory%potential,coenzyme%Q10%has%been%used%as%an%adjuvant%therapy%in%patients%with%various%types%of%cancer.[17,20,28-33]

While%coenzyme%Q10%may%show%indirect%anticancer%activity%through%its%effect(s)%on%the%immunesystem,%there%is%evidence%to%suggest%that%analogs%of%this%compound%can%suppress%cancer%growthdirectly.%Analogs%of%coenzyme%Q10%have%been%shown%to%inhibit%the%proliferation%of%cancer%cells%invitro and%the%growth%of%cancer%cells%transplanted%into%rats%and%mice.[12,34]%In%view%of%thesefindings,%it%has%been%proposed%that%analogs%of%coenzyme%Q10%may%function%as%antimetabolites%to

http://www.cancer.gov/about-cancer/treatment/cam/hp/coenzyme-q10-pdq#cit/section_2.1

disrupt%normal%biochemical%reactions%that%are%required%for%cell%growth%and/or%survival%and,%thus,that%they%may%be%useful%as%chemotherapeutic%agents.[12,34]

Several%companies%distribute%coenzyme%Q10%as%a%dietary%supplement.%In%the%United%States,%dietarysupplements%are%regulated%as%foods,%not%drugs.%Therefore,%premarket%evaluation%and%approval%bythe%U.S.%Food%and%Drug%Administration%(FDA)%are%not%required%unless%specific%disease%preventionor%treatment%claims%are%made.%The%FDA%can,%however,%remove%from%the%market%dietarysupplements%that%it%deems%unsafe.%Because%dietary%supplements%are%not%formally%reviewed%formanufacturing%consistency,%there%may%be%considerable%variation%from%lot%to%lot.%The%FDA%has%notapproved%coenzyme%Q10%for%the%treatment%of%cancer%or%any%other%medical%condition.

To%conduct%clinical%drug%research%in%the%United%States,%researchers%must%file%an%InvestigationalNew%Drug%(IND)%application%with%the%FDA.%The%IND%application%process%is%highly%confidential,%andIND%information%can%be%disclosed%only%by%the%applicants.%To%date,%no%investigators%haveannounced%that%they%have%applied%for%an%IND%to%study%coenzyme%Q10%as%a%treatment%for%cancer.

In%animal%studies,%coenzyme%Q10%has%been%administered%by%injection%(intravenous,intraperitoneal,%intramuscular,%or%subcutaneous).%In%humans,%it%is%usually%taken%orally%as%a%pill%(gelbead%or%capsule),%but%intravenous%infusions%have%been%given.[4]%Coenzyme%Q10%is%absorbed%bestwith%fat;%therefore,%lipid%preparations%are%better%absorbed%than%the%purified%compound.[2,4]%Inhuman%studies,%supplementation%doses%and%administration%schedules%have%varied,%but%usuallyhave%been%in%the%range%of%90%to%390%mg/day.

References

1.% Crane%FL,%Sun%IL,%Sun%EE:%The%essential%functions%of%coenzyme%Q.%Clin%Investig%71%(8%Suppl):S55-9,%1993.%[PUBMED%Abstract]

2.% Pepping%J:%Coenzyme%Q10.%Am%J%Health%Syst%Pharm%56%(6):%519-21,%1999.%[PUBMED%Abstract]

3.% Folkers%K,%Wolaniuk%A:%Research%on%coenzyme%Q10%in%clinical%medicine%and%inimmunomodulation.%Drugs%Exp%Clin%Res%11%(8):%539-45,%1985.%[PUBMED%Abstract]

4.% Overvad%K,%Diamant%B,%Holm%L,%et%al.:%Coenzyme%Q10%in%health%and%disease.%Eur%J%Clin%Nutr%53(10):%764-70,%1999.%[PUBMED%Abstract]

5.% Beyer%RE,%Nordenbrand%K,%Ernster%L:%The%role%of%coenzyme%Q%as%a%mitochondrial%antioxidant:%ashort%review.%In:%Folkers%K,%Yamamura%Y,%eds.:%Biomedical%and%Clinical%Aspects%of%Coenzyme%Q.Vol%5.%Amsterdam,%The%Netherlands:%Elsevier%Science%Publishers%B%V%(Biomedical%Division),1986,%pp%17-24.

6.% Gordon%M:%Dietary%antioxidants%in%disease%prevention.%Nat%Prod%Rep%13%(4):%265-73,1996.%[PUBMED%Abstract]

7.% Palazzoni%G,%Pucello%D,%Littarru%GP,%et%al.:%Coenzyme%Q10%and%colorectal%neoplasms%in%agedpatients.%Rays%22%(1%Suppl):%73-6,%1997%Jan-Mar.%[PUBMED%Abstract]

8.% Ernster%L,%Dallner%G:%Biochemical,%physiological%and%medical%aspects%of%ubiquinone%function.Biochim%Biophys%Acta%1271%(1):%195-204,%1995.%[PUBMED%Abstract]

9.% Yamamoto%Y,%Yamashita%S,%Fujisawa%A,%et%al.:%Oxidative%stress%in%patients%with%hepatitis,cirrhosis,%and%hepatoma%evaluated%by%plasma%antioxidants.%Biochem%Biophys%Res%Commun247%(1):%166-70,%1998.%[PUBMED%Abstract]

10.% Yamamoto%Y,%Yamashita%S:%Plasma%ratio%of%ubiquinol%and%ubiquinone%as%a%marker%of%oxidativestress.%Mol%Aspects%Med%18%(Suppl):%S79-84,%1997.%[PUBMED%Abstract]

11.% Ernster%L,%Forsmark-Andrée%P:%Ubiquinol:%an%endogenous%antioxidant%in%aerobic%organisms.Clin%Investig%71%(8%Suppl):%S60-5,%1993.%[PUBMED%Abstract]

12.% Folkers%K:%The%potential%of%coenzyme%Q%10%(NSC-140865)%in%cancer%treatment.%CancerChemother%Rep%2%4%(4):%19-22,%1974.%[PUBMED%Abstract]

13.% Folkers%K,%Osterborg%A,%Nylander%M,%et%al.:%Activities%of%vitamin%Q10%in%animal%models%and%aserious%deficiency%in%patients%with%cancer.%Biochem%Biophys%Res%Commun%234%(2):%296-9,1997.%[PUBMED%Abstract]

14.% Jolliet%P,%Simon%N,%Barré%J,%et%al.:%Plasma%coenzyme%Q10%concentrations%in%breast%cancer:prognosis%and%therapeutic%consequences.%Int%J%Clin%Pharmacol%Ther%36%(9):%506-9,1998.%[PUBMED%Abstract]

15.% Baggio%E,%Gandini%R,%Plancher%AC,%et%al.:%Italian%multicenter%study%on%the%safety%and%efficacy%ofcoenzyme%Q10%as%adjunctive%therapy%in%heart%failure.%CoQ10%Drug%Surveillance%Investigators.Mol%Aspects%Med%15%(Suppl):%s287-94,%1994.%[PUBMED%Abstract]

16.% Cortes%EP,%Gupta%M,%Chou%C,%et%al.:%Adriamycin%cardiotoxicity:%early%detection%by%systolic%timeinterval%and%possible%prevention%by%coenzyme%Q10.%Cancer%Treat%Rep%62%(6):%887-91,1978.%[PUBMED%Abstract]

17.% Folkers%K,%Brown%R,%Judy%WV,%et%al.:%Survival%of%cancer%patients%on%therapy%with%coenzyme%Q10.Biochem%Biophys%Res%Commun%192%(1):%241-5,%1993.%[PUBMED%Abstract]

18.% Iarussi%D,%Auricchio%U,%Agretto%A,%et%al.:%Protective%effect%of%coenzyme%Q10%on%anthracyclinescardiotoxicity:%control%study%in%children%with%acute%lymphoblastic%leukemia%and%non-Hodgkinlymphoma.%Mol%Aspects%Med%15%(Suppl):%s207-12,%1994.%[PUBMED%Abstract]

19.% Folkers%K,%Shizukuishi%S,%Takemura%K,%et%al.:%Increase%in%levels%of%IgG%in%serum%of%patientstreated%with%coenzyme%Q10.%Res%Commun%Chem%Pathol%Pharmacol%38%(2):%335-8,1982.%[PUBMED%Abstract]

20.% Complementary%treatments%highlighted%at%recent%meeting.%Oncology%(Huntingt)%13%(2):%166,1999.%[PUBMED%Abstract]

21.% Bliznakov%E,%Casey%A,%Premuzic%E:%Coenzymes%Q:%stimulants%of%the%phagocytic%activity%in%ratsand%immune%response%in%mice.%Experientia%26%(9):%953-4,%1970.%[PUBMED%Abstract]

22.% Folkers%K,%Hanioka%T,%Xia%LJ,%et%al.:%Coenzyme%Q10%increases%T4/T8%ratios%of%lymphocytes%inordinary%subjects%and%relevance%to%patients%having%the%AIDS%related%complex.%BiochemBiophys%Res%Commun%176%(2):%786-91,%1991.%[PUBMED%Abstract]

23.% Kawase%I,%Niitani%H,%Saijo%N,%et%al.:%Enhancing%effect%of%coenzyme,%Q10%on%immunorestorationwith%Mycobacterium%bovis%BCG%in%tumor-bearing%mice.%Gann%69%(4):%493-7,%1978.%[PUBMEDAbstract]

24.% Bliznakov%EG:%Effect%of%stimulation%of%the%host%defense%system%by%coenzyme%Q%10%ondibenzpyrene-induced%tumors%and%infection%with%Friend%leukemia%virus%in%mice.%Proc%NatlAcad%Sci%U%S%A%70%(2):%390-4,%1973.%[PUBMED%Abstract]

25.% Bliznakov%EG,%Adler%AD:%Nonlinear%response%of%the%reticuloendothelial%system%uponstimulation.%Pathol%Microbiol%(Basel)%38%(6):%393-410,%1972.%[PUBMED%Abstract]

26.% Bliznakov%EG:%Coenzyme%Q%in%experimental%infections%and%neoplasia.%In:%Folkers%K,%YamamuraY,%eds.:%Biomedical%and%Clinical%Aspects%of%Coenzyme%Q.%Vol%1.%Amsterdam,%The%Netherlands:Elsevier/North-Holland%Biomedical%Press,%1977,%pp%73-83.

27.% Barbieri%B,%Lund%B,%Lundström%B,%et%al.:%Coenzyme%Q10%administration%increases%antibody%titerin%hepatitis%B%vaccinated%volunteers--a%single%blind%placebo-controlled%and%randomizedclinical%study.%Biofactors%9%(2-4):%351-7,%1999.%[PUBMED%Abstract]

28.% Lockwood%K,%Moesgaard%S,%Hanioka%T,%et%al.:%Apparent%partial%remission%of%breast%cancer%in'high%risk'%patients%supplemented%with%nutritional%antioxidants,%essential%fatty%acids%andcoenzyme%Q10.%Mol%Aspects%Med%15%(Suppl):%s231-40,%1994.%[PUBMED%Abstract]

29.% Lockwood%K,%Moesgaard%S,%Folkers%K:%Partial%and%complete%regression%of%breast%cancer%inpatients%in%relation%to%dosage%of%coenzyme%Q10.%Biochem%Biophys%Res%Commun%199%(3):%1504-8,%1994.%[PUBMED%Abstract]

30.% Lockwood%K,%Moesgaard%S,%Yamamoto%T,%et%al.:%Progress%on%therapy%of%breast%cancer%withvitamin%Q10%and%the%regression%of%metastases.%Biochem%Biophys%Res%Commun%212%(1):%172-7,1995.%[PUBMED%Abstract]

31.% Folkers%K:%Relevance%of%the%biosynthesis%of%coenzyme%Q10%and%of%the%four%bases%of%DNA%as%arationale%for%the%molecular%causes%of%cancer%and%a%therapy.%Biochem%Biophys%Res%Commun224%(2):%358-61,%1996.%[PUBMED%Abstract]

32.% Ren%S,%Lien%EJ:%Natural%products%and%their%derivatives%as%cancer%chemopreventive%agents.%ProgDrug%Res%48:%147-71,%1997.%[PUBMED%Abstract]

33.% Hodges%S,%Hertz%N,%Lockwood%K,%et%al.:%CoQ10:%could%it%have%a%role%in%cancer%management?Biofactors%9%(2-4):%365-70,%1999.%[PUBMED%Abstract]

34.% Folkers%K,%Porter%TH,%Bertino%JR,%et%al.:%Inhibition%of%two%human%tumor%cell%lines%byantimetabolites%of%coenzyme%Q10.%Res%Commun%Chem%Pathol%Pharmacol%19%(3):%485-90,1978.%[PUBMED%Abstract]

HistoryCoenzyme%Q10%was%first%isolated%in%1957,%and%its%chemical%structure%(benzoquinone%compound)was%determined%in%1958.[1,2]%Interest%in%coenzyme%Q10%as%a%therapeutic%agent%in%cancer%began%in1961,%when%a%deficiency%was%noted%in%the%blood%of%both%Swedish%and%American%cancer%patients,especially%in%the%blood%of%patients%with%breast%cancer.[2-4]%A%subsequent%study%showed%astatistically%significant%relationship%between%the%level%of%plasma%coenzyme%Q10%deficiency%andbreast%cancer%prognosis.[5]%Low%blood%levels%of%this%compound%have%been%reported%in%patientswith%malignancies%other%than%breast%cancer,%including%myeloma,%lymphoma,%and%cancers%of%thelung,%prostate,%pancreas,%colon,%kidney,%and%head%and%neck.[2,6,7]%Furthermore,%decreased%levelsof%coenzyme%Q10%have%been%detected%in%malignant%human%tissue,[8-12]%but%increased%levels%havebeen%reported%as%well.[8]

A%large%amount%of%laboratory%and%animal%data%on%coenzyme%Q10%have%accumulated%since%1962.[2]Research%into%cellular%energy-producing%mechanisms%that%involve%this%compound%was%awardedthe%Nobel%Prize%in%Chemistry%in%1978.%Some%of%the%accumulated%data%show%that%coenzyme%Q10stimulates%animal%immune%systems,%leading%to%higher%antibody%levels,[13]%greater%numbersand/or%activities%of%macrophages%and%T%cells%(T%lymphocytes),[13,14]%and%increased%resistance%toinfection.[15-17]%Coenzyme%Q10%has%also%been%reported%to%increase%IgG%(immunoglobulin%G)antibody%levels%and%to%increase%the%CD4%to%CD8%T-cell%ratio%in%humans.[18-20]%CD4%and%CD8%areproteins%found%on%the%surface%of%T%cells,%with%CD4%and%CD8%identifying%helper%T%cells%and%cytotoxicT%cells,%respectively;%decreased%CD4%to%CD8%T-cell%ratios%have%been%reported%for%cancer%patients.[21,22]%Research%subsequently%delineated%the%antioxidant%properties%of%coenzyme%Q10.[23-27]

Proposed%mechanisms%of%action%for%coenzyme%Q10%that%are%relevant%to%cancer%include%its%essentialfunction%in%cellular%energy%production%and%its%stimulation%of%the%immune%system%(which%may%bothbe%related),%as%well%as%its%role%as%an%antioxidant.%Coenzyme%Q10%is%essential%to%aerobic%energyproduction,[1,25,28]%and%it%has%been%suggested%that%increased%cellular%energy%leads%to%increasedantibody%synthesis%in%B%cells%(B%lymphocytes).[6,18]%As%noted%previously%(General%Informationsection),%coenzyme%Q10%can%also%behave%as%an%antioxidant.[1,25-27,29-32]%In%this%capacity,

http://www.cancer.gov/about-cancer/treatment/cam/hp/coenzyme-q10-pdq/#link/_5

coenzyme%Q10%is%thought%to%stabilize%cell%membranes%(lipid%-containing%structures%essential%tomaintaining%cell%integrity)%and%to%prevent%free%radical%damage%to%other%important%cellularcomponents.[1,25,27,32]%Free%radical%damage%to%DNA%(and%possibly%to%other%cellular%molecules)may%be%a%factor%in%cancer%development.[11,23,30,33-36]

References

5.% Jolliet%P,%Simon%N,%Barré%J,%et%al.:%Plasma%coenzyme%Q10%concentrations%in%breast%cancer:prognosis%and%therapeutic%consequences.%Int%J%Clin%Pharmacol%Ther%36%(9):%506-9,1998.%[PUBMED%Abstract]

8.% Chipperfield%B:%Ubiquinone%concentrations%in%some%tumour-bearing%tissues.%Ubiquinoneconcentrations%in%tumours%and%some%normal%tissues%in%man.%Nature%209%(29):%1207-8,1966.%[PUBMED%Abstract]

9.% Eggens%I,%Elmberger%PG,%Löw%P:%Polyisoprenoid,%cholesterol%and%ubiquinone%levels%in%humanhepatocellular%carcinomas.%Br%J%Exp%Pathol%70%(1):%83-92,%1989.%[PUBMED%Abstract]

10.% Mano%T,%Iwase%K,%Hayashi%R,%et%al.:%Vitamin%E%and%coenzyme%Q%concentrations%in%the%thyroidtissues%of%patients%with%various%thyroid%disorders.%Am%J%Med%Sci%315%(4):%230-2,%1998.%[PUBMEDAbstract]

11.% Picardo%M,%Grammatico%P,%Roccella%F,%et%al.:%Imbalance%in%the%antioxidant%pool%in%melanomacells%and%normal%melanocytes%from%patients%with%melanoma.%J%Invest%Dermatol%107%(3):%322-6,

12.% Portakal%O,%Ozkaya%O,%Erden%Inal%M,%et%al.:%Coenzyme%Q10%concentrations%and%antioxidantstatus%in%tissues%of%breast%cancer%patients.%Clin%Biochem%33%(4):%279-84,%2000.%[PUBMEDAbstract]

13.% Bliznakov%E,%Casey%A,%Premuzic%E:%Coenzymes%Q:%stimulants%of%the%phagocytic%activity%in%ratsand%immune%response%in%mice.%Experientia%26%(9):%953-4,%1970.%[PUBMED%Abstract]

14.% Kawase%I,%Niitani%H,%Saijo%N,%et%al.:%Enhancing%effect%of%coenzyme,%Q10%on%immunorestorationwith%Mycobacterium%bovis%BCG%in%tumor-bearing%mice.%Gann%69%(4):%493-7,%1978.%[PUBMEDAbstract]

18.% Folkers%K,%Shizukuishi%S,%Takemura%K,%et%al.:%Increase%in%levels%of%IgG%in%serum%of%patientstreated%with%coenzyme%Q10.%Res%Commun%Chem%Pathol%Pharmacol%38%(2):%335-8,1982.%[PUBMED%Abstract]

19.% Folkers%K,%Hanioka%T,%Xia%LJ,%et%al.:%Coenzyme%Q10%increases%T4/T8%ratios%of%lymphocytes%inordinary%subjects%and%relevance%to%patients%having%the%AIDS%related%complex.%BiochemBiophys%Res%Commun%176%(2):%786-91,%1991.%[PUBMED%Abstract]

20.% Barbieri%B,%Lund%B,%Lundström%B,%et%al.:%Coenzyme%Q10%administration%increases%antibody%titerin%hepatitis%B%vaccinated%volunteers--a%single%blind%placebo-controlled%and%randomizedclinical%study.%Biofactors%9%(2-4):%351-7,%1999.%[PUBMED%Abstract]

21.% Shaw%M,%Ray%P,%Rubenstein%M,%et%al.:%Lymphocyte%subsets%in%urologic%cancer%patients.%Urol%Res15%(3):%181-5,%1987.%[PUBMED%Abstract]

22.% Tsuyuguchi%I,%Shiratsuchi%H,%Fukuoka%M:%T-lymphocyte%subsets%in%primary%lung%cancer.%Jpn%JClin%Oncol%17%(1):%13-7,%1987.%[PUBMED%Abstract]

23.% Yamamoto%Y,%Yamashita%S,%Fujisawa%A,%et%al.:%Oxidative%stress%in%patients%with%hepatitis,cirrhosis,%and%hepatoma%evaluated%by%plasma%antioxidants.%Biochem%Biophys%Res%Commun247%(1):%166-70,%1998.%[PUBMED%Abstract]

24.% Yamamoto%Y,%Yamashita%S:%Plasma%ratio%of%ubiquinol%and%ubiquinone%as%a%marker%of%oxidativestress.%Mol%Aspects%Med%18%(Suppl):%S79-84,%1997.%[PUBMED%Abstract]

25.% Crane%FL,%Sun%IL,%Sun%EE:%The%essential%functions%of%coenzyme%Q.%Clin%Investig%71%(8%Suppl):S55-9,%1993.%[PUBMED%Abstract]

27.% Ernster%L,%Forsmark-Andrée%P:%Ubiquinol:%an%endogenous%antioxidant%in%aerobic%organisms.Clin%Investig%71%(8%Suppl):%S60-5,%1993.%[PUBMED%Abstract]

29.% Beyer%RE,%Nordenbrand%K,%Ernster%L:%The%role%of%coenzyme%Q%as%a%mitochondrial%antioxidant:%ashort%review.%In:%Folkers%K,%Yamamura%Y,%eds.:%Biomedical%and%Clinical%Aspects%of%Coenzyme%Q.Vol%5.%Amsterdam,%The%Netherlands:%Elsevier%Science%Publishers%B%V%(Biomedical%Division),1986,%pp%17-24.

30.% Gordon%M:%Dietary%antioxidants%in%disease%prevention.%Nat%Prod%Rep%13%(4):%265-73,1996.%[PUBMED%Abstract]

31.% Palazzoni%G,%Pucello%D,%Littarru%GP,%et%al.:%Coenzyme%Q10%and%colorectal%neoplasms%in%agedpatients.%Rays%22%(1%Suppl):%73-6,%1997%Jan-Mar.%[PUBMED%Abstract]

32.% Ernster%L,%Dallner%G:%Biochemical,%physiological%and%medical%aspects%of%ubiquinone%function.Biochim%Biophys%Acta%1271%(1):%195-204,%1995.%[PUBMED%Abstract]

33.% Aust%AE,%Eveleigh%JF:%Mechanisms%of%DNA%oxidation.%Proc%Soc%Exp%Biol%Med%222%(3):%246-52,1999.%[PUBMED%Abstract]

34.% Halliwell%B:%Oxygen%and%nitrogen%are%pro-carcinogens.%Damage%to%DNA%by%reactive%oxygen,chlorine%and%nitrogen%species:%measurement,%mechanism%and%the%effects%of%nutrition.%MutatRes%443%(1-2):%37-52,%1999.%[PUBMED%Abstract]

35.% Burcham%PC:%Internal%hazards:%baseline%DNA%damage%by%endogenous%products%of%normalmetabolism.%Mutat%Res%443%(1-2):%11-36,%1999.%[PUBMED%Abstract]

36.% Dreher%D,%Junod%AF:%Role%of%oxygen%free%radicals%in%cancer%development.%Eur%J%Cancer%32A%(1):30-8,%1996.%[PUBMED%Abstract]

Laboratory/Animal/Preclinical StudiesLaboratory%work%on%coenzyme%Q10%has%focused%primarily%on%its%structure%and%its%function%in%cell

respiration.%Studies%in%animals%have%demonstrated%that%coenzyme%Q10%is%capable%of%stimulatingthe%immune%system,%with%treated%animals%showing%increased%resistance%to%protozoal%infections[1,2]%and%to%viral%and%chemically-induced%neoplasia.[1-4]%Early%studies%of%coenzyme%Q10%showedincreased%hematopoiesis%(the%formation%of%new%blood%cells)%in%monkeys,[4,5]%rabbits,[6]%andpoultry.[5]%Coenzyme%Q10%demonstrated%a%protective%effect%on%the%heart%muscle%of%mice,%rats,%andrabbits%given%the%anthracycline%anticancer%drug%doxorubicin.[7-12]%Although%another%studyconfirmed%this%protective%effect%with%intraperitoneal%administration%of%doxorubicin%in%mice,%itfailed%to%demonstrate%a%protective%effect%when%the%anthracycline%was%given%intravenously,%which%isthe%route%of%administration%in%humans.[13]%Researchers%in%one%study%sounded%a%cautionary%notewhen%they%found%that%coadministration%of%coenzyme%Q10%and%radiation%therapy%decreased%theeffectiveness%of%the%radiation%therapy.[14]%In%this%study,%mice%inoculated%with%human%small%celllung%cancer%cells%(a%xenograft%study),%and%then%given%coenzyme%Q10%and%single-dose%radiationtherapy,%showed%substantially%less%inhibition%of%tumor%growth%than%mice%in%the%control%group%thatwere%treated%with%radiation%therapy%alone.%Since%radiation%leads%to%the%production%of%free%radicals,and%since%antioxidants%protect%against%free%radical%damage,%the%effect%in%this%study%might%beexplained%by%coenzyme%Q10%acting%as%an%antioxidant.%As%noted%previously%(General%Information),there%is%some%evidence%from%laboratory%and%animal%studies%that%analogs%of%coenzyme%Q10%mayhave%direct%anticancer%activity.[15,16]

References

5.% Folkers%K,%Brown%R,%Judy%WV,%et%al.:%Survival%of%cancer%patients%on%therapy%with%coenzyme%Q10.Biochem%Biophys%Res%Commun%192%(1):%241-5,%1993.%[PUBMED%Abstract]

6.% Ludwig%FC,%Elashoff%RM,%Smith%JL,%et%al.:%Response%of%the%bone%marrow%of%the%vitamin%E-deficient%rabbit%to%coenzyme%Q%and%vitamin%E.%Scand%J%Haematol%4%(4):%292-300,

7.% Choe%JY,%Combs%AB,%Folkers%K:%Prevention%by%coenzyme%Q10%of%the%electrocardiographicchanges%induced%by%adriamycin%in%rats.%Res%Commun%Chem%Pathol%Pharmacol%23%(1):%199-202,1979.%[PUBMED%Abstract]

8.% Combs%AB,%Choe%JY,%Truong%DH,%et%al.:%Reduction%by%coenzyme%Q10%of%the%acute%toxicity%ofadriamycin%in%mice.%Res%Commun%Chem%Pathol%Pharmacol%18%(3):%565-8,%1977.%[PUBMEDAbstract]

9.% Folkers%K,%Choe%JY,%Combs%AB:%Rescue%by%coenzyme%Q10%from%electrocardiographicabnormalities%caused%by%the%toxicity%of%adriamycin%in%the%rat.%Proc%Natl%Acad%Sci%U%S%A%75%(10):5178-80,%1978.%[PUBMED%Abstract]

10.% Lubawy%WC,%Dallam%RA,%Hurley%LH:%Protection%against%anthramycin-induced%toxicity%in%mice%bycoenzyme%Q10.%J%Natl%Cancer%Inst%64%(1):%105-9,%1980.%[PUBMED%Abstract]

11.% Shinozawa%S,%Gomita%Y,%Araki%Y:%Protective%effects%of%various%drugs%on%adriamycin(doxorubicin)-induced%toxicity%and%microsomal%lipid%peroxidation%in%mice%and%rats.%Biol%PharmBull%16%(11):%1114-7,%1993.%[PUBMED%Abstract]

12.% Usui%T,%Ishikura%H,%Izumi%Y,%et%al.:%Possible%prevention%from%the%progression%of%cardiotoxicity%inadriamycin-treated%rabbits%by%coenzyme%Q10.%Toxicol%Lett%12%(1):%75-82,%1982.%[PUBMEDAbstract]

13.% Shaeffer%J,%El-Mahdi%AM,%Nichols%RK:%Coenzyme%Q10%and%adriamycin%toxicity%in%mice.%ResCommun%Chem%Pathol%Pharmacol%29%(2):%309-15,%1980.%[PUBMED%Abstract]

14.% Lund%EL,%Quistorff%B,%Spang-Thomsen%M,%et%al.:%Effect%of%radiation%therapy%on%small-cell%lungcancer%is%reduced%by%ubiquinone%intake.%Folia%Microbiol%(Praha)%43%(5):%505-6,%1998.%[PUBMEDAbstract]

16.% Folkers%K,%Porter%TH,%Bertino%JR,%et%al.:%Inhibition%of%two%human%tumor%cell%lines%byantimetabolites%of%coenzyme%Q10.%Res%Commun%Chem%Pathol%Pharmacol%19%(3):%485-90,1978.%[PUBMED%Abstract]

Human/Clinical StudiesThe%use%of%coenzyme%Q10%as%a%treatment%for%cancer%in%humans%has%been%investigated%in%only%alimited%manner.%The%studies%that%have%been%published%consist%of%randomized%controlled%trials,anecdotal%reports,%case%reports,%case%series,%and%uncontrolled%clinical%studies.[1-12]

In%view%of%the%promising%results%from%animal%studies,%coenzyme%Q10%was%tested%as%a%protectiveagent%against%the%cardiac%toxicity%observed%in%cancer%patients%treated%with%the%anthracycline%drugdoxorubicin.%It%has%been%postulated%that%doxorubicin%interferes%with%energy-generatingbiochemical%reactions%that%involve%coenzyme%Q10%in%heart%muscle%mitochondria%and%that%thisinterference%can%be%overcome%by%coenzyme%Q10%supplementation.[2,13,14]%Studies%with%adultsand%children,%including%the%aforementioned%randomized%trial,%have%confirmed%the%decrease%incardiac%toxicity%observed%in%animal%studies.[1-3,7]%A%randomized%trial%[7]%of%20%patients%tested%theability%of%coenzyme%Q10%to%reduce%cardiotoxicity%caused%by%anthracycline%drugs.

A%larger%randomized,%placebo-controlled%trial%of%236%breast%cancer%patients%concluded%thatcoenzyme%Q10%at%a%daily%dose%of%300%mg%combined%with%300%IU%of%vitamin%E,%divided%into%threedoses,%did%not%improve%fatigue%levels%or%quality%of%life%after%24%weeks%of%supplementation.[8]

The%potential%of%coenzyme%Q10%as%an%adjuvant%therapy%for%cancer%has%also%been%explored.%In%viewof%observations%that%blood%levels%of%coenzyme%Q10%are%frequently%reduced%in%cancer%patients,[6,10,11,15,16]%supplementation%with%this%compound%has%been%tested%in%patients%undergoingconventional%treatment.%An%open-label%(nonblinded),%uncontrolled%clinical%study%in%Denmarkfollowed%32%breast%cancer%patients%for%18%months.[4]%The%disease%in%these%patients%had%spread%tothe%axillary%lymph%nodes,%and%an%unreported%number%had%distant%metastases.%The%patientsreceived%antioxidant%supplementation%(vitamin%C,%vitamin%E,%and%beta%carotene),%other%vitaminsand%trace%minerals,%essential%fatty%acids,%and%coenzyme%Q10%(at%a%dose%of%90%mg/day),%in%additionto%standard%therapy%(surgery,%radiation%therapy,%and%chemotherapy,%with%or%without%tamoxifen).The%patients%were%seen%every%3%months%to%monitor%disease%status%(progressive%disease%orrecurrence),%and,%if%there%was%a%suspicion%of%recurrence,%mammography,%bone%scan,%x-ray,%orbiopsy%was%performed.%The%survival%rate%for%the%study%period%was%100%%(4%deaths%were%expected).Six%patients%were%reported%to%show%some%evidence%of%remission;%however,%incomplete%clinical%datawere%provided,%and%information%suggestive%of%remission%was%presented%for%only%3%of%the%6patients.%None%of%the%6%patients%had%evidence%of%further%metastases.%For%all%32%patients,%decreaseduse%of%painkillers,%improved%quality%of%life,%and%an%absence%of%weight%loss%were%reported.%Whetherpainkiller%use%and%quality%of%life%were%measured%objectively%(e.g.,%from%pharmacy%records%andvalidated%questionnaires,%respectively)%or%subjectively%(from%patient%self-reports)%was%notspecified.

In%a%follow-up%study,%1%of%the%6%patients%with%a%reported%remission%and%a%new%patient%were%treatedfor%several%months%with%higher%doses%of%coenzyme%Q10%(390%and%300%mg/day,%respectively).[5]Surgical%removal%of%the%primary%breast%tumor%in%both%patients%had%been%incomplete.%After%3%to%4months%of%high-level%coenzyme%Q10%supplementation,%both%patients%appeared%to%experiencecomplete%regression%of%their%residual%breast%tumors%(assessed%by%clinical%examination%andmammography).%It%should%be%noted%that%a%different%patient%identifier%was%used%in%the%follow-up

study%for%the%patient%who%had%participated%in%the%original%study.%Therefore,%it%is%impossible%todetermine%which%of%the%6%patients%with%a%reported%remission%took%part%in%the%follow-up%study.%Inthe%follow-up%study%report,%the%researchers%noted%that%all%32%patients%from%the%original%studyremained%alive%at%24%months%of%observation,%whereas%6%deaths%had%been%expected.[5]

In%another%report%by%the%same%investigators,%3%breast%cancer%patients%were%followed%for%a%total%of3%to%5%years%on%high-dose%coenzyme%Q10%(390%mg/day).[6]%One%patient%had%complete%remission%ofliver%metastases%(determined%by%clinical%examination%and%ultrasonography),%another%hadremission%of%a%tumor%that%had%spread%to%the%chest%wall%(determined%by%clinical%examination%andchest%x-ray),%and%the%third%patient%had%no%microscopic%evidence%of%remaining%tumor%after%amastectomy%(determined%by%biopsy%of%the%tumor%bed).

All%3%of%the%above-mentioned%human%studies%[4-6]%had%important%design%flaws%that%could%haveinfluenced%their%outcome.%Study%weaknesses%include%the%absence%of%a%control%group%(i.e.,%allpatients%received%coenzyme%Q10),%possible%selection%bias%in%the%follow-up%investigations,%andmultiple%confounding%variables%(i.e.,%the%patients%received%a%variety%of%supplements%in%addition%tocoenzyme%Q10,%and%they%received%standard%therapy%either%during%or%immediately%beforesupplementation%with%coenzyme%Q10).%Thus,%it%is%impossible%to%determine%whether%any%of%thebeneficial%results%was%directly%related%to%coenzyme%Q10%therapy.

Anecdotal%reports%of%coenzyme%Q10%lengthening%the%survival%of%patients%with%pancreatic,%lung,rectal,%laryngeal,%colon,%and%prostate%cancers%also%exist%in%the%peer-reviewed%scientific%literature.[3]%The%patients%described%in%these%reports%also%received%therapies%other%than%coenzyme%Q10,including%chemotherapy,%radiation%therapy,%and%surgery.

Check%NCI’s%list%of%cancer%clinical%trials%for%cancer%CAM%clinical%trials%on%coenzyme%Q10%that%areactively%enrolling%patients.

References

2.% Cortes%EP,%Gupta%M,%Chou%C,%et%al.:%Adriamycin%cardiotoxicity:%early%detection%by%systolic%timeinterval%and%possible%prevention%by%coenzyme%Q10.%Cancer%Treat%Rep%62%(6):%887-91,1978.%[PUBMED%Abstract]

3.% Folkers%K,%Brown%R,%Judy%WV,%et%al.:%Survival%of%cancer%patients%on%therapy%with%coenzyme%Q10.

Biochem%Biophys%Res%Commun%192%(1):%241-5,%1993.%[PUBMED%Abstract]

5.% Lockwood%K,%Moesgaard%S,%Folkers%K:%Partial%and%complete%regression%of%breast%cancer%inpatients%in%relation%to%dosage%of%coenzyme%Q10.%Biochem%Biophys%Res%Commun%199%(3):%1504-8,%1994.%[PUBMED%Abstract]

7.% Iarussi%D,%Auricchio%U,%Agretto%A,%et%al.:%Protective%effect%of%coenzyme%Q10%on%anthracyclinescardiotoxicity:%control%study%in%children%with%acute%lymphoblastic%leukemia%and%non-Hodgkinlymphoma.%Mol%Aspects%Med%15%(Suppl):%s207-12,%1994.%[PUBMED%Abstract]

8.% Lesser%GJ,%Case%D,%Stark%N,%et%al.:%A%randomized,%double-blind,%placebo-controlled%study%of%oralcoenzyme%Q10%to%relieve%self-reported%treatment-related%fatigue%in%newly%diagnosed%patientswith%breast%cancer.%J%Support%Oncol%11%(1):%31-42,%2013.%[PUBMED%Abstract]

9.% Complementary%treatments%highlighted%at%recent%meeting.%Oncology%(Huntingt)%13%(2):%166,1999.%[PUBMED%Abstract]

13.% Usui%T,%Ishikura%H,%Izumi%Y,%et%al.:%Possible%prevention%from%the%progression%of%cardiotoxicity%inadriamycin-treated%rabbits%by%coenzyme%Q10.%Toxicol%Lett%12%(1):%75-82,%1982.%[PUBMEDAbstract]

14.% Iwamoto%Y,%Hansen%IL,%Porter%TH,%et%al.:%Inhibition%of%coenzyme%Q10-enzymes,%succinoxidaseand%NADH-oxidase,%by%adriamycin%and%other%quinones%having%antitumor%activity.%BiochemBiophys%Res%Commun%58%(3):%633-8,%1974.%[PUBMED%Abstract]

Adverse EffectsNo%serious%toxicity%associated%with%the%use%of%coenzyme%Q10%has%been%reported.[1-4]%Doses%of%100mg%/day%or%higher%have%caused%mild%insomnia%in%some%individuals.%Liver%enzyme%elevation%hasbeen%detected%in%patients%taking%doses%of%300%mg/day%for%extended%periods%of%time,%but%no%livertoxicity%has%been%reported.[1]%Researchers%in%one%cardiovascular%study%reported%that%coenzymeQ10%caused%rashes,%nausea,%and%epigastric%(upper%abdominal)%pain%that%required%withdrawal%of%asmall%number%of%patients%from%the%study.[5]%Other%reported%side%effects%have%included%dizziness,photophobia%(abnormal%visual%sensitivity%to%light),%irritability,[5]%headache,%heartburn,%and%fatigue.[6]

Certain%lipid%-lowering%drugs,%such%as%the%statins%(lovastatin,%pravastatin,%and%simvastatin)%andgemfibrozil,%as%well%as%oral%agents%that%lower%blood%sugar,%such%as%glyburide%and%tolazamide,cause%a%decrease%in%serum%levels%of%coenzyme%Q10%and%reduce%the%effects%of%coenzyme%Q10supplementation.[1,7-9]%Beta-blockers%(drugs%that%slow%the%heart%rate%and%lower%blood%pressure)can%inhibit%coenzyme%Q10-dependent%enzyme%reactions.%The%contractile%force%of%the%heart%inpatients%with%high%blood%pressure%can%be%increased%by%coenzyme%Q10%administration.[1]Coenzyme%Q10%can%reduce%the%body’s%response%to%the%anticoagulant%drug%warfarin.[9]%Finally,coenzyme%Q10%can%decrease%insulin%requirements%in%individuals%with%diabetes.

References

4.% Heller%JH:%Disease,%the%host%defense,%and%Q-10.%Perspect%Biol%Med%16%(2):%181-7,%1973Winter.%[PUBMED%Abstract]

5.% Baggio%E,%Gandini%R,%Plancher%AC,%et%al.:%Italian%multicenter%study%on%the%safety%and%efficacy%ofcoenzyme%Q10%as%adjunctive%therapy%in%heart%failure.%CoQ10%Drug%Surveillance%Investigators.Mol%Aspects%Med%15%(Suppl):%s287-94,%1994.%[PUBMED%Abstract]

6.% Feigin%A,%Kieburtz%K,%Como%P,%et%al.:%Assessment%of%coenzyme%Q10%tolerability%in%Huntington's

disease.%Mov%Disord%11%(3):%321-3,%1996.%[PUBMED%Abstract]

7.% Kaikkonen%J,%Nyyssönen%K,%Tuomainen%TP,%et%al.:%Determinants%of%plasma%coenzyme%Q10%inhumans.%FEBS%Lett%443%(2):%163-6,%1999.%[PUBMED%Abstract]

8.% Thibault%A,%Samid%D,%Tompkins%AC,%et%al.:%Phase%I%study%of%lovastatin,%an%inhibitor%of%themevalonate%pathway,%in%patients%with%cancer.%Clin%Cancer%Res%2%(3):%483-91,%1996.%[PUBMEDAbstract]

9.% Coenzyme%Q10.%In:%Jellin%JM,%Hitchens%K,%eds.:%Natural%Medicines%Comprehensive%Database.Stockton,%Calif:%Therapeutic%Research%Faculty,%1999,%pp%241-42.

Summary of the Evidence for Coenzyme Q10To%assist%readers%in%evaluating%the%results%of%human%studies%of%complementary%and%alternativemedicine%(CAM)%treatments%for%cancer,%the%strength%of%the%evidence%(i.e.,%the%“%levels%of%evidence”)%associated%with%each%type%of%treatment%is%provided%whenever%possible.%To%qualify%for%a%level%ofevidence%analysis,%a%study%must:

Report%on%a%therapeutic%outcome%or%outcomes,%such%as%tumor%response,%improvement%insurvival,%or%measured%improvement%in%quality%of%life.

Describe%clinical%findings%in%sufficient%detail%that%a%meaningful%evaluation%can%be%made.

Separate%levels%of%evidence%scores%are%assigned%to%qualifying%human%studies%on%the%basis%ofstatistical%strength%of%the%study%design%and%scientific%strength%of%the%treatment%outcomes%(i.e.,endpoints)%measured.%The%resulting%two%scores%are%then%combined%to%produce%an%overall%score.%Atable%showing%the%levels%of%evidence%scores%for%qualifying%human%studies%cited%in%this%summary%ispresented%below.%For%an%explanation%of%the%scores%and%additional%information%about%levels%ofevidence%analysis%of%CAM%treatments%for%cancer,%refer%to%Levels%of%Evidence%for%Human%Studies%ofCancer%Complementary%and%Alternative%Medicine.

••

•

Coenzyme Q10 Summary: Reference Numbers and theCorresponding Levels of Evidence

Reference'Number Statistical'Strengthof'Study'Design

Strength'ofEndpointsMeasured

Combined'Score

http://www.cancer.gov/about-cancer/pdq/levels-evidence-cam/HealthProfessional

References

This%PDQ%cancer%information%summary%for%health%professionals%provides%comprehensive,%peer-reviewed,%evidence-based%information%about%the%use%of%coenzyme%Q10%in%the%treatment%of%peoplewith%cancer.%It%is%intended%as%a%resource%to%inform%and%assist%clinicians%who%care%for%cancerpatients.%It%does%not%provide%formal%guidelines%or%recommendations%for%making%health%caredecisions.

[1] 3iii%%Nonconsecutivecase%series

Diii%%Indirectsurrogates%--%tumorresponse%rate

3iiiDiii

http://www.cancer.gov/about-cancer/treatment/cam/hp/coenzyme-q10-pdq/#link/_AboutThis_1

This%summary%is%reviewed%regularly%and%updated%as%necessary%by%the%PDQ%CancerComplementary%and%Alternative%Medicine%Editorial%Board,%which%is%editorially%independent%of%theNational%Cancer%Institute%(NCI).%The%summary%reflects%an%independent%review%of%the%literature%anddoes%not%represent%a%policy%statement%of%NCI%or%the%National%Institutes%of%Health%(NIH).

The%lead%reviewer%for%Coenzyme%Q10%is:

Jeffrey%D.%White,%MD%(National%Cancer%Institute)

Levels of Evidence

•••

•

http://www.cancer.gov/about-cancer/pdq/levels-evidence-cam/HealthProfessional

National%Cancer%Institute:%PDQ®%Coenzyme%Q10.%Bethesda,%MD:%National%Cancer%Institute.%Datelast%modified%<MM/DD/YYYY>.%Available%at:%http://www.cancer.gov/about-cancer/treatment/cam/hp/coenzyme-q10-pdq.%Accessed%<MM/DD/YYYY>.

Images%in%this%summary%are%used%with%permission%of%the%author(s),%artist,%and/or%publisher%foruse%within%the%PDQ%summaries%only.%Permission%to%use%images%outside%the%context%of%PDQinformation%must%be%obtained%from%the%owner(s)%and%cannot%be%granted%by%the%National%CancerInstitute.%Information%about%using%the%illustrations%in%this%summary,%along%with%many%othercancer-related%images,%is%available%in%Visuals%Online,%a%collection%of%over%2,000%scientific%images.

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Contact Us

Updated:%May%14,%2014

http://www.cancer.gov/about-cancer/treatment/cam/hp/coenzyme-q10-pdq

7/24/15, 12:04Milk Thistle - National Cancer Institute

Page 1 of 27http://www.cancer.gov/about-cancer/treatment/cam/hp/milk-thistle-pdq#section/all

Milk Thistle–for health professionals (PDQ®)

OverviewThis%complementary%and%alternative%medicine%(CAM)%information%summary%provides%an%overviewof%the%use%of%milk%thistle%as%a%treatment%and%adjunct%agent%for%people%with%cancer.

The%summary%includes%a%brief%history%of%milk%thistle,%a%review%of%the%laboratory%studies%and%clinicaltrials,%and%a%description%of%adverse%effects%associated%with%milk%thistle%use.

Milk%thistle%is%a%plant%whose%fruit%and%seeds%have%been%used%for%more%than%2,000%years%as%atreatment%for%liver%and%biliary%disorders.

The%active%substance%in%milk%thistle,%silymarin,%is%a%complex%mixture%of%flavonolignans,primarily%consisting%of%the%following%isomers:%silybin%(consisting%of%silybins%A%and%B),%isosilybin(consisting%of%isosilybins%A%and%B),%silychristin%(also%known%as%silichristin),%and%silydianin%(alsoknown%as%silidianin).%In%the%literature,%silybin%is%often%referred%to%as%silibinin.

Laboratory%studies%demonstrate%that%silymarin%functions%as%an%antioxidant,%stabilizes%cellularmembranes,%stimulates%detoxification%pathways,%stimulates%regeneration%of%liver%tissue,inhibits%the%growth%of%certain%cancer%cell%lines,%exerts%direct%cytotoxic%activity%toward%certaincancer%cell%lines,%and%may%increase%the%efficacy%of%certain%chemotherapy%agents.

Human%clinical%trials%have%investigated%milk%thistle%or%silymarin%primarily%in%individuals%withhepatitis%or%cirrhosis.

Few%adverse%side%effects%have%been%reported%for%milk%thistle,%but%little%information%aboutinteractions%with%anticancer%medications%or%other%drugs%is%available.

Milk%thistle%is%available%in%the%United%States%as%a%dietary%supplement.

Many%of%the%medical%and%scientific%terms%used%in%the%summary%are%hypertext%linked%(at%first%use%ineach%section)%to%the%NCI%Dictionary%of%Cancer%Terms,%which%is%oriented%toward%nonexperts.%Whena%linked%term%is%clicked,%a%definition%will%appear%in%a%separate%window.

Reference%citations%in%some%PDQ%CAM%information%summaries%may%include%links%to%external%Websites%that%are%operated%by%individuals%or%organizations%for%the%purpose%of%marketing%or%advocating

•

http://cancer.gov/dictionary/

the%use%of%specific%treatments%or%products.%These%reference%citations%are%included%forinformational%purposes%only.%Their%inclusion%should%not%be%viewed%as%an%endorsement%of%thecontent%of%the%Web%sites,%or%of%any%treatment%or%product,%by%the%PDQ%Cancer%CAM%Editorial%Boardor%the%National%Cancer%Institute.

General InformationThe%botanical%name%for%milk%thistle%is%Silybum marianum (L.)%Gaertn.%Milk%thistle%is%also%referred%toas%holy%thistle,%Marian%thistle,%Mary%thistle,%Our%Lady’s%thistle,%St.%Mary%thistle,%wild%artichoke,Mariendistel%(German),%and%Chardon-Marie%(French).%The%plant%is%indigenous%to%Europe%but%canalso%be%found%in%the%United%States%and%South%America.%Traditionally,%the%leaves%have%been%used%insalads,%and%the%fruit%of%the%flower%has%been%roasted%as%a%coffee%substitute.%The%seeds%of%milkthistle%are%the%medicinal%parts%of%the%plant.[1]%The%primary%active%constituent%of%milk%thistle%issilymarin,%which%is%composed%of%the%following%isomers:%silybin%(consisting%of%silybins%A%and%B),isosilybin%(consisting%of%isosilybins%A%and%B),%silychristin,%and%silydianin.%Most%supplements%arestandardized%according%to%their%silybin%content.%Silybin%and%isosilybin%are%both%mixtures%of%twodiastereomers,%silybins%A%and%B%and%isosilybins%A%and%B,%respectively.[2,3]%Special%formulations%ofsilybin%have%been%developed%to%enhance%the%bioavailability%of%the%herbal%product;%these%forms%aresold%under%the%names%Legalon,%silipide,%and%Siliphos.%Because%of%milk%thistle’s%lipophilic%nature,%itis%usually%administered%in%capsule%or%tablet%form%rather%than%as%an%herbal%tea.%In%Europe,%silybin%isadministered%intravenously%as%the%only%effective%antidote%for%Amanita phalloides (Fr.).[4]%Humansexposed%to%this%mushroom%toxin%develop%serious%liver%failure%that%ultimately%progresses%to%death.

Several%companies%distribute%milk%thistle%as%a%dietary%supplement.%In%the%United%States,%dietarysupplements%are%regulated%as%foods,%not%drugs.%Therefore,%premarket%evaluation%and%approval%bythe%Food%and%Drug%Administration%(FDA)%are%not%required%unless%specific%disease%prevention%ortreatment%claims%are%made.%Because%dietary%supplements%are%not%formally%reviewed%formanufacturing%consistency,%ingredients%may%vary%considerably%from%lot%to%lot;%in%addition,%there%isno%guarantee%that%ingredients%identified%on%product%labels%are%present%at%all%or%are%present%in%thespecified%amounts.%It%is%important%to%note%that%the%FDA%has%not%approved%the%use%of%milk%thistle%asa%treatment%for%cancer%patients%or%patients%with%any%other%medical%condition.

To%conduct%clinical%drug%research%in%the%United%States,%researchers%must%file%an%InvestigationalNew%Drug%(IND)%application%with%the%FDA.%The%IND%application%process%is%confidential,%and%INDinformation%can%be%disclosed%only%by%the%applicants.%To%date,%only%one%investigator%hasannounced%holding%an%IND%to%study%milk%thistle%as%an%adjunct%cancer%treatment.

Despite%milk%thistle’s%long%history%of%being%used%to%treat%liver%and%biliary%complaints,%it%was%notuntil%1968%that%silymarin%was%isolated%from%the%seeds%of%the%plant,%and%it%was%proposed%that

http://www.cancer.gov/about-cancer/treatment/cam/hp/milk-thistle-pdq#cit/section_2.1

silymarin%might%be%the%active%ingredient.[5]%Silymarin%was%later%determined%to%be%a%flavonolignanthat%is%composed%of%four%structurally%similar%compounds:%silybin,%isosilybin,%silydianin,%andsilychristin.[2]%Researchers%have%investigated%the%role%that%silibinin%may%play%in%the%treatment%ofhepatitis%and%cirrhosis.%Most%studies%have%investigated%the%isolated%compound%silymarin%or%itsmost%active%isomer%silybin,%rather%than%the%herbal%plant%in%its%whole%form.

Silymarin%is%most%well%known%for%its%purported%effects%on%the%liver.%In%laboratory%studies,%silymarinhas%been%found%to%stabilize%cell%membranes,%thus%preventing%toxic%chemicals%from%entering%thecell.[4,6-8]%Laboratory%studies%have%also%demonstrated%that%silymarin%stimulates%synthesis%andactivity%of%enzymes%responsible%for%detoxification%pathways%and%exhibits%antioxidant%properties.[7-18]%Specifically,%silymarin%has%been%shown%to%stimulate%the%glutathione%S-transferase%pathway%andalter%the%intracellular%concentration%of%glutathione%(a%potent%antioxidant).%Silymarin%has%also%beenshown%to%neutralize%a%wide%range%of%free%radicals.

Laboratory%experiments%conducted%using%cancer%cell%lines%have%suggested%that%silibinin%enhancesthe%efficacy%of%cisplatin%and%doxorubicin%against%ovarian%and%breast%cancer%cells.[19]%Silybinappears%to%have%direct%anticancer%effects%against%prostate,%breast,%and%ectocervical%tumor%cells.[20]%Silybin%may%also%affect%the%cell%cycle%in%cancer%cells%by%slowing%down%cell%growth,%asdemonstrated%with%prostate%cancer%cell%lines.[21]%Laboratory%studies%using%leukemia%cell%linesfound%that%silybin%did%not%stimulate%growth%of%leukemia%cells.[22]

No%human%clinical%trials%on%milk%thistle%or%silymarin%as%a%cancer%treatment%or%as%an%adjunctivetherapy%in%individuals%with%cancer%have%been%published.%Most%clinical%trials%have%investigatedsilymarin’s%effectiveness%in%the%treatment%of%patients%with%hepatitis,%cirrhosis,%or%biliary%disorders.[23-32]%These%studies%have%employed%a%wide%range%of%doses%(120–560%mg%/day)%and%have%yieldedconflicting%results.Many%of%the%well-designed,%large-scale%trials%have%reported%a%beneficial%effectrather%than%no%effect.%The%most%commonly%reported%adverse%effects%are%a%mild%laxative%effect%andgastrointestinal%upset.

References

1.% PDR®%for%Herbal%Medicines™.%2nd%ed.%Montvale,%NJ:%Medical%Economics,%2000.

2.% Lee%DY,%Liu%Y:%Molecular%structure%and%stereochemistry%of%silybin%A,%silybin%B,%isosilybin%A,%andisosilybin%B,%Isolated%from%Silybum%marianum%(milk%thistle).%J%Nat%Prod%66%(9):%1171-4,2003.%[PUBMED%Abstract]

3.% Napolitano%JG,%Lankin%DC,%Graf%TN,%et%al.:%HiFSA%fingerprinting%applied%to%isomers%with%near-identical%NMR%spectra:%the%silybin/isosilybin%case.%J%Org%Chem%78%(7):%2827-39,%2013.%[PUBMEDAbstract]

4.% Hruby%K,%Csomos%G,%Fuhrmann%M,%et%al.:%Chemotherapy%of%Amanita%phalloides%poisoning%with

intravenous%silibinin.%Hum%Toxicol%2%(2):%183-95,%1983.%[PUBMED%Abstract]

5.% Wagner%H,%Hörhammer%L,%Münster%R:%[On%the%chemistry%of%silymarin%(silybin),%the%activeprinciple%of%the%fruits%from%Silybum%marianum%(L.)%Gaertn.%(Carduus%marianus%L.)]Arzneimittelforschung%18%(6):%688-96,%1968.%[PUBMED%Abstract]

6.% Campos%R,%Garrido%A,%Guerra%R,%et%al.:%Silybin%dihemisuccinate%protects%against%glutathionedepletion%and%lipid%peroxidation%induced%by%acetaminophen%on%rat%liver.%Planta%Med%55%(5):417-9,%1989.%[PUBMED%Abstract]

7.% Farghali%H,%Kameniková%L,%Hynie%S,%et%al.:%Silymarin%effects%on%intracellular%calcuim%andcytotoxicity:%a%study%in%perfused%rat%hepatocytes%after%oxidative%stress%injury.%Pharmacol%Res41%(2):%231-7,%2000.%[PUBMED%Abstract]

8.% Lettéron%P,%Labbe%G,%Degott%C,%et%al.:%Mechanism%for%the%protective%effects%of%silymarin%againstcarbon%tetrachloride-induced%lipid%peroxidation%and%hepatotoxicity%in%mice.%Evidence%thatsilymarin%acts%both%as%an%inhibitor%of%metabolic%activation%and%as%a%chain-breakingantioxidant.%Biochem%Pharmacol%39%(12):%2027-34,%1990.%[PUBMED%Abstract]

9.% Zhao%J,%Agarwal%R:%Tissue%distribution%of%silibinin,%the%major%active%constituent%of%silymarin,%inmice%and%its%association%with%enhancement%of%phase%II%enzymes:%implications%in%cancerchemoprevention.%Carcinogenesis%20%(11):%2101-8,%1999.%[PUBMED%Abstract]

10.% Valenzuela%A,%Guerra%R,%Videla%LA:%Antioxidant%properties%of%the%flavonoids%silybin%and%(+)-cyanidanol-3:%comparison%with%butylated%hydroxyanisole%and%butylated%hydroxytoluene.Planta%Med%(6):%438-40,%1986.%[PUBMED%Abstract]

11.% Valenzuela%A,%Guerra%R,%Garrido%A:%Silybin%dihemisuccinate%protects%rat%erythrocytes%againstphenylhydrazine-induced%lipid%peroxidation%and%hemolysis.%Planta%Med%53%(5):%402-5,1987.%[PUBMED%Abstract]

12.% Valenzuela%A,%Aspillaga%M,%Vial%S,%et%al.:%Selectivity%of%silymarin%on%the%increase%of%theglutathione%content%in%different%tissues%of%the%rat.%Planta%Med%55%(5):%420-2,%1989.%[PUBMEDAbstract]

13.% Mira%ML,%Azevedo%MS,%Manso%C:%The%neutralization%of%hydroxyl%radical%by%silibin,%sorbinil%andbendazac.%Free%Radic%Res%Commun%4%(2):%125-9,%1987.%[PUBMED%Abstract]

14.% Mira%L,%Silva%M,%Manso%CF:%Scavenging%of%reactive%oxygen%species%by%silibinin%dihemisuccinate.Biochem%Pharmacol%48%(4):%753-9,%1994.%[PUBMED%Abstract]

15.% Koch%HP,%Löffler%E:%Influence%of%silymarin%and%some%flavonoids%on%lipid%peroxidation%in%humanplatelets.%Methods%Find%Exp%Clin%Pharmacol%7%(1):%13-8,%1985.%[PUBMED%Abstract]

16.% Garrido%A,%Arancibia%C,%Campos%R,%et%al.:%Acetaminophen%does%not%induce%oxidative%stress%in

isolated%rat%hepatocytes:%its%probable%antioxidant%effect%is%potentiated%by%the%flavonoidsilybin.%Pharmacol%Toxicol%69%(1):%9-12,%1991.%[PUBMED%Abstract]

17.% Bosisio%E,%Benelli%C,%Pirola%O:%Effect%of%the%flavanolignans%of%Silybum%marianum%L.%on%lipidperoxidation%in%rat%liver%microsomes%and%freshly%isolated%hepatocytes.%Pharmacol%Res%25%(2):147-54,%1992%Feb-Mar.%[PUBMED%Abstract]

18.% Altorjay%I,%Dalmi%L,%Sári%B,%et%al.:%The%effect%of%silibinin%(Legalon)%on%the%the%free%radicalscavenger%mechanisms%of%human%erythrocytes%in%vitro.%Acta%Physiol%Hung%80%(1-4):%375-80,1992.%[PUBMED%Abstract]

19.% Scambia%G,%De%Vincenzo%R,%Ranelletti%FO,%et%al.:%Antiproliferative%effect%of%silybin%ongynaecological%malignancies:%synergism%with%cisplatin%and%doxorubicin.%Eur%J%Cancer%32A%(5):877-82,%1996.%[PUBMED%Abstract]

20.% Bhatia%N,%Zhao%J,%Wolf%DM,%et%al.:%Inhibition%of%human%carcinoma%cell%growth%and%DNAsynthesis%by%silibinin,%an%active%constituent%of%milk%thistle:%comparison%with%silymarin.%CancerLett%147%(1-2):%77-84,%1999.%[PUBMED%Abstract]

21.% Zi%X,%Agarwal%R:%Silibinin%decreases%prostate-specific%antigen%with%cell%growth%inhibition%via%G1arrest,%leading%to%differentiation%of%prostate%carcinoma%cells:%implications%for%prostate%cancerintervention.%Proc%Natl%Acad%Sci%U%S%A%96%(13):%7490-5,%1999.%[PUBMED%Abstract]

22.% Duthie%SJ,%Johnson%W,%Dobson%VL:%The%effect%of%dietary%flavonoids%on%DNA%damage%(strandbreaks%and%oxidised%pyrimdines)%and%growth%in%human%cells.%Mutat%Res%390%(1-2):%141-51,1997.%[PUBMED%Abstract]

23.% Vailati%A,%Aristia%L,%Sozzé%E,%et%al.:%Randomized%open%study%of%the%dose-effect%relationship%of%ashort%course%of%IdB%1016%in%patients%with%viral%or%alcoholic%hepatitis.%Fitoterapia%64%(3),%219-28,1993.

24.% Salmi%HA,%Sarna%S:%Effect%of%silymarin%on%chemical,%functional,%and%morphological%alterationsof%the%liver.%A%double-blind%controlled%study.%Scand%J%Gastroenterol%17%(4):%517-21,1982.%[PUBMED%Abstract]

25.% Parés%A,%Planas%R,%Torres%M,%et%al.:%Effects%of%silymarin%in%alcoholic%patients%with%cirrhosis%ofthe%liver:%results%of%a%controlled,%double-blind,%randomized%and%multicenter%trial.%J%Hepatol%28(4):%615-21,%1998.%[PUBMED%Abstract]

26.% Moscarella%S,%Giusti%A,%Marra%F,%et%al.:%Therapeutic%and%antilipoperoxidant%effects%of%silybin-phosphatidylcholine%complex%in%chronic%liver%disease:%preliminary%results.%CurrentTherapeutic%Research%53%(1):%98-102.

27.% Marena%C,%Lampertico%M:%Preliminary%clinical%development%of%silipide:%a%new%complex%of

silybin%in%toxic%liver%disorders.%Planta%Med%57%(Suppl%2):%A124-5,%1991.

28.% Marcelli%R,%Bizzoni%P,%Conte%D,%et%al.:%Randomized%controlled%study%of%the%efficacy%andtolerability%of%a%short%course%of%IdB%1016%in%the%treatment%of%chronic%persistent%hepatitis.European%Bulletin%of%Drug%Research%1%(3):%131-5,%1992.

29.% Flisiak%R,%Prokopowicz%D:%Effect%of%misoprostol%on%the%course%of%viral%hepatitis%B.Hepatogastroenterology%44%(17):%1419-25,%1997%Sep-Oct.%[PUBMED%Abstract]

30.% Ferenci%P:%[Therapy%of%chronic%hepatitis%C]%Wien%Med%Wochenschr%150%(23-24):%481-5,2000.%[PUBMED%Abstract]

31.% Buzzelli%G,%Moscarella%S,%Giusti%A,%et%al.:%Therapeutic%effects%of%a%new%silybin%complex%inchronic%active%hepatitis%(CAH).%[Abstract]%Hellenic%Journal%of%Gastroenterology%5%(Suppl):%A-151,%38,%1992.

32.% Albrecht%M,%Frerick%H,%Kuhn%U,%et%al.:%Therapy%of%toxic%liver%pathologies%with%Legalon®.%Z%KlinMed%47:%87-92,%1992.

HistoryMilk%thistle%has%been%used%for%more%than%2,000%years,%primarily%as%a%treatment%for%liverdysfunction.%The%oldest%reported%use%of%milk%thistle%was%by%Dioscorides,%who%recommended%theherb%as%a%treatment%for%serpent%bites.[1]%Pliny%the%Elder%(A.D.%23–79)%reported%that%the%juice%of%theplant%mixed%with%honey%is%indicated%for%“carrying%off%bile.”[1,2]%In%the%Middle%Ages,%milk%thistlewas%revered%as%an%antidote%for%liver%toxins.[1,2]%The%British%herbalist%Culpepper%reported%it%to%beeffective%for%relieving%obstructions%of%the%liver.[1,2]%In%1898,%eclectic%physicians%Felter%and%Lloydstated%the%herb%was%good%for%congestion%of%the%liver,%spleen,%and%kidney.[1,2]%Native%Americansuse%milk%thistle%to%treat%boils%and%other%skin%diseases.%Homeopathic%practitioners%usedpreparations%from%the%seeds%to%treat%jaundice,%gallstones,%peritonitis,%hemorrhage,%bronchitis,%andvaricose%veins.[2]%The%German%Commission%E%recommends%milk%thistle%use%for%dyspepticcomplaints,%toxin-induced%liver%damage,%hepatic%cirrhosis,%and%as%a%supportive%therapy%for%chronicinflammatory%liver%conditions.[3]

References

1.% Flora%K,%Hahn%M,%Rosen%H,%et%al.:%Milk%thistle%(Silybum%marianum)%for%the%therapy%of%liverdisease.%Am%J%Gastroenterol%93%(2):%139-43,%1998.%[PUBMED%Abstract]

2.% Foster%S:%Milk%Thistle:%Silybum%marianum.%Rev.%ed.%Austin,%Tex:%American%Botanical%Council,1999.

3.% Blumenthal%M,%Busse%WR,%et%al.,%eds.:%The%Complete%German%Commission%E%Monographs:Therapeutic%Guide%to%Herbal%Medicines.%Austin,%Tex:%American%Botanical%Council,%1998.

Laboratory/Animal/Preclinical StudiesResearch%studies%conducted%in%the%laboratory%have%investigated%the%properties%of%silymarin%or%itsisomer%silybin%using%cell%lines%and%animal%models.%Other%substances%in%milk%thistle%have%not%beenextensively%studied.

Several%research%studies%have%investigated%the%effects%of%silymarin%or%silybin%in%a%noncancercontext.%These%studies%have%tested%silymarin%or%silybin:

In%healthy%animal%liver%and%kidney%cells.

As%a%prophylaxis%against%toxic%chemicals.

In%stimulating%detoxification%pathways%(enzyme%concentrations%and%activity).

For%antioxidant%properties.

Silymarin%or%silybin%has%also%been%investigated%in%cancer%models.%The%effects%of%silymarin%and/orsilybin%have%been%investigated%in%prostate%(DU%145,%LNCaP,%PC-3),[1-6]%breast%(MDA-MB%468,%MCF-7),[7-9]%hepatic%(HepG2),[10,11]%epidermoid%(A431),[11]%colon%(Caco-2),[12]%ovarian%(OVCA%433,A2780),[13]%histiocytic%lymphoma%(U-937),[14]%and%leukemia%(HL-60)%[15,16]%cells.%In%animal%tumormodels,%tongue%cancer,[17]%skin%cancer,[18-23]%bladder%cancer,[24]%and%adenocarcinoma%of%thecolon%[25,26]%and%small%intestine%[26]%have%been%investigated.%These%studies%have%tested%the%abilityof%silymarin%or%silibinin%to:

Mitigate%the%toxicity%associated%with%chemotherapy%agents.

Enhance%the%efficacy%of%chemotherapy%agents.

Inhibit%the%growth%of%cancer%cell%lines%and%inhibit%tumor%initiation%or%tumor%promotion.

Although%many%of%these%studies%have%produced%encouraging%results,%none%of%the%findings%havebeen%replicated%in%human%clinical%trials.

Laboratory%data%suggest%that%silymarin%and%silybin%protect%the%liver%from%damage%induced%by%toxicchemicals.%Animal%studies%have%found%that%liver%cells%treated%with%silybin%and%then%exposed%totoxins%do%not%incur%cell%damage%or%death%at%the%same%rate%as%liver%cells%that%are%not%treated%withsilybin.%This%finding%suggests%that%silybin%can%prevent%toxins%from%entering%the%cell%or%effectivelyexports%toxins%out%of%the%cell%before%damage%ensues.[11,27-31]%Alternatively,%this%may%be%relatedto%the%effect%of%silymarin%on%detoxification%systems.%In vitro data%have%shown%silybin%to%stimulateand/or%inhibit%phase%I%detoxification%pathways%in%silybin-treated%human%liver%cells.%However,%this

•

effect%was%found%to%be%dose-dependent,%and%these%levels%are%not%physiologically%attainable%withthe%current%manufacturer%dose%recommendations.[32,33]

Silymarin%has%been%shown%to%stimulate%phase%II%detoxification%pathways%in%mice.%Administration%ofsilymarin%(100%or%200%mg%/kg%body%weight/day)%to%SENCAR%mice%for%3%days%significantly%increasedglutathione%S-transferase%activity%in%the%liver%(P%<%.01–.001),%lung%(P%<%.05–.01),%stomach%(P%<%.05),small%bowel%(P%<%.01),%and%skin%(P%<%.01).%This%effect%appeared%to%be%dose-dependent.[34]Administration%of%silymarin%to%rats%challenged%with%a%toxin%(50%mg/kg%body%weight)%resulted%inhigher%levels%of%glutathione%in%liver%cells,%decreased%levels%of%oxidative%stress%(measured%bymalondialdehyde%concentrations),%and%less%elevated%liver%function%tests%(measured%by%levels%ofaspartate%aminotransferase%[AST]%and%alanine%aminotransferase%[ALT]).[31]%Silymarin%and%silybinhave%also%been%found%to%accelerate%cell%regeneration%in%the%liver%through%stimulation%ofprecursors%to%DNA%synthesis%and%enhancement%of%production%of%the%cellular%enzymes%required%forsynthesis%of%DNA.[35-40]%Laboratory%studies%have%also%shown%silymarin%and%silybin%to%be%potentantioxidants.[28,29,41-48]%Silymarin%has%been%shown%to%mitigate%oxidative%stress%in%cells%treatedwith%pro-oxidant%compounds.

A%number%of%laboratory%studies%have%investigated%the%effect%of%silymarin%or%silybin%on%the%efficacyand%toxicity%of%chemotherapy%agents%or%have%measured%their%direct%cytotoxic%activity.%In%aninvestigation%of%the%effect%of%a%variety%of%flavonoids%on%the%formation%of%DNA%damage,%silymarindid%not%induce%DNA%damage%in%colon%(Caco-2)%cells,%hepatoma%(HepG2)%cells,%and%humanlymphocytes.[12]%At%higher%concentrations%of%silymarin%(400–1,000%µmol/L)%DNA%damage%wasinduced%in%an%epithelial%cell%line%(HeLa%cells).%At%higher%concentrations%(1,000%µmol/L)%DNAdamage%was%observed%in%human%lymphocytes.%Cell%growth%was%inhibited%as%the%flavonoidconcentration%was%increased%in%human%lymphocytes%and%HeLa%cells.%Only%at%very%highconcentrations%was%cell%viability%affected%by%silymarin%in%HepG2%cells.%Although%this%studydemonstrated%that%the%flavonolignans%of%Silybum marianum (L.)%are%capable%of%inhibiting%cellularproliferation%and%inducing%DNA%strand%breaks,%the%results%were%obtained%at%very%highconcentrations%that%may%be%difficult%to%achieve%in%humans.%This%study%also%showed%that%silymarindoes%not%stimulate%cell%growth%in%the%HeLa,%Burkitt%lymphoma,%and%human%hepatoma%cell%lines.

Silymarin%has%also%been%investigated%as%a%possible%adjunctive%agent%in%mitigating%some%of%thetoxicity%associated%with%chemotherapy%agents.%Silybin%and%silychristin%exerted%a%protective%effecton%monkey%kidney%cells%exposed%to%vincristine%and%especially%cisplatin%chemotherapy.[49]%Silybin(200%mg/kg%body%weight)%administration%with%cisplatin%in%rats%resulted%in%statistically%significantreductions%in%measures%of%kidney%toxicity.[50]%Significant%decreases%in%weight%loss,%faster%recoveryof%urinary%osmolality%measures,%and%depressions%in%the%increase%in%activity%of%urinary%alanineaminopeptidase%([AAP],%a%marker%of%kidney%toxicity)%were%observed.%Silybin%had%no%effect%onmagnesium%excretion%or%glomerular%function.%Silybin%(2%g%/kg%body%weight)%administration%in%rats

receiving%cisplatin%prevented%reductions%in%creatinine%clearance,%increases%in%urea%plasma%levels,and%large%increases%in%urinary%AAP.[51]%No%effect%on%magnesium%excretion%was%observed.%Silybindid%not%interfere%with%the%antineoplastic%effects%of%cisplatin%or%ifosfamide%in%germ%cell%tumors.%Inexperiments%with%ovarian%and%breast%cancer%cell%lines,%silybin%potentiated%the%effect%of%cisplatinand%doxorubicin.[13]%IdB%1,016,%a%form%of%silybin%bound%to%a%phospholipid%complex,%was%found%toenhance%the%activity%of%cisplatin%against%A2780%ovarian%cancer%cells%but%had%no%effect%on%its%own.[52]%Silybin%increased%the%chemosensitivity%of%DU%145%prostate%cancer%cells%resistant%tochemotherapy.[53]

Studies%have%also%investigated%the%effect%of%silymarin%on%tumor%initiation%and%promotion.%Silymarinappears%to%have%a%chemopreventive%effect%through%perturbations%in%the%cell%cycle,%altering%cellsignaling%that%induces%cellular%proliferation,%affecting%angiogenesis,%or%through%its%anti-inflammatory%properties.[1,7,13,19,54]%These%findings%have%been%supported%in%human%prostate,breast,%ectocervical,%ovarian,%hepatic,%leukemia,%and%epidermoid%cell%lines.[4,7,9,10,15,55]%Aninvestigation%of%the%effect%of%silymarin%on%ultraviolet%B%radiation-induced%nonmelanoma%skincancer%in%mice%found%that%silymarin%treatment%significantly%reduced%tumor%incidence%(P%<%.003),tumor%multiplicity%(P%<%.0001),%and%tumor%volume%(P%<%.0001).[19]%These%findings%suggest%thatsilymarin%plays%a%prominent%role%in%the%reduction%of%cancer%cells%and%in%preventing%the%formationof%cancer%cells.%A%number%of%studies%have%investigated%the%mechanism%through,%which%silymarinmay%affect%tumor%promotion%in%mouse%skin%tumor%models.%Studies%have%found%that%silymarinreduces%transcription%of%markers%of%tumor%promotion%and%activity,[19]%inhibits%transcription%oftumor%promoters,[56]%stimulates%antioxidant%activities,[19,23]%interferes%with%cell%signaling,[55]inhibits%inflammatory%actions,[19,22]%and%modulates%cell-cycle%regulation.[57]

In%prostate%cancer%cell%lines,%silybin%has%been%shown%to%inhibit%growth%factors%and%stimulate%cellgrowth,[1-3,5]%promote%cell%cycle%arrest,[1,4]%and%inhibit%antiapoptotic%activity.[53]%In%rats%withazoxymethane%-induced%colon%cancer,%dietary%silymarin%resulted%in%a%reduction%in%the%incidenceand%multiplicity%of%adenocarcinoma%of%the%colon%in%a%dose-dependent%manner.[25,26]%Dietarysilymarin%had%no%effect%on%small%intestinal%adenocarcinoma,[26]%but%exerted%a%preventive%effect%inmice%with%N-butyl-N-(4-hydroxybutyl)%nitrosamine%–induced%bladder%cancer%[24]%and%in%F344%ratswith%4-nitroquinoline%1-oxide%–induced%cancer%of%the%tongue.[17]%Dietary%silybin%administered%tonude%mice%with%prostate%carcinoma%increased%production%of%insulin-like%growth%factor-bindingprotein-3%in%the%plasma%of%mice%and%significantly%inhibited%tumor%volume%(P%<%.05).[2]%Silibininadministered%twice%daily%reduced%the%growth%of%colorectal%tumor%xenografts%in%mice%for%a%periodof%6%weeks.[58,59]

References

1.% Zi%X,%Agarwal%R:%Silibinin%decreases%prostate-specific%antigen%with%cell%growth%inhibition%via%G1

arrest,%leading%to%differentiation%of%prostate%carcinoma%cells:%implications%for%prostate%cancerintervention.%Proc%Natl%Acad%Sci%U%S%A%96%(13):%7490-5,%1999.%[PUBMED%Abstract]

2.% Singh%RP,%Dhanalakshmi%S,%Tyagi%AK,%et%al.:%Dietary%feeding%of%silibinin%inhibits%advance%humanprostate%carcinoma%growth%in%athymic%nude%mice%and%increases%plasma%insulin-like%growthfactor-binding%protein-3%levels.%Cancer%Res%62%(11):%3063-9,%2002.%[PUBMED%Abstract]

3.% Zi%X,%Zhang%J,%Agarwal%R,%et%al.:%Silibinin%up-regulates%insulin-like%growth%factor-binding%protein3%expression%and%inhibits%proliferation%of%androgen-independent%prostate%cancer%cells.%CancerRes%60%(20):%5617-20,%2000.%[PUBMED%Abstract]

4.% Zi%X,%Grasso%AW,%Kung%HJ,%et%al.:%A%flavonoid%antioxidant,%silymarin,%inhibits%activation%of%erbB1signaling%and%induces%cyclin-dependent%kinase%inhibitors,%G1%arrest,%and%anticarcinogeniceffects%in%human%prostate%carcinoma%DU145%cells.%Cancer%Res%58%(9):%1920-9,%1998.%[PUBMEDAbstract]

5.% Sharma%Y,%Agarwal%C,%Singh%AK,%et%al.:%Inhibitory%effect%of%silibinin%on%ligand%binding%to%erbB1and%associated%mitogenic%signaling,%growth,%and%DNA%synthesis%in%advanced%human%prostatecarcinoma%cells.%Mol%Carcinog%30%(4):%224-36,%2001.%[PUBMED%Abstract]

6.% Flaig%TW,%Glodé%M,%Gustafson%D,%et%al.:%A%study%of%high-dose%oral%silybin-phytosome%followedby%prostatectomy%in%patients%with%localized%prostate%cancer.%Prostate%70%(8):%848-55,2010.%[PUBMED%Abstract]

7.% Bhatia%N,%Zhao%J,%Wolf%DM,%et%al.:%Inhibition%of%human%carcinoma%cell%growth%and%DNAsynthesis%by%silibinin,%an%active%constituent%of%milk%thistle:%comparison%with%silymarin.%CancerLett%147%(1-2):%77-84,%1999.%[PUBMED%Abstract]

8.% Jiang%C,%Agarwal%R,%Lü%J:%Anti-angiogenic%potential%of%a%cancer%chemopreventive%flavonoidantioxidant,%silymarin:%inhibition%of%key%attributes%of%vascular%endothelial%cells%and%angiogeniccytokine%secretion%by%cancer%epithelial%cells.%Biochem%Biophys%Res%Commun%276%(1):%371-8,2000.%[PUBMED%Abstract]

9.% Zi%X,%Feyes%DK,%Agarwal%R:%Anticarcinogenic%effect%of%a%flavonoid%antioxidant,%silymarin,%inhuman%breast%cancer%cells%MDA-MB%468:%induction%of%G1%arrest%through%an%increase%inCip1/p21%concomitant%with%a%decrease%in%kinase%activity%of%cyclin-dependent%kinases%andassociated%cyclins.%Clin%Cancer%Res%4%(4):%1055-64,%1998.%[PUBMED%Abstract]

10.% Saliou%C,%Rihn%B,%Cillard%J,%et%al.:%Selective%inhibition%of%NF-kappaB%activation%by%the%flavonoidhepatoprotector%silymarin%in%HepG2.%Evidence%for%different%activating%pathways.%FEBS%Lett%440(1-2):%8-12,%1998.%[PUBMED%Abstract]

11.% Shear%NH,%Malkiewicz%IM,%Klein%D,%et%al.:%Acetaminophen-induced%toxicity%to%humanepidermoid%cell%line%A431%and%hepatoblastoma%cell%line%Hep%G2,%in%vitro,%is%diminished%by

silymarin.%Skin%Pharmacol%8%(6):%279-91,%1995.%[PUBMED%Abstract]

12.% Duthie%SJ,%Johnson%W,%Dobson%VL:%The%effect%of%dietary%flavonoids%on%DNA%damage%(strandbreaks%and%oxidised%pyrimdines)%and%growth%in%human%cells.%Mutat%Res%390%(1-2):%141-51,1997.%[PUBMED%Abstract]

13.% Scambia%G,%De%Vincenzo%R,%Ranelletti%FO,%et%al.:%Antiproliferative%effect%of%silybin%ongynaecological%malignancies:%synergism%with%cisplatin%and%doxorubicin.%Eur%J%Cancer%32A%(5):877-82,%1996.%[PUBMED%Abstract]

14.% Manna%SK,%Mukhopadhyay%A,%Van%NT,%et%al.:%Silymarin%suppresses%TNF-induced%activation%ofNF-kappa%B,%c-Jun%N-terminal%kinase,%and%apoptosis.%J%Immunol%163%(12):%6800-9,1999.%[PUBMED%Abstract]

15.% Kang%SN,%Lee%MH,%Kim%KM,%et%al.:%Induction%of%human%promyelocytic%leukemia%HL-60%celldifferentiation%into%monocytes%by%silibinin:%involvement%of%protein%kinase%C.%BiochemPharmacol%61%(12):%1487-95,%2001.%[PUBMED%Abstract]

16.% Clinton%SK:%The%dietary%antioxidant%network%and%prostate%carcinoma.%Cancer%86%(9):%1629-31,1999.%[PUBMED%Abstract]

17.% Yanaida%Y,%Kohno%H,%Yoshida%K,%et%al.:%Dietary%silymarin%suppresses%4-nitroquinoline%1-oxide-induced%tongue%carcinogenesis%in%male%F344%rats.%Carcinogenesis%23%(5):%787-94,2002.%[PUBMED%Abstract]

18.% Agarwal%R,%Katiyar%SK,%Lundgren%DW,%et%al.:%Inhibitory%effect%of%silymarin,%an%anti-hepatotoxicflavonoid,%on%12-O-tetradecanoylphorbol-13-acetate-induced%epidermal%ornithinedecarboxylase%activity%and%mRNA%in%SENCAR%mice.%Carcinogenesis%15%(6):%1099-103,1994.%[PUBMED%Abstract]

19.% Katiyar%SK,%Korman%NJ,%Mukhtar%H,%et%al.:%Protective%effects%of%silymarin%againstphotocarcinogenesis%in%a%mouse%skin%model.%J%Natl%Cancer%Inst%89%(8):%556-66,%1997.%[PUBMEDAbstract]

20.% Lahiri-Chatterjee%M,%Katiyar%SK,%Mohan%RR,%et%al.:%A%flavonoid%antioxidant,%silymarin,%affordsexceptionally%high%protection%against%tumor%promotion%in%the%SENCAR%mouse%skintumorigenesis%model.%Cancer%Res%59%(3):%622-32,%1999.%[PUBMED%Abstract]

21.% Singh%RP,%Tyagi%AK,%Zhao%J,%et%al.:%Silymarin%inhibits%growth%and%causes%regression%ofestablished%skin%tumors%in%SENCAR%mice%via%modulation%of%mitogen-activated%protein%kinasesand%induction%of%apoptosis.%Carcinogenesis%23%(3):%499-510,%2002.%[PUBMED%Abstract]

22.% Zhao%J,%Sharma%Y,%Agarwal%R:%Significant%inhibition%by%the%flavonoid%antioxidant%silymarinagainst%12-O-tetradecanoylphorbol%13-acetate-caused%modulation%of%antioxidant%and

inflammatory%enzymes,%and%cyclooxygenase%2%and%interleukin-1alpha%expression%in%SENCARmouse%epidermis:%implications%in%the%prevention%of%stage%I%tumor%promotion.%Mol%Carcinog%26(4):%321-33,%1999.%[PUBMED%Abstract]

23.% Zhao%J,%Lahiri-Chatterjee%M,%Sharma%Y,%et%al.:%Inhibitory%effect%of%a%flavonoid%antioxidantsilymarin%on%benzoyl%peroxide-induced%tumor%promotion,%oxidative%stress%and%inflammatoryresponses%in%SENCAR%mouse%skin.%Carcinogenesis%21%(4):%811-6,%2000.%[PUBMED%Abstract]

24.% Vinh%PQ,%Sugie%S,%Tanaka%T,%et%al.:%Chemopreventive%effects%of%a%flavonoid%antioxidantsilymarin%on%N-butyl-N-(4-hydroxybutyl)nitrosamine-induced%urinary%bladder%carcinogenesisin%male%ICR%mice.%Jpn%J%Cancer%Res%93%(1):%42-9,%2002.%[PUBMED%Abstract]

25.% Kohno%H,%Tanaka%T,%Kawabata%K,%et%al.:%Silymarin,%a%naturally%occurring%polyphenolicantioxidant%flavonoid,%inhibits%azoxymethane-induced%colon%carcinogenesis%in%male%F344%rats.Int%J%Cancer%101%(5):%461-8,%2002.%[PUBMED%Abstract]

26.% Gershbein%LL:%Action%of%dietary%trypsin,%pressed%coffee%oil,%silymarin%and%iron%salt%on%1,2-dimethylhydrazine%tumorigenesis%by%gavage.%Anticancer%Res%14%(3A):%1113-6,%1994%May-Jun.%[PUBMED%Abstract]

27.% Campos%R,%Garrido%A,%Guerra%R,%et%al.:%Silybin%dihemisuccinate%protects%against%glutathionedepletion%and%lipid%peroxidation%induced%by%acetaminophen%on%rat%liver.%Planta%Med%55%(5):417-9,%1989.%[PUBMED%Abstract]

28.% Farghali%H,%Kameniková%L,%Hynie%S,%et%al.:%Silymarin%effects%on%intracellular%calcuim%andcytotoxicity:%a%study%in%perfused%rat%hepatocytes%after%oxidative%stress%injury.%Pharmacol%Res41%(2):%231-7,%2000.%[PUBMED%Abstract]

29.% Lettéron%P,%Labbe%G,%Degott%C,%et%al.:%Mechanism%for%the%protective%effects%of%silymarin%againstcarbon%tetrachloride-induced%lipid%peroxidation%and%hepatotoxicity%in%mice.%Evidence%thatsilymarin%acts%both%as%an%inhibitor%of%metabolic%activation%and%as%a%chain-breakingantioxidant.%Biochem%Pharmacol%39%(12):%2027-34,%1990.%[PUBMED%Abstract]

30.% Valenzuela%A,%Guerra%R,%Garrido%A:%Silybin%dihemisuccinate%protects%rat%erythrocytes%againstphenylhydrazine-induced%lipid%peroxidation%and%hemolysis.%Planta%Med%53%(5):%402-5,1987.%[PUBMED%Abstract]

31.% Campos%R,%Garrido%A,%Guerra%R,%et%al.:%Acetaminophen%hepatotoxicity%in%rats%is%attenuated%bysilybin%dihemisuccinate.%Prog%Clin%Biol%Res%280:%375-8,%1988.%[PUBMED%Abstract]

32.% Zuber%R,%Modrianský%M,%Dvorák%Z,%et%al.:%Effect%of%silybin%and%its%congeners%on%human%livermicrosomal%cytochrome%P450%activities.%Phytother%Res%16%(7):%632-8,%2002.%[PUBMED%Abstract]

33.% Venkataramanan%R,%Ramachandran%V,%Komoroski%BJ,%et%al.:%Milk%thistle,%a%herbal%supplement,

decreases%the%activity%of%CYP3A4%and%uridine%diphosphoglucuronosyl%transferase%in%humanhepatocyte%cultures.%Drug%Metab%Dispos%28%(11):%1270-3,%2000.%[PUBMED%Abstract]

34.% Zhao%J,%Agarwal%R:%Tissue%distribution%of%silibinin,%the%major%active%constituent%of%silymarin,%inmice%and%its%association%with%enhancement%of%phase%II%enzymes:%implications%in%cancerchemoprevention.%Carcinogenesis%20%(11):%2101-8,%1999.%[PUBMED%Abstract]

35.% Sonnenbichler%J,%Mattersberger%J,%Rosen%H:%[Stimulation%of%RNA%synthesis%in%rat%liver%andisolated%hepatocytes%by%silybin,%an%antihepatotoxic%agent%from%Silybum%marianum%L.%Gaertn(author's%transl)]%Hoppe%Seylers%Z%Physiol%Chem%357%(8):%1171-80,%1976.%[PUBMED%Abstract]

36.% Sonnenbichler%J,%Zetl%I:%[Mechanism%of%action%of%silibinin.%V.%Effect%of%silibinin%on%the%synthesisof%ribosomal%RNA,%mRNA%and%tRNA%in%rat%liver%in%vivo]%Hoppe%Seylers%Z%Physiol%Chem%365%(5):555-66,%1984.%[PUBMED%Abstract]

37.% Sonnenbichler%J,%Zetl%I:%Biochemical%effects%of%the%flavonolignane%silibinin%on%RNA,%protein%andDNA%synthesis%in%rat%livers.%Prog%Clin%Biol%Res%213:%319-31,%1986.%[PUBMED%Abstract]

38.% Sonnenbichler%J,%Goldberg%M,%Hane%L,%et%al.:%Stimulatory%effect%of%Silibinin%on%the%DNAsynthesis%in%partially%hepatectomized%rat%livers:%non-response%in%hepatoma%and%other%maligncell%lines.%Biochem%Pharmacol%35%(3):%538-41,%1986.%[PUBMED%Abstract]

39.% Machicao%F,%Sonnenbichler%J:%Mechanism%of%the%stimulation%of%RNA%synthesis%in%rat%liver%nucleiby%silybin.%Hoppe%Seylers%Z%Physiol%Chem%358%(2):%141-7,%1977.%[PUBMED%Abstract]

40.% Dehmlow%C,%Erhard%J,%de%Groot%H:%Inhibition%of%Kupffer%cell%functions%as%an%explanation%for%thehepatoprotective%properties%of%silibinin.%Hepatology%23%(4):%749-54,%1996.%[PUBMED%Abstract]

41.% Valenzuela%A,%Guerra%R,%Videla%LA:%Antioxidant%properties%of%the%flavonoids%silybin%and%(+)-cyanidanol-3:%comparison%with%butylated%hydroxyanisole%and%butylated%hydroxytoluene.Planta%Med%(6):%438-40,%1986.%[PUBMED%Abstract]

42.% Valenzuela%A,%Aspillaga%M,%Vial%S,%et%al.:%Selectivity%of%silymarin%on%the%increase%of%theglutathione%content%in%different%tissues%of%the%rat.%Planta%Med%55%(5):%420-2,%1989.%[PUBMEDAbstract]

43.% Mira%ML,%Azevedo%MS,%Manso%C:%The%neutralization%of%hydroxyl%radical%by%silibin,%sorbinil%andbendazac.%Free%Radic%Res%Commun%4%(2):%125-9,%1987.%[PUBMED%Abstract]

44.% Mira%L,%Silva%M,%Manso%CF:%Scavenging%of%reactive%oxygen%species%by%silibinin%dihemisuccinate.Biochem%Pharmacol%48%(4):%753-9,%1994.%[PUBMED%Abstract]

45.% Koch%HP,%Löffler%E:%Influence%of%silymarin%and%some%flavonoids%on%lipid%peroxidation%in%humanplatelets.%Methods%Find%Exp%Clin%Pharmacol%7%(1):%13-8,%1985.%[PUBMED%Abstract]

46.% Garrido%A,%Arancibia%C,%Campos%R,%et%al.:%Acetaminophen%does%not%induce%oxidative%stress%in

isolated%rat%hepatocytes:%its%probable%antioxidant%effect%is%potentiated%by%the%flavonoidsilybin.%Pharmacol%Toxicol%69%(1):%9-12,%1991.%[PUBMED%Abstract]

47.% Bosisio%E,%Benelli%C,%Pirola%O:%Effect%of%the%flavanolignans%of%Silybum%marianum%L.%on%lipidperoxidation%in%rat%liver%microsomes%and%freshly%isolated%hepatocytes.%Pharmacol%Res%25%(2):147-54,%1992%Feb-Mar.%[PUBMED%Abstract]

48.% Altorjay%I,%Dalmi%L,%Sári%B,%et%al.:%The%effect%of%silibinin%(Legalon)%on%the%the%free%radicalscavenger%mechanisms%of%human%erythrocytes%in%vitro.%Acta%Physiol%Hung%80%(1-4):%375-80,1992.%[PUBMED%Abstract]

49.% Sonnenbichler%J,%Scalera%F,%Sonnenbichler%I,%et%al.:%Stimulatory%effects%of%silibinin%and%silicristinfrom%the%milk%thistle%Silybum%marianum%on%kidney%cells.%J%Pharmacol%Exp%Ther%290%(3):%1375-83,%1999.%[PUBMED%Abstract]

50.% Gaedeke%J,%Fels%LM,%Bokemeyer%C,%et%al.:%Cisplatin%nephrotoxicity%and%protection%by%silibinin.Nephrol%Dial%Transplant%11%(1):%55-62,%1996.%[PUBMED%Abstract]

51.% Bokemeyer%C,%Fels%LM,%Dunn%T,%et%al.:%Silibinin%protects%against%cisplatin-inducednephrotoxicity%without%compromising%cisplatin%or%ifosfamide%anti-tumour%activity.%Br%J%Cancer74%(12):%2036-41,%1996.%[PUBMED%Abstract]

52.% Giacomelli%S,%Gallo%D,%Apollonio%P,%et%al.:%Silybin%and%its%bioavailable%phospholipid%complex(IdB%1016)%potentiate%in%vitro%and%in%vivo%the%activity%of%cisplatin.%Life%Sci%70%(12):%1447-59,2002.%[PUBMED%Abstract]

53.% Dhanalakshmi%S,%Singh%RP,%Agarwal%C,%et%al.:%Silibinin%inhibits%constitutive%and%TNFalpha-induced%activation%of%NF-kappaB%and%sensitizes%human%prostate%carcinoma%DU145%cells%toTNFalpha-induced%apoptosis.%Oncogene%21%(11):%1759-67,%2002.%[PUBMED%Abstract]

54.% Zi%X,%Agarwal%R:%Modulation%of%mitogen-activated%protein%kinase%activation%and%cell%cycleregulators%by%the%potent%skin%cancer%preventive%agent%silymarin.%Biochem%Biophys%ResCommun%263%(2):%528-36,%1999.%[PUBMED%Abstract]

55.% Ahmad%N,%Gali%H,%Javed%S,%et%al.:%Skin%cancer%chemopreventive%effects%of%a%flavonoidantioxidant%silymarin%are%mediated%via%impairment%of%receptor%tyrosine%kinase%signaling%andperturbation%in%cell%cycle%progression.%Biochem%Biophys%Res%Commun%247%(2):%294-301,1998.%[PUBMED%Abstract]

56.% Zi%X,%Mukhtar%H,%Agarwal%R:%Novel%cancer%chemopreventive%effects%of%a%flavonoid%antioxidantsilymarin:%inhibition%of%mRNA%expression%of%an%endogenous%tumor%promoter%TNF%alpha.Biochem%Biophys%Res%Commun%239%(1):%334-9,%1997.%[PUBMED%Abstract]

57.% Singh%RP,%Agarwal%R:%Flavonoid%antioxidant%silymarin%and%skin%cancer.%Antioxid%Redox%Signal%4

(4):%655-63,%2002.%[PUBMED%Abstract]

58.% Kaur%M,%Velmurugan%B,%Tyagi%A,%et%al.:%Silibinin%suppresses%growth%and%induces%apoptoticdeath%of%human%colorectal%carcinoma%LoVo%cells%in%culture%and%tumor%xenograft.%Mol%CancerTher%8%(8):%2366-74,%2009.%[PUBMED%Abstract]

59.% Velmurugan%B,%Gangar%SC,%Kaur%M,%et%al.:%Silibinin%exerts%sustained%growth%suppressive%effectagainst%human%colon%carcinoma%SW480%xenograft%by%targeting%multiple%signaling%molecules.Pharm%Res%27%(10):%2085-97,%2010.%[PUBMED%Abstract]

Human/Clinical StudiesTwo%published%case%reports%describe%the%use%of%milk%thistle%as%either%a%treatment%or%an%adjunctivetherapy%in%individuals%with%cancer.%One%case%report%describes%the%use%of%milk%thistle%in%a%34-year-old%woman%with%promyelocytic%leukemia.[1]%The%investigators%administered%800%mg%of%silymarinduring%the%patient’s%maintenance%therapy,%which%consisted%of%treatment%with%methotrexate%and6-mercaptopurine.%During%the%4%months%of%treatment%with%silymarin,%the%patient%who%previouslyrequired%intermittent%breaks%in%therapy%due%to%abnormal%liver%enzyme%levels%had%normal%liverenzyme%levels%with%no%further%interruption%of%therapy.%A%second%case%report%describes%a%52-year-old%man%with%hepatocellular%carcinoma.[2]%The%patient%began%taking%450%mg%of%silymarin%per%day,and%spontaneous%regression%of%the%tumor%was%reported%in%the%absence%of%initiation%of%anticancertherapy.

In%a%double-blind,%placebo-controlled%trial,%50%children%who%were%undergoing%treatment%for%acutelymphoblastic%leukemia%and%who%had%chemotherapy%-related%hepatotoxicity%were%randomlyassigned%to%receive%silymarin%or%placebo%for%a%4-week%period.[3]%Four%weeks%following%completionof%the%intervention,%the%silymarin%group%had%a%significantly%lower%aspartate%aminotransferase(AST)%(P%=%.05)%and%a%trend%towards%a%significantly%lower%alanine%aminotransferase%(ALT)%(P%=%.07).Fewer%chemotherapy%dose%reductions%were%observed%in%the%silymarin%group%compared%to%theplacebo%group;%however,%the%difference%was%not%significant.%No%adverse%events%were%reported.

Most%clinical%trials%of%milk%thistle%have%been%conducted%in%patients%with%either%hepatitis%orcirrhosis.%Other%studies%have%investigated%milk%thistle%in%patients%with%hyperlipidemia,%diabetes,and%Amanita phalloides mushroom%poisoning.%Ten%randomized%trials%[3-12]%have%been%reported%inpatients%with%hepatitis%or%cirrhosis,%and%one%randomized%trial%has%reported%the%use%of%silymarin%asa%prophylaxis%to%iatrogenic%hepatic%toxicity.[13]%Endpoints%for%these%trials%have%included%serumlevels%of%bilirubin%and/or%the%liver%enzymes%AST%and%ALT,%as%higher%levels%are%an%indicator%of%liverinflammation,%damage,%or%disease.%The%lowering%of%these%serum%levels%is%a%sign%of%an%improvingcondition.%In%patients%with%hepatitis%A%and%B,%one%clinical%trial%found%silymarin%(140%mg%daily%for%3–4weeks)%resulting%in%lower%levels%of%AST,%ALT,%and%bilirubin%by%day%5,%compared%with%a%placebo

group.[14]%In%another%randomized,%placebo-controlled%study%of%patients%with%viral%hepatitis%B,silymarin%(210%mg%daily)%had%no%effect%on%course%of%disease%or%enzyme%levels.[7]

A%randomized,%controlled%trial%supported%by%the%National%Institute%of%Diabetes%and%Digestive%andKidney%Diseases%examined%patients%with%chronic%hepatitis%C%who%had%failed%prior%antiviral%therapy.All%patients%had%advanced%chronic%liver%disease%consisting%of%histologic%evidence%of%either%markedfibrosis%or%cirrhosis.%The%Hepatitis%C%Antiviral%Long-Term%Treatment%Against%Cirrhosis%trial%used%ahalf%dose%of%pegylated%interferon%versus%no%treatment;%the%treatment%was%to%be%administered%for3.5%years.[12]%The%aim%was%to%reduce%progression%of%chronic%hepatitis%C,%particularly%in%thedevelopment%of%hepatocellular%carcinoma.%Among%1,145%study%participants,%56%%had%never%takenherbals,%21%%admitted%past%use,%and%23%%were%using%herbals%at%enrollment.%Silymarin%constituted72%%of%the%60%herbals%used%at%enrollment.%Users%had%significantly%fewer%symptoms%and%a%betterquality%of%life%than%nonusers.%In%follow-up,%silymarin%use%was%associated%with%reduced%progressionof%fibrosis%to%cirrhosis%but%without%an%impact%on%clinical%outcome.[15]

Although%there%are%many%reports%of%the%use%of%herbals%for%the%treatment%of%chronic%liver%diseases,most%treatment%trials%have%suffered%from%poor%scientific%design,%uncertainty%of%the%requireddosage%of%herbals,%and%an%insufficient%number%of%study%participants.%A%recent%review%ofcomplementary%and%alternative%medications%(CAM)%to%treat%liver%diseases%focused%on%theclassification,%epidemiology,%and%the%philosophy%of%CAM%and%reviewed%the%criteria%needed%toconduct%a%scientifically%valid%research%study%focusing%on%herbal%products.[16]

There%has%been%skepticism%regarding%the%evidence%that%silymarin%has%a%direct%impact%on%thehepatitis%C%virus%(HCV)—some%studies%suggest%that%it%does,%but%most%studies%are%unable%toconfirm%these%reports.%However,%at%least%two%articles%in%major%journals%have%suggested%thatsilymarin%or%its%congeners%may%inhibit%HCV.%In%one%report,%investigators%found%that%a%standardizedsilymarin%extract%inhibited%tumor%necrosis%factor%-alpha%in%anti-CD3–stimulated%human%peripheralblood%mononuclear%cells%and%nuclear%factor-kappa%B-dependent%transcription%in%humanhepatoma%Huh-7%cells.[17]%Silymarin%also%displayed%prophylactic%and%therapeutic%effects%againstHCV%infection%and%when%combined%with%interferon-alpha,%was%more%inhibitory%of%HCV%replicationthan%was%interferon%alone.%This%indicates%that%silymarin%has%anti-inflammatory%and%antiviral%effectsin%patients%with%chronic%hepatitis%C.

In%a%case%series%/phase%I%study,%patients%with%HCV%were%treated%with%intravenous%silibinin%with%andwithout%PEG-interferon%and%ribavirin.[18]%In%the%case%series,%16%HCV%nonresponder%patients%wereadministered%intravenous%silibinin%in%a%dose%of%10%mg/kg/day%for%7%days.%Subjects%then%begantreatment%with%oral%silibinin%in%combination%with%PEG-interferon%and%ribavirin%for%12%weeks.%At%theend%of%the%study%period,%all%patients%were%positive%for%HCV%RNA,%but%5%of%13%completed%patientshad%reductions%in%HCV%RNA.%Significance%was%not%reported.%In%the%same%study,%the%authorspresented%results%of%a%phase%I%study%in%which%20%patients%were%administered%5%mg/kg,%10%mg/kg,

15%mg/kg,%or%20%mg/kg%of%silibinin%for%14%days%in%combination%with%PEG-interferon%and%ribavirin(initiated%on%day%8).%A%significant%drop%in%HCV%RNA%was%observed%on%day%7%in%patients%administeredthe%10%mg/kg,%15%mg/kg,%and%20%mg/kg%doses%of%silybinin.%Further%declines%were%observed%in%HCVRNA%with%administration%of%PEG-interferon%and%ribavirin.%Except%for%mild%gastroenteritis,intravenous%silibinin%monotherapy%was%well%tolerated.

Patients%in%a%phase%I%pharmacokinetics%study%for%the%evaluation%of%absorption%characteristics%anddetermination%of%effective%doses%received%increasing%oral%doses%of%silymarin.[19]%A%subsequentmulticenter,%double-blind,%placebo-controlled%trial,%involving%154%patients%with%chronic%HCVinfection%who%had%previously%failed%interferon-based%treatment%and%had%raised%ALT%levels,%wasperformed.[20]%Patients%were%randomly%assigned%to%receive%420%mg%of%silymarin,%700%mg%ofsilymarin,%or%a%matching%placebo%orally%3%times%per%day%for%24%weeks,%with%the%aim%of%reducing%ALTlevels%to%less%than%40%U/L%or%less%than%65%U/L%if%this%was%at%least%a%50%%decline%from%the%baselinelevel.%In%this%study,%silymarin%given%orally%in%higher-than-usual%doses%failed%to%significantly%reduceserum%ALT%levels.%No%significant%adverse%effects%were%associated%with%silymarin.%In%one%of%thelargest%observational%studies%involving%2,637%patients%with%chronic%liver%disease,%8-week%treatmentwith%560%mg/day%of%silymarin%resulted%in%reductions%of%serum%AST,%ALT,%and%gamma-glutamyltranspeptidase%([GGT],%a%marker%of%bile%duct%disease)%and%a%decrease%in%the%frequency%ofpalpable%hepatomegaly.[21]

Another%published%report%describes%the%use%of%silybinin%as%the%only%effective%antidote%in%patientswith%liver%damage%from%Amanita phalloides%(Fr.)%Link%poisoning.[22]%Patients%were%administereddoses%of%35%to%55%mg/kg%body%weight,%with%no%reports%of%adverse%events.%A%recent%retrospectivereview%of%the%treatment%for%Amanita phalloides%poisoning%suggests%that%silymarin%continues%to%bea%promising%drug%in%the%treatment%of%this%mushroom%poisoning.[23]%The%beneficial%effect%ofsilymarin%on%liver%histology%suggests%it%has%a%role%in%the%prevention%of%hepatitis%and/orhepatocellular%carcinoma;%however,%no%clinical%trials%in%humans%have%investigated%these%uses%ofsilymarin.

Clinical Studies Investigating Silymarin in the Treatment orPrevention of Liver Disease

ReferenceCitation

Type/of/Study Type/ofDisease

No./ofPatients:Enrolled;Treated;Control

StrongestBenefitReported

a

b

[5] Double-blind,

placebo-

controlled,

randomized

clinical%trial

Acute%and

subacute%liver

disease

106 ;%47;%50 Decreased

LFTs;%improved

histology

[9] Double-blind,

placebo-

controlled,

randomized

clinical%trial

Cirrhosis 170;%87;%83 Increased

survival

[4] Phase%II

randomized

open%trial

Viral%or

alcoholic

hepatitis

60 ;%60;%0 Reduction%in

ALT%and

gamma-

glutamyl

transpeptidase

[7] Controlled,

randomized%trial

Viral%hepatitis%B 52 ;%20-

silymarin,%20-

misoprostol;%12

No%significant

findings

[6] Double-blind,

placebo-

controlled,

randomized

clinical%trial

Alcohol-

induced

cirrhosis

200 ;%58;%67 No%significant

findings

[10] Double-blind,

placebo-

controlled,

randomized

clinical%trial

Alcohol-

induced

cirrhosis

60 ;%24;%25 Significant

increases%in

erythrocyte

glutathione%and

decreased

platelet%MDA

values;%no

significant

b

c

d

e

f

differences%in

liver%function

tests

[8] Nonrandomized

pilot%study

Primary%biliary

cirrhosis

27;%27;%0 No%significant

findings

[18] Nonrandomized,

controlled%trial

HCV

nonresponder

patients

16;%16;%0%and

20;%20;%0

Increased

antiviral%effect

[11] Controlled,

randomized%trial

Diabetic

patients%with

cirrhosis

60;%30;%30 Decrease%in

lipid

peroxidation

and%insulin

resistance

[12] Randomized,

controlled%trial

Chronic

hepatitis%C

1,145;%195;%772 Decreased

fatigue,%nausea,

liver%pain,

anorexia,%and

muscle%and

joint%pain

[13] Double-blind,

placebo-

controlled,

randomized

clinical%trial

Patients%treated

with%silymarin

as%a

prophylaxis%to

psychotropic

drug-induced

hepatic

damage

60;%15-

psychotropic

drug+silymarin;

15-silymarin

alone;%15-

psychotropic

drug+placebo;

15-placebo

alone

Silymarin

effective%at

reducing

hepatotoxicity

associated%with

psychotropic

drug%use

[3] Double-blind, Children%with 50;%24;%26 Significant

Check%NCI’s%list%of%cancer%clinical%trials%for%cancer%CAM%clinical%trials%on%milk%thistle%and%silymarinthat%are%actively%enrolling%patients.

References

1.% Invernizzi%R,%Bernuzzi%S,%Ciani%D,%et%al.:%Silymarine%during%maintenance%therapy%of%acute

ALL%=%acute%lymphoblastic%leukemia;%ALT%=%alanine%aminotransferase;%HCV%=%hepatitis%C%virus;%LFT%=%liver

function%test;%No.%=%number.

Number%of%patients%treated%plus%number%of%patients%controlled%may%not%equal%number%of%patients%enrolled;

number%of%patients%enrolled%=%number%of%patients%initially%recruited/considered%by%the%researchers%who

conducted%a%study;%number%of%patients%treated%=%number%of%enrolled%patients%who%were%administered%the

treatment%being%studied%AND%for%whom%results%were%reported;%historical%control%subjects%are%not%included%in

number%of%patients%enrolled.

Nine%patients%were%excluded%from%the%final%analysis%(seven%patients%missed%appointments,%and%two%patients

were%missing%data%requirements).

Study%investigated%dose-response%relationships.%Patients%were%randomly%assigned%to%receive%80%mg%2%times

a%day%(n%=%20),%120%mg%2%times%a%day%(n%=%20),%or%120%mg%3%times%a%day%(n%=%20).%The%effective%dose%was%120%mg

2%times%a%day%and%120%mg%3%times%a%day.

Patients%were%randomly%assigned%to%the%misoprostol%and%silymarin%groups.%Twelve%nonrandomized%patients

served%as%controls.

Fifteen%patients%were%lost%to%follow-up,%18%patients%were%deceased,%and%42%patients%withdrew%from%the%study

(adverse%events,%noncompliance,%and%voluntary%withdrawal).

Eleven%patients%did%not%complete%the%trial%(voluntary%withdrawal,%disease%progression,%and%one%adverse

event).

placebo-

controlled,

randomized

clinical%trial

ALL

experiencing

elevated%LFTs

decrease%in

AST;%trend

towards

reduction%in

ALT

a

b

c

d

e

f

promyelocytic%leukemia.%Haematologica%78%(5):%340-1,%1993%Sep-Oct.%[PUBMED%Abstract]

2.% Grossmann%M,%Hoermann%R,%Weiss%M,%et%al.:%Spontaneous%regression%of%hepatocellularcarcinoma.%Am%J%Gastroenterol%90%(9):%1500-3,%1995.%[PUBMED%Abstract]

3.% Ladas%EJ,%Kroll%DJ,%Oberlies%NH,%et%al.:%A%randomized,%controlled,%double-blind,%pilot%study%ofmilk%thistle%for%the%treatment%of%hepatotoxicity%in%childhood%acute%lymphoblastic%leukemia(ALL).%Cancer%116%(2):%506-13,%2010.%[PUBMED%Abstract]

5.% Salmi%HA,%Sarna%S:%Effect%of%silymarin%on%chemical,%functional,%and%morphological%alterationsof%the%liver.%A%double-blind%controlled%study.%Scand%J%Gastroenterol%17%(4):%517-21,1982.%[PUBMED%Abstract]

6.% Parés%A,%Planas%R,%Torres%M,%et%al.:%Effects%of%silymarin%in%alcoholic%patients%with%cirrhosis%ofthe%liver:%results%of%a%controlled,%double-blind,%randomized%and%multicenter%trial.%J%Hepatol%28(4):%615-21,%1998.%[PUBMED%Abstract]

7.% Flisiak%R,%Prokopowicz%D:%Effect%of%misoprostol%on%the%course%of%viral%hepatitis%B.Hepatogastroenterology%44%(17):%1419-25,%1997%Sep-Oct.%[PUBMED%Abstract]

8.% Angulo%P,%Patel%T,%Jorgensen%RA,%et%al.:%Silymarin%in%the%treatment%of%patients%with%primarybiliary%cirrhosis%with%a%suboptimal%response%to%ursodeoxycholic%acid.%Hepatology%32%(5):%897-900,%2000.%[PUBMED%Abstract]

9.% Ferenci%P,%Dragosics%B,%Dittrich%H,%et%al.:%Randomized%controlled%trial%of%silymarin%treatment%inpatients%with%cirrhosis%of%the%liver.%J%Hepatol%9%(1):%105-13,%1989.%[PUBMED%Abstract]

10.% Lucena%MI,%Andrade%RJ,%de%la%Cruz%JP,%et%al.:%Effects%of%silymarin%MZ-80%on%oxidative%stress%inpatients%with%alcoholic%cirrhosis.%Results%of%a%randomized,%double-blind,%placebo-controlledclinical%study.%Int%J%Clin%Pharmacol%Ther%40%(1):%2-8,%2002.%[PUBMED%Abstract]

11.% Velussi%M,%Cernigoi%AM,%De%Monte%A,%et%al.:%Long-term%(12%months)%treatment%with%an%anti-oxidant%drug%(silymarin)%is%effective%on%hyperinsulinemia,%exogenous%insulin%need%andmalondialdehyde%levels%in%cirrhotic%diabetic%patients.%J%Hepatol%26%(4):%871-9,%1997.%[PUBMEDAbstract]

12.% Seeff%LB,%Curto%TM,%Szabo%G,%et%al.:%Herbal%product%use%by%persons%enrolled%in%the%hepatitis%CAntiviral%Long-Term%Treatment%Against%Cirrhosis%(HALT-C)%Trial.%Hepatology%47%(2):%605-12,2008.%[PUBMED%Abstract]

13.% Palasciano%G,%Portincasa%P,%Palmieri%V,%et%al.:%The%effect%of%silymarin%on%plasma%levels%of

malon-dialdehyde%in%patients%receiving%long-term%treatment%with%psychotropic%drugs.%CurrentTherapeutic%Research%55%(5):%537-45.

14.% Magliulo%E,%Gagliardi%B,%Fiori%GP:%[Results%of%a%double%blind%study%on%the%effect%of%silymarin%inthe%treatment%of%acute%viral%hepatitis,%carried%out%at%two%medical%centres%(author's%transl)]Med%Klin%73%(28-29):%1060-5,%1978.%[PUBMED%Abstract]

15.% Freedman%ND,%Curto%TM,%Morishima%C,%et%al.:%Silymarin%use%and%liver%disease%progression%inthe%Hepatitis%C%Antiviral%Long-Term%Treatment%against%Cirrhosis%trial.%Aliment%Pharmacol%Ther33%(1):%127-37,%2011.%[PUBMED%Abstract]

16.% Azzam%HS,%Goertz%C,%Fritts%M,%et%al.:%Natural%products%and%chronic%hepatitis%C%virus.%Liver%Int%27(1):%17-25,%2007.%[PUBMED%Abstract]

17.% Polyak%SJ,%Morishima%C,%Shuhart%MC,%et%al.:%Inhibition%of%T-cell%inflammatory%cytokines,hepatocyte%NF-kappaB%signaling,%and%HCV%infection%by%standardized%Silymarin.Gastroenterology%132%(5):%1925-36,%2007.%[PUBMED%Abstract]

18.% Ferenci%P,%Scherzer%TM,%Kerschner%H,%et%al.:%Silibinin%is%a%potent%antiviral%agent%in%patients%withchronic%hepatitis%C%not%responding%to%pegylated%interferon/ribavirin%therapy.Gastroenterology%135%(5):%1561-7,%2008.%[PUBMED%Abstract]

19.% Hawke%RL,%Schrieber%SJ,%Soule%TA,%et%al.:%Silymarin%ascending%multiple%oral%dosing%phase%Istudy%in%noncirrhotic%patients%with%chronic%hepatitis%C.%J%Clin%Pharmacol%50%(4):%434-49,2010.%[PUBMED%Abstract]

20.% Fried%MW,%Navarro%VJ,%Afdhal%N,%et%al.:%Effect%of%silymarin%(milk%thistle)%on%liver%disease%inpatients%with%chronic%hepatitis%C%unsuccessfully%treated%with%interferon%therapy:%arandomized%controlled%trial.%JAMA%308%(3):%274-82,%2012.%[PUBMED%Abstract]

21.% Albrecht%M,%Frerick%H,%Kuhn%U,%et%al.:%Therapy%of%toxic%liver%pathologies%with%Legalon®.%Z%KlinMed%47:%87-92,%1992.

22.% Hruby%K,%Csomos%G,%Fuhrmann%M,%et%al.:%Chemotherapy%of%Amanita%phalloides%poisoning%withintravenous%silibinin.%Hum%Toxicol%2%(2):%183-95,%1983.%[PUBMED%Abstract]

23.% Enjalbert%F,%Rapior%S,%Nouguier-Soulé%J,%et%al.:%Treatment%of%amatoxin%poisoning:%20-yearretrospective%analysis.%J%Toxicol%Clin%Toxicol%40%(6):%715-57,%2002.%[PUBMED%Abstract]

Adverse EffectsHuman%studies%of%silymarin%have%shown%minimal%adverse%effects%in%multiple%large,%blinded,placebo-controlled,%randomized%studies.%Silymarin%is%well%tolerated,%with%only%rare%reports%of%amild%laxative%effect.%Mild%allergic%reactions%have%been%seen%at%high%doses%(>1,500%mg%/day),

although%the%details%of%these%allergic%reactions%were%not%reported.[1]%A%recent%case%report%fromAustralia%described%a%reaction%to%a%milk%thistle%extract%that%included%intermittent%episodes%ofsweating,%abdominal%cramping,%nausea,%vomiting,%diarrhea,%and%weakness.[2]%All%symptomsresolved%when%the%silymarin%was%discontinued.%The%authors%suggested%that%the%capsules%werecontaminated;%the%type%of%contamination%was%unknown.

According%to%the%German%Commission%E,%there%are%no%reported%side%effects%with%milk%thistle%withinthe%recommended%doses.%Rare%cases%of%milk%thistle%having%a%laxative%effect%have%been%reported.Human%studies%have%reported%stomach%upset,%heartburn,%and%transient%headaches;%however,none%of%these%symptoms%were%attributed%to%supplementation%with%milk%thistle,%andsupplementation%was%not%discontinued.[3]%One%human%dosing%study%reported%nausea,%heartburn,and%dyspepsia%in%patients%treated%with%160%mg/day,%dyspepsia%in%patients%treated%with%240mg/day,%and%postprandial%nausea%and%meteorism%in%patients%treated%with%360%mg/day.%None%ofthese%side%effects%were%dose%related.

Silymarin%has%been%well%tolerated%in%high%doses.%Silymarin%has%been%used%in%pregnant%women%withintrahepatic%cholestasis%at%doses%of%560%mg/day%for%16%days,%with%no%toxicity%to%the%patient%or%thefetus.[4]%The%published%data%on%silymarin%use%in%children%focuses%on%intravenous%doses%of%20%to%50mg/kg%body%weight%for%mushroom%poisoning.[5]%Silymarin%has%also%proved%nontoxic%in%rats%andmice%when%administered%in%doses%as%high%as%5,000%mg/kg%body%weight.%Rats%and%dogs%havereceived%silymarin%at%doses%of%50%to%2,500%mg/kg%body%weight%for%a%12-month%period.Investigations,%including%postmortem%analyses,%showed%no%evidence%of%toxicity.

It%is%not%known%whether%milk%thistle%may%reduce,%enhance,%or%have%no%effect%on%the%effectivenessof%chemotherapy.%Silymarin%decreases%the%activity%of%the%cytochrome%P450%enzyme%system,%whichis%involved%in%the%clearance%of%certain%chemotherapy%drugs.[6]%However,%the%dose%at%whichinhibition%is%observed%is%high%and%not%achieved%with%oral%intake%of%silymarin.[7]%One%studyinvestigated%the%effects%of%silymarin%on%the%pharmacokinetics%of%irinotecan.%Oral%administration%ofmilk%thistle%(200%mg,%a%clinically%relevant%dose,%3%times%per%day)%had%no%significant%effects%on%thepharmacokinetics%of%irinotecan.%The%authors%concluded%that%the%recommended%doses%of%milkthistle%are%too%low%to%affect%activity%of%CYP3A4%or%UGT1A1%enzyme%pathways.[8]

Theoretically,%milk%thistle%may%also%interact%adversely%with%chemotherapy%drugs%that%exert%theircytotoxic%effects%through%the%generation%of%free%radicals.%Silymarin%and%its%metabolite%inhibit%P-glycoprotein–mediated%cellular%efflux,%leading%to%the%potentiation%of%doxorubicin%cytotoxicity.[9]No%trials%have%been%performed%to%support%or%negate%these%theoretical%considerations.%No%effectson%indinavir%and%alcohol%pharmacokinetics%have%been%observed.%Enhancement%of%antiarrhythmiceffects%of%amiodarone%in%rats%has%been%observed.[9]

References

1.% PDR®%for%Herbal%Medicines™.%2nd%ed.%Montvale,%NJ:%Medical%Economics,%2000.

2.% An%adverse%reaction%to%the%herbal%medication%milk%thistle%(Silybum%marianum).%Adverse%DrugReactions%Advisory%Committee.%Med%J%Aust%170%(5):%218-9,%1999.%[PUBMED%Abstract]

4.% Hernández%R,%Nazar%E:%[Effect%of%silymarin%in%intrahepatic%cholestasis%of%pregnancy(preliminary%communication)]%Rev%Chil%Obstet%Ginecol%47%(1):%22-9,%1982.%[PUBMED%Abstract]

5.% Hruby%K,%Csomos%G,%Fuhrmann%M,%et%al.:%Chemotherapy%of%Amanita%phalloides%poisoning%withintravenous%silibinin.%Hum%Toxicol%2%(2):%183-95,%1983.%[PUBMED%Abstract]

6.% Venkataramanan%R,%Ramachandran%V,%Komoroski%BJ,%et%al.:%Milk%thistle,%a%herbal%supplement,decreases%the%activity%of%CYP3A4%and%uridine%diphosphoglucuronosyl%transferase%in%humanhepatocyte%cultures.%Drug%Metab%Dispos%28%(11):%1270-3,%2000.%[PUBMED%Abstract]

7.% Zuber%R,%Modrianský%M,%Dvorák%Z,%et%al.:%Effect%of%silybin%and%its%congeners%on%human%livermicrosomal%cytochrome%P450%activities.%Phytother%Res%16%(7):%632-8,%2002.%[PUBMED%Abstract]

8.% van%Erp%NP,%Baker%SD,%Zhao%M,%et%al.:%Effect%of%milk%thistle%(Silybum%marianum)%on%thepharmacokinetics%of%irinotecan.%Clin%Cancer%Res%11%(21):%7800-6,%2005.%[PUBMED%Abstract]

9.% Hu%Z,%Yang%X,%Ho%PC,%et%al.:%Herb-drug%interactions:%a%literature%review.%Drugs%65%(9):%1239-82,2005.%[PUBMED%Abstract]

Summary of the Evidence for Milk ThistleTo%assist%readers%in%evaluating%the%results%of%human%studies%of%complementary%and%alternativemedicine%(CAM)%treatments%for%cancer,%the%strength%of%the%evidence%(i.e.,%the%levels%of%evidence)associated%with%each%type%of%treatment%is%provided%whenever%possible.%To%qualify%for%a%level%ofevidence%analysis,%a%study%must:

Report%on%therapeutic%outcome%or%outcomes,%such%as%tumor%response,%improvement%insurvival,%or%measured%improvement%in%quality%of%life.

Describe%clinical%findings%in%sufficient%detail%for%a%meaningful%evaluation%to%be%made.

Separate%levels%of%evidence%scores%are%assigned%to%qualifying%human%studies%on%the%basis%ofstatistical%strength%of%the%study%design%and%scientific%strength%of%the%treatment%outcomes%(i.e.,endpoints)%measured.%The%resulting%two%scores%are%then%combined%to%produce%an%overall%score.%A

•

level%of%evidence%score%cannot%be%assigned%to%milk%thistle%because%there%has%been%insufficientclinical%research%to%date.%For%an%explanation%of%the%scores%and%additional%information%about%levelsof%evidence%analysis%of%CAM%treatments%for%cancer,%refer%to%Levels%of%Evidence%for%Human%Studiesof%Cancer%Complementary%and%Alternative%Medicine.

Given%the%limited%amount%of%human%data,%the%use%of%milk%thistle/silymarin%as%a%treatment%forcancer%patients%cannot%be%recommended%outside%the%context%of%well-designed%clinical%trials.

An%editorial%change%was%made%to%this%summary.

This%PDQ%cancer%information%summary%for%health%professionals%provides%comprehensive,%peer-reviewed,%evidence-based%information%about%the%use%of%milk%thistle%in%the%treatment%of%peoplewith%cancer.%It%is%intended%as%a%resource%to%inform%and%assist%clinicians%who%care%for%cancerpatients.%It%does%not%provide%formal%guidelines%or%recommendations%for%making%health%caredecisions.

This%summary%is%reviewed%regularly%and%updated%as%necessary%by%the%PDQ%CancerComplementary%and%Alternative%Medicine%Editorial%Board,%which%is%editorially%independent%of%theNational%Cancer%Institute%(NCI).%The%summary%reflects%an%independent%review%of%the%literature%anddoes%not%represent%a%policy%statement%of%NCI%or%the%National%Institutes%of%Health%(NIH).

http://www.cancer.gov/about-cancer/treatment/cam/hp/milk-thistle-pdq/#link/_AboutThis_1

The%lead%reviewers%for%Milk%Thistle%are:

Kara%Kelly,%MD%(Columbia%University)

Elena%J.%Ladas,%PhD,%RD%(Columbia%University)

Levels of Evidence

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National%Cancer%Institute:%PDQ®%Milk%Thistle.%Bethesda,%MD:%National%Cancer%Institute.%Date%lastmodified%<MM/DD/YYYY>.%Available%at:%http://www.cancer.gov/about-cancer/treatment/cam/hp/milk-thistle-pdq.%Accessed%<MM/DD/YYYY>.

Images%in%this%summary%are%used%with%permission%of%the%author(s),%artist,%and/or%publisher%foruse%within%the%PDQ%summaries%only.%Permission%to%use%images%outside%the%context%of%PDQinformation%must%be%obtained%from%the%owner(s)%and%cannot%be%granted%by%the%National%CancerInstitute.%Information%about%using%the%illustrations%in%this%summary,%along%with%many%othercancer-related%images,%is%available%in%Visuals%Online,%a%collection%of%over%2,000%scientific%images.

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Contact Us

Updated:%March%26,%2015

http://www.cancer.gov/about-cancer/treatment/cam/hp/milk-thistle-pdq

7/24/15, 12:01Mistletoe Extracts - National Cancer Institute

Page 1 of 42http://www.cancer.gov/about-cancer/treatment/cam/hp/mistletoe-pdq#section/all

Mistletoe Extracts–for health professionals(PDQ®)

OverviewThis%complementary%and%alternative%medicine%(CAM)%information%summary%provides%an%overviewof%the%use%of%mistletoe%as%a%treatment%for%people%with%cancer.%The%summary%includes%a%briefhistory%of%mistletoe%research,%the%results%of%clinical%trials,%and%possible%side%effects%of%mistletoeuse.

Mistletoe%is%a%semiparasitic%plant%that%has%been%used%for%centuries%to%treat%numerous%humanailments.

Mistletoe%is%used%commonly%in%Europe,%where%a%variety%of%different%extracts%are%manufacturedand%marketed%as%injectable%prescription%drugs.%These%injectable%drugs%are%not%availablecommercially%in%the%United%States%and%are%not%approved%as%a%treatment%for%people%withcancer.

Mistletoe%is%one%of%the%most%widely%studied%CAM%therapies%for%cancer.%In%certain%Europeancountries,%the%preparations%made%from%European%mistletoe%(Viscum album,%Loranthaceae)%areamong%the%most%prescribed%drugs%offered%to%cancer%patients.[1]

Although%mistletoe%plants%and%berries%are%considered%poisonous%to%humans,%few%serious%sideeffects%have%been%associated%with%mistletoe%extract%use.

The%use%of%mistletoe%as%a%treatment%for%people%with%cancer%has%been%investigated%in%clinicalstudies.%Reports%of%improved%survival%and/or%quality%of%life%have%been%common,%but%nearly%allof%the%studies%had%major%weaknesses%that%raise%doubts%about%the%reliability%of%the%findings.

At%present,%the%use%of%mistletoe%cannot%be%recommended%outside%the%context%of%well-designed%clinical%trials.%Such%trials%will%be%valuable%to%determine%more%clearly%whethermistletoe%can%be%useful%in%the%treatment%of%specific%subsets%of%cancer%patients.

Many%of%the%medical%and%scientific%terms%used%in%this%summary%are%hypertext%linked%(at%first%use%ineach%section)%to%the%NCI%Dictionary%of%Cancer%Terms,%which%is%oriented%toward%nonexperts.%When%a

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http://www.cancer.gov/about-cancer/treatment/cam/hp/mistletoe-pdq#cit/section_1.1

linked%term%is%clicked,%a%definition%will%appear%in%a%separate%window.

References

1.% Horneber%MA,%Bueschel%G,%Huber%R,%et%al.:%Mistletoe%therapy%in%oncology.%Cochrane%DatabaseSyst%Rev%(2):%CD003297,%2008.%[PUBMED%Abstract]

General InformationMistletoe,%a%semiparasitic%plant,%holds%interest%as%a%potential%anticancer%agent%because%extractsderived%from%it%have%been%shown%to%kill%cancer%cells%in vitro [1-10]%and%to%stimulate%immune%systemcells%both%in vitro%and%in vivo .[10-24]%Two%components%of%mistletoe,%namely%viscotoxins,polysaccharides%and%lectins,%may%be%responsible%for%these%effects.[10-13,17-19,21-23,25-32]Viscotoxins%are%small%proteins%that%exhibit%cell-killing%activity%and%possible%immune-system-stimulating%activity.[1,6,18,19,33,34]%Lectins%are%complex%molecules%made%of%both%protein%andcarbohydrates%that%are%capable%of%binding%to%the%outside%of%cells%(e.g.,%immune%system%cells)%andinducing%biochemical%changes%in%them.[10,35-38]%In%view%of%mistletoe’s%ability%to%stimulate%theimmune%system,%it%has%been%classified%as%a%type%of%biological%response%modifier.[35]%Biologicalresponse%modifiers%constitute%a%diverse%group%of%biological%molecules%that%have%been%usedindividually,%or%in%combination%with%other%agents,%to%treat%cancer%or%to%lessen%the%side%effects%ofanticancer%drugs.%Mistletoe%extracts%have%been%demonstrated%in%preclinical%settings%to%have%othermechanisms%of%action,%such%as%antiangiogenesis.[39]

Preparations%from%mistletoe%extracts%are%most%frequently%used%in%the%treatment%of%cancer%patientsin%German-speaking%countries.[40]%Commercially%available%extracts%are%marketed%under%a%varietyof%brand%names,%including%Iscador%(see%explanation%of%suffixes%below),%Eurixor,%Helixor,%Isorel,Iscucin,%Plenosol,%and%abnobaVISCUM.%Some%extracts%are%marketed%under%more%than%one%name.Iscador,%Isorel,%and%Plenosol%are%also%sold%as%Iscar,%Vysorel,%and%Lektinol,%respectively.%All%of%theseproducts%are%prepared%from%Viscum album%(Loranthaceae)%(Viscum album%L.%or%Europeanmistletoe).%They%are%not%sold%as%a%drug%in%the%United%States.%Eurixor,%Isorel,%and%Vysorel%are%nolonger%available%on%the%market%for%sale.

In%addition%to%European%mistletoe,%extracts%from%a%type%of%Korean%mistletoe%(Viscum album var.

coloratum%[Kom.]%Ohwi)%have%demonstrated%in vitro%and%in vivo%cytotoxicity%in%laboratory%studies.[41-45]

Mistletoe%grows%on%several%types%of%trees,%and%the%chemical%composition%of%extracts%derived%fromit%depends%on%the%species%of%the%host%tree%(e.g.,%apple,%elm,%oak,%pine,%poplar,%and%spruce),%thetime%of%year%harvested,%how%the%extracts%are%prepared,%and%the%commercial%producer.[8,36,46-49]

Mistletoe%extracts%are%prepared%as%aqueous%solutions%or%solutions%of%water%and%alcohol,%and%theycan%be%fermented%or%unfermented.[4,6,20,46,47,50-53]%Some%extracts%are%prepared%according%tohomeopathic%principles,%and%others%are%not.%Accordingly,%as%homeopathic%preparations,%they%aretypically%not%chemically%standardized%extracts.[10,54]%In%addition,%the%commercial%products%can%besubdivided%according%to%the%species%of%host%tree,%which%is%typically%indicated%in%the%product%nameby%a%suffix%letter.%Iscador,%a%fermented%aqueous%extract%of%Viscum album%L.%that%is%prepared%as%ahomeopathic%drug,%is%marketed%as%IscadorM%(from%apple%trees;%Malus domestica),%IscadorP%(frompine%trees;%Pinus sylvestris),%IscadorQu%(from%oak%trees;%Quercus robur),%and%IscadorU%(from%elmtrees;%Ulmus minor).%Helixor,%an%unfermented%aqueous%extract%of%Viscum album%L.%that%isstandardized%by%its%biological%effect%on%human%leukemia%cells%in vitro,%is%marketed%as%HelixorA(from%spruce%trees;%Picea abies),%HelixorM%(from%apple%trees),%and%HelixorP%(from%pine%trees;%Pinussylvestris).[51]%Eurixor%(which%is%no%longer%available%on%the%market%for%sale),%an%unfermentedaqueous%extract%of%Viscum album%L.%harvested%from%poplar%trees,%is%reportedly%standardized%tocontain%a%specific%amount%of%one%of%mistletoe’s%lectins%(i.e.,%the%lectin%ML-1;%refer%to%the%Historysection%of%this%summary%for%more%information).[51]%Some%proponents%contend%the%choice%ofextract%should%depend%on%the%type%of%tumor%and%the%gender%of%the%patient.[49,51,55,56]

A%recombinant%ML-1%from%Escherichia coli%bacteria%known%as%rViscumin%or%aviscumine%has%beenstudied%in%the%laboratory%and%in%phase%I%clinical%trials.%Since%this%is%not%an%extract%of%mistletoe,%it%isout%of%the%purview%of%this%summary.[57]

Mistletoe%extracts%are%usually%given%by%subcutaneous%injection,%although%administration%by%otherroutes%(i.e.,%oral,%intrapleural,%intratumoral,%and%intravenous)%has%been%described.[17,20-24,32,36,49,51,54,58-63]%In%most%reported%studies,%subcutaneous%injections%were%given%2%to%3%timesa%week,%but%the%overall%duration%of%treatment%varied%considerably.

Viscum album%is%listed%in%the%Homeopathic%Pharmacopoeia%of%the%United%States,%which%is%theofficially%recognized%compendium%for%homeopathic%drugs%in%this%country.[64]%Although%the%U.S.Food%and%Drug%Administration%(FDA)%has%regulatory%authority%over%homeopathic%drugs,%thisauthority%is%usually%not%exercised%unless%the%drugs%are%formulated%for%injection%or%there%isevidence%of%severe%toxicity.%At%present,%the%FDA%does%not%allow%the%importation%or%distribution%ofinjectable%preparations%of%mistletoe,%including%homeopathic%formulations,%except%for%the%purposeof%clinical%research.%The%extracts%are%not%available%commercially%in%the%United%States%and%are%not

http://www.cancer.gov/about-cancer/treatment/cam/hp/mistletoe-pdq/#link/_17

approved%as%a%treatment%for%people%with%cancer.

Before%researchers%can%conduct%clinical%drug%research%in%the%United%States,%they%must%file%anInvestigational%New%Drug%(IND)%application%with%the%FDA.%IND%approval%is%also%required%for%clinicalinvestigation%of%homeopathic%drugs.%The%FDA%does%not%disclose%information%about%INDapplications%or%approvals;%this%information%can%be%released%only%by%the%applicants.%At%least%twoU.S.%investigators%were%given%IND%approval%to%study%mistletoe%as%a%treatment%for%people%withcancer%(NCCAM-02-AT-260%and%TJUH-01F.45).

In%this%summary,%the%mistletoe%extract%or%product%used%in%each%study%will%be%specified%whereverpossible.

References

1.% Jung%ML,%Baudino%S,%Ribéreau-Gayon%G,%et%al.:%Characterization%of%cytotoxic%proteins%frommistletoe%(Viscum%album%L.).%Cancer%Lett%51%(2):%103-8,%1990.%[PUBMED%Abstract]

2.% Kuttan%G,%Vasudevan%DM,%Kuttan%R:%Effect%of%a%preparation%from%Viscum%album%on%tumordevelopment%in%vitro%and%in%mice.%J%Ethnopharmacol%29%(1):%35-41,%1990.%[PUBMED%Abstract]

3.% Walzel%H,%Jonas%L,%Rosin%T,%et%al.:%Relationship%between%internalization%kinetics%and%cytotoxicityof%mistletoe%lectin%I%to%L1210%leukaemia%cells.%Folia%Biol%(Praha)%36%(3-4):%181-8,%1990.%[PUBMEDAbstract]

4.% Janssen%O,%Scheffler%A,%Kabelitz%D:%In%vitro%effects%of%mistletoe%extracts%and%mistletoe%lectins.Cytotoxicity%towards%tumor%cells%due%to%the%induction%of%programmed%cell%death%(apoptosis).Arzneimittelforschung%43%(11):%1221-7,%1993.%[PUBMED%Abstract]

5.% Jurin%M,%Zarković%N,%Hrzenjak%M,%et%al.:%Antitumorous%and%immunomodulatory%effects%of%theViscum%album%L.%preparation%Isorel.%Oncology%50%(6):%393-8,%1993%Nov-Dec.%[PUBMED%Abstract]

6.% Schaller%G,%Urech%K,%Giannattasio%M:%Cytotoxicity%of%different%viscotoxins%and%extracts%from%theEuropean%subspecies%Viscum%album%L.%Phytother%Res%10%(6):%473-7,%1996.

7.% Gabius%HJ,%Darro%F,%Remmelink%M,%et%al.:%Evidence%for%stimulation%of%tumor%proliferation%in%celllines%and%histotypic%cultures%by%clinically%relevant%low%doses%of%the%galactoside-bindingmistletoe%lectin,%a%component%of%proprietary%extracts.%Cancer%Invest%19%(2):%114-26,2001.%[PUBMED%Abstract]

8.% Maier%G,%Fiebig%HH:%Absence%of%tumor%growth%stimulation%in%a%panel%of%16%human%tumor%celllines%by%mistletoe%extracts%in%vitro.%Anticancer%Drugs%13%(4):%373-9,%2002.%[PUBMED%Abstract]

9.% Franz%H:%Mistletoe%lectins%and%their%A%and%B%chains.%Oncology%43%(Suppl%1):%23-34,1986.%[PUBMED%Abstract]

10.% Mengs%U,%Göthel%D,%Leng-Peschlow%E:%Mistletoe%extracts%standardized%to%mistletoe%lectins%inoncology:%review%on%current%status%of%preclinical%research.%Anticancer%Res%22%(3):%1399-407,2002%May-Jun.%[PUBMED%Abstract]

11.% Hostanska%K,%Hajto%T,%Spagnoli%GC,%et%al.:%A%plant%lectin%derived%from%Viscum%album%inducescytokine%gene%expression%and%protein%production%in%cultures%of%human%peripheral%bloodmononuclear%cells.%Nat%Immun%14%(5-6):%295-304,%1995.%[PUBMED%Abstract]

12.% Beuth%J,%Stoffel%B,%Ko%HL,%et%al.:%Immunomodulating%ability%of%galactoside-specific%lectinstandardized%and%depleted%mistletoe%extract.%Arzneimittelforschung%45%(11):%1240-2,1995.%[PUBMED%Abstract]

13.% Lenartz%D,%Stoffel%B,%Menzel%J,%et%al.:%Immunoprotective%activity%of%the%galactoside-specificlectin%from%mistletoe%after%tumor%destructive%therapy%in%glioma%patients.%Anticancer%Res%16(6B):%3799-802,%1996%Nov-Dec.%[PUBMED%Abstract]

14.% Fischer%S,%Scheffler%A,%Kabelitz%D:%Oligoclonal%in%vitro%response%of%CD4%T%cells%to%vesicles%ofmistletoe%extracts%in%mistletoe-treated%cancer%patients.%Cancer%Immunol%Immunother%44%(3):150-6,%1997.%[PUBMED%Abstract]

15.% Preisfeld%A:%Influence%of%aqueous%mistletoe%preparations%on%humoral%immune%parameterswith%emphasis%on%the%cytotoxicity%of%human%complement%in%breast%cancer%patients.%ForschKomplementarmed%4%(4):%224-8,%1997.

16.% Chernyshov%VP,%Omelchenko%LI,%Heusser%P,%et%al.:%Immunomodulatory%actions%of%Viscumalbum%(Iscador)%in%children%with%recurrent%respiratory%disease%as%a%result%of%the%Chernobylnuclear%accident.%Complement%Ther%Med%5%(3):%141-6,%1997.

17.% Heiny%BM,%Albrecht%V,%Beuth%J:%Correlation%of%immune%cell%activities%and%beta-endorphinrelease%in%breast%carcinoma%patients%treated%with%galactose-specific%lectin%standardizedmistletoe%extract.%Anticancer%Res%18%(1B):%583-6,%1998%Jan-Feb.%[PUBMED%Abstract]

18.% Stein%GM,%Schaller%G,%Pfüller%U,%et%al.:%Characterisation%of%granulocyte%stimulation%by%thioninsfrom%European%mistletoe%and%from%wheat.%Biochim%Biophys%Acta%1426%(1):%80-90,1999.%[PUBMED%Abstract]

19.% Stein%GM,%Schaller%G,%Pfüller%U,%et%al.:%Thionins%from%Viscum%album%L:%influence%of%theviscotoxins%on%the%activation%of%granulocytes.%Anticancer%Res%19%(2A):%1037-42,%1999%Mar-Apr.%[PUBMED%Abstract]

20.% Mistletoe.%In:%Murray%MT:%The%Healing%Power%of%Herbs.%Roseville,%Calif:%Prima%Publishing,%1995,pp%253-9.

21.% Lenartz%D,%Dott%U,%Menzel%J,%et%al.:%Survival%of%glioma%patients%after%complementary%treatment

with%galactoside-specific%lectin%from%mistletoe.%Anticancer%Res%20%(3B):%2073-6,%2000%May-Jun.%[PUBMED%Abstract]

22.% Steuer-Vogt%MK,%Bonkowsky%V,%Ambrosch%P,%et%al.:%The%effect%of%an%adjuvant%mistletoetreatment%programme%in%resected%head%and%neck%cancer%patients:%a%randomised%controlledclinical%trial.%Eur%J%Cancer%37%(1):%23-31,%2001.%[PUBMED%Abstract]

23.% Goebell%PJ,%Otto%T,%Suhr%J,%et%al.:%Evaluation%of%an%unconventional%treatment%modality%withmistletoe%lectin%to%prevent%recurrence%of%superficial%bladder%cancer:%a%randomized%phase%IItrial.%J%Urol%168%(1):%72-5,%2002.%[PUBMED%Abstract]

24.% Stauder%H,%Kreuser%ED:%Mistletoe%extracts%standardised%in%terms%of%mistletoe%lectins%(ML%I)%inoncology:%current%state%of%clinical%research.%Onkologie%25%(4):%374-80,%2002.%[PUBMEDAbstract]

25.% Frohne%D,%Pfander%HJ:%Viscum%album.%In:%Frohne%D,%Pfander%HJ:%Giftpflanzen:%ein%Handbuch%fürApotheker,%Ärzte,%Toxikologen%und%Biologen.%3rd%rev.%ed.%Stuttgart,%Germany:Wissenschaftliche%Verlagsgesellschaft,%1987,%pp%179-80.

26.% Pusztai%A,%Grant%G,%Pfuller%U,%et%al.:%Nutritional%and%metabolic%effects%of%mistletoe%lectin%ML-1(type%2%RIP)%in%the%rat.%In:%European%Cooperation%in%the%Field%of%Scientific%and%TechnicalResearch:%COST%98:%Effects%of%Antinutrients%on%the%Nutritional%Value%of%Legume%Diets.Brussels,%Belgium:%European%Commission,%Directorate-General%XII,%Science,%Research%andDevelopment,%1998,%pp%164-7.

27.% Pusztai%A,%Grant%G,%Gelencsér%E,%et%al.:%Effects%of%an%orally%administered%mistletoe%(type-2%RIP)lectin%on%growth,%body%composition,%small%intestinal%structure,%and%insulin%levels%in%young%rats.J%Nutr%Biochem%9%(1):%31-6,%1998.

28.% Ewen%SWB,%Bardocz%S,%Grant%G,%et%al.:%The%effects%of%PHA%and%mistletoe%lectin%binding%toepithelium%of%rat%and%mouse%gut.%In:%European%Cooperation%in%the%Field%of%Scientific%andTechnical%Research:%COST%98:%Effects%of%Antinutrients%on%the%Nutritional%Value%of%LegumeDiets.%Brussels,%Belgium:%European%Commission,%Directorate-General%XII,%Science,%Researchand%Development,%1998,%pp%221-5.

29.% Pryme%IF,%Bardocz%S,%Grant%G,%et%al.:%The%plant%lectins%PHA%and%ML-1%suppress%the%growth%of%alymphosarcoma%tumour%in%mice.%In:%European%Cooperation%in%the%Field%of%Scientific%andTechnical%Research:%COST%98:%Effects%of%Antinutrients%on%the%Nutritional%Value%of%LegumeDiets.%Brussels,%Belgium:%European%Commission,%Directorate-General%XII,%Science,%Researchand%Development,%1998,%pp%215-20.

30.% Tubeuf%KFv,%Neckel%G,%Marzell%H:%Monographie%der%Mistel.%Munchen,%Berlin:%R.%Oldenbourg,1923.

31.% Teuscher%E:%Viscum%album.%In:%Hansel%R,%Keller%K,%Rimpler%H,%et%al.:%Hagers%Handbuch%derPharmazeutischen%Praxis,%Vol.%6.%5th%ed.%Berlin,%Germany:%Springer-Verlag,%1994,%pp%1160-83.

32.% Grossarth-Maticek%R,%Kiene%H,%Baumgartner%SM,%et%al.:%Use%of%Iscador,%an%extract%of%Europeanmistletoe%(Viscum%album),%in%cancer%treatment:%prospective%nonrandomized%and%randomizedmatched-pair%studies%nested%within%a%cohort%study.%Altern%Ther%Health%Med%7%(3):%57-66,%68-72,74-6%passim,%2001%May-Jun.%[PUBMED%Abstract]

33.% Capernaros%Z:%The%golden%bough:%the%case%for%mistletoe.%Eur%J%Herbal%Med%1%(1):19-24,%1994.

34.% Schrader%G,%Apel%K:%Isolation%and%characterization%of%cDNAs%encoding%viscotoxins%of%mistletoe(Viscum%album).%Eur%J%Biochem%198%(3):%549-53,%1991.%[PUBMED%Abstract]

35.% Gabius%HJ,%Gabius%S,%Joshi%SS,%et%al.:%From%ill-defined%extracts%to%the%immunomodulatory%lectin:will%there%be%a%reason%for%oncological%application%of%mistletoe?%Planta%Med%60%(1):%2-7,1994.%[PUBMED%Abstract]

36.% Samtleben%R,%Hajto%T,%Hostanska%K,%et%al.:%Mistletoe%lectins%as%immunostimulants%(chemistry,pharmacology%and%clinic).%In:%Wagner%H,%ed.:%Immunomodulatory%Agents%from%Plants.%Basel,Switzerland:%Birkhauser%Verlag,%1999,%pp%223-41.

37.% Abdullaev%FI,%de%Mejia%EG:%Antitumor%effect%of%plant%lectins.%Nat%Toxins%5%(4):%157-63,1997.%[PUBMED%Abstract]

38.% Kilpatrick%DC:%Mechanisms%and%assessment%of%lectin-mediated%mitogenesis.%Mol%Biotechnol11%(1):%55-65,%1999.%[PUBMED%Abstract]

39.% Elluru%SR,%VAN%Huyen%JP,%Delignat%S,%et%al.:%Antiangiogenic%properties%of%viscum%album%extractsare%associated%with%endothelial%cytotoxicity.%Anticancer%Res%29%(8):%2945-50,%2009.%[PUBMEDAbstract]

41.% Khil%LY,%Kim%W,%Lyu%S,%et%al.:%Mechanisms%involved%in%Korean%mistletoe%lectin-inducedapoptosis%of%cancer%cells.%World%J%Gastroenterol%13%(20):%2811-8,%2007.%[PUBMED%Abstract]

42.% Kim%MS,%Lee%J,%Lee%KM,%et%al.:%Involvement%of%hydrogen%peroxide%in%mistletoe%lectin-II-inducedapoptosis%of%myeloleukemic%U937%cells.%Life%Sci%73%(10):%1231-43,%2003.%[PUBMED%Abstract]

43.% Choi%SH,%Lyu%SY,%Park%WB:%Mistletoe%lectin%induces%apoptosis%and%telomerase%inhibition%inhuman%A253%cancer%cells%through%dephosphorylation%of%Akt.%Arch%Pharm%Res%27%(1):%68-76,2004.%[PUBMED%Abstract]

44.% Romagnoli%S,%Fogolari%F,%Catalano%M,%et%al.:%NMR%solution%structure%of%viscotoxin%C1%fromViscum%album%species%Coloratum%ohwi:%toward%a%structure-function%analysis%of%viscotoxins.

Biochemistry%42%(43):%12503-10,%2003.%[PUBMED%Abstract]

45.% Yoon%TJ,%Yoo%YC,%Kang%TB,%et%al.:%Antitumor%activity%of%the%Korean%mistletoe%lectin%is%attributedto%activation%of%macrophages%and%NK%cells.%Arch%Pharm%Res%26%(10):%861-7,%2003.%[PUBMEDAbstract]

46.% Ribéreau-Gayon%G,%Jung%ML,%Di%Scala%D,%et%al.:%Comparison%of%the%effects%of%fermented%andunfermented%mistletoe%preparations%on%cultured%tumor%cells.%Oncology%43%(Suppl%1):%35-41,1986.%[PUBMED%Abstract]

47.% Jäggy%C,%Musielski%H,%Urech%K,%et%al.:%Quantitative%determination%of%lectins%in%mistletoepreparations.%Arzneimittelforschung%45%(8):%905-9,%1995.%[PUBMED%Abstract]

48.% Zee-Cheng%RK:%Anticancer%research%on%Loranthaceae%plants.%Drugs%Future%22%(5):%519-30,1997.

49.% Kaegi%E:%Unconventional%therapies%for%cancer:%3.%Iscador.%Task%Force%on%Alternative%Therapiesof%the%Canadian%Breast%Cancer%Research%Initiative.%CMAJ%158%(9):%1157-9,%1998.%[PUBMEDAbstract]

50.% Stein%G,%Berg%PA:%Non-lectin%component%in%a%fermented%extract%from%Viscum%album%L.%grownon%pines%induces%proliferation%of%lymphocytes%from%healthy%and%allergic%individuals%in%vitro.Eur%J%Clin%Pharmacol%47%(1):%33-8,%1994.%[PUBMED%Abstract]

51.% Kleijnen%J,%Knipschild%P:%Mistletoe%treatment%for%cancer:%review%of%controlled%trials%in%humans.Phytomedicine%1:%255-60,%1994.

52.% Wagner%H,%Jordan%E,%Feil%B:%Studies%on%the%standardization%of%mistletoe%preparations.Oncology%43%(Suppl%1):%16-22,%1986.%[PUBMED%Abstract]

53.% Zarkovic%N,%Vukovic%T,%Loncaric%I,%et%al.:%An%overview%on%anticancer%activities%of%the%Viscumalbum%extract%Isorel.%Cancer%Biother%Radiopharm%16%(1):%55-62,%2001.%[PUBMED%Abstract]

54.% Mellor%D:%Mistletoe%in%homoeopathic%cancer%treatment.%Prof%Nurse%4%(12):%605-7,1989.%[PUBMED%Abstract]

55.% Fellmer%KE:%A%clinical%trial%of%Iscador:%follow-up%treatment%of%irradiated%genital%carcinomata%forthe%prevention%of%recurrences.%Br%Homeopath%J%57:%43-7,%1968.

56.% Kjaer%M:%Mistletoe%(Iscador)%therapy%in%stage%IV%renal%adenocarcinoma.%A%phase%II%study%inpatients%with%measurable%lung%metastases.%Acta%Oncol%28%(4):%489-94,%1989.%[PUBMEDAbstract]

57.% Schöffski%P,%Riggert%S,%Fumoleau%P,%et%al.:%Phase%I%trial%of%intravenous%aviscumine%(rViscumin)in%patients%with%solid%tumors:%a%study%of%the%European%Organization%for%Research%andTreatment%of%Cancer%New%Drug%Development%Group.%Ann%Oncol%15%(12):%1816-24,

58.% Matthes%HF,%Schad%F,%Buchwald%D,%et%al.:%Endoscopic%ultrasound-guided%fine-needle%Injectionof%Viscum%album%L.%(mistletoe;%Helixor%M)%in%the%therapy%of%primary%inoperable%pancreascancer:%a%pilot%study.%[Abstract]%Gastroenterology%128%(Suppl%2):%A-T988,%A433-A434,%2005.

59.% Matthes%HF,%Schad%F,%Schenk%G:%Viscum%album%in%the%therapy%of%primary%inoperablehepatocellular%carcinoma%(HCC).%[Abstract]%Gastroenterology%126%(Suppl%2):%A-755,%A101-A102,2004.

60.% Schaefermeyer%G,%Schaefermeyer%H:%Treatment%of%pancreatic%cancer%with%Viscum%album(Iscador):%a%retrospective%study%of%292%patients%1986-1996.%Complement%Ther%Med%6%(4):%172-7,1998.

61.% Kleeberg%UR,%Brocker%EB,%Lejeune%F,%et%al.:%Adjuvant%trial%in%melanoma%patients%comparingrlFN-alpha%to%rlFN-gamma%to%Iscador%to%a%control%group%after%curative%resection%of%high%riskprimary%(>=3mm)%or%regional%lymphnode%metastasis%(EORTC%18871).%[Abstract]%Eur%J%Cancer35%(Suppl%4):%A-264,%s82,%1999.

62.% Heiny%BM,%Albrecht%V,%Beuth%J:%Stabilization%of%quality%of%life%with%mistletoe%lectin-1-standardized%extract%in%advanced%colorectal%carcinoma.%Onkologe%4%(Suppl%1):%S35-9,%1998.

63.% Wetzel%D,%Schäfer%M:%Results%of%a%randomised%placebo-controlled%multicentre%study%withPS76A2%(standardised%mistletoe%preparation)%in%patients%with%breast%cancer%receivingadjuvant%chemotherapy.%[Abstract]%Phytomedicine%7%(Suppl%2):%A-SL-66,%2000.

64.% Viscum%album.%In:%Homoeopathic%Pharmacopoeia%Convention%of%the%United%States:Homoeopathic%Pharmacopoeia%of%the%United%States.%Washington,%DC:%2002,%Monograph%9444Visc.

HistoryMistletoe%has%been%used%for%centuries%for%its%medicinal%properties.[1-6]%It%was%reportedly%used%bythe%Druids%and%the%ancient%Greeks,%and%it%appears%in%legend%and%folklore%as%a%panacea.%It%has%beenused%in%various%forms%to%treat%cancer,%epilepsy,%infertility,%menopausal%symptoms,%nervoustension,%asthma,%hypertension,%headache,%and%dermatitis.%Modern%interest%in%mistletoe%as%ananticancer%treatment%began%in%the%1920s.%Most%of%the%results%of%clinical%studies%have%beenpublished%exclusively%in%German.%Refer%to%the%Human/Clinical%Studies%section%of%this%summary%formore%information.

Another%reported%activity%that%may%be%relevant%to%optimum%functioning%of%the%immune%system%inindividuals%with%cancer%is%stabilization%of%the%DNA%in%white%blood%cells,%including%white%blood%cells

that%have%been%exposed%to%DNA-damaging%chemotherapy%drugs.[7-11]

Mistletoe%has%been%shown%to%stimulate%increases%in%the%number%and%the%activity%of%various%typesof%white%blood%cells.[2,3,9,11-53]%Immune-system-enhancing%cytokines,%such%as%interleukin-1,interleukin-6,%and%tumor%necrosis%factor%-alpha,%are%released%by%white%blood%cells%after%exposure%tomistletoe%extracts.[1,3,7,9-11,14,19,29,33,37,42-46,48-50,52-54]%Other%evidence%suggests%thatmistletoe%exerts%its%cytotoxic%effects%by%interfering%with%protein%synthesis%in%target%cells[3,4,8,11,33,42-46,52,55-63]%and%by%inducing%apoptosis.[3,11,36,42,46,52,64-66]%Mistletoe%may%alsoserve%a%bridging%function,%bringing%together%immune%system%effector%cells%and%tumor%cells.[18,67]

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1.% Capernaros%Z:%The%golden%bough:%the%case%for%mistletoe.%Eur%J%Herbal%Med%1%(1):19-24,%1994.

4.% Olsnes%S,%Stirpe%F,%Sandvig%K,%et%al.:%Isolation%and%characterization%of%viscumin,%a%toxic%lectinfrom%Viscum%album%L.%(mistletoe).%J%Biol%Chem%257%(22):%13263-70,%1982.%[PUBMED%Abstract]

5.% Becker%H:%Botany%of%European%mistletoe%(Viscum%album%L.).%Oncology%43%(Suppl%1):%2-7,1986.%[PUBMED%Abstract]

6.% Watkins%D:%A%berry%Christmas.%Nurs%Times%93%(51):%28-9,%1997%Dec%17-23.%[PUBMED%Abstract]

7.% Büssing%A,%Azhari%T,%Ostendorp%H,%et%al.:%Viscum%album%L.%extracts%reduce%sister%chromatidexchanges%in%cultured%peripheral%blood%mononuclear%cells.%Eur%J%Cancer%30A%(12):%1836-41,1994.%[PUBMED%Abstract]

8.% Büssing%A,%Lehnert%A,%Schink%M,%et%al.:%Effect%of%Viscum%album%L.%on%rapidly%proliferatingamniotic%fluid%cells.%Sister%chromatid%exchange%frequency%and%proliferation%index.Arzneimittelforschung%45%(1):%81-3,%1995.%[PUBMED%Abstract]

9.% Büssing%A,%Regnery%A,%Schweizer%K:%Effects%of%Viscum%album%L.%on%cyclophosphamide-treatedperipheral%blood%mononuclear%cells%in%vitro:%sister%chromatid%exchanges%andactivation/proliferation%marker%expression.%Cancer%Lett%94%(2):%199-205,%1995.%[PUBMEDAbstract]

10.% Bussing%A,%Jungmann%H,%Suzart%K,%et%al.:%Suppression%of%sister%chromatid%exchange-inducingDNA%lesions%in%cultured%peripheral%blood%mononuclear%cells%by%Viscum%album%L.%J%Exp%Clin

Cancer%Res%15%(2):%107-14,%1996.

11.% Büssing%A,%Suzart%K,%Bergmann%J,%et%al.:%Induction%of%apoptosis%in%human%lymphocytes%treatedwith%Viscum%album%L.%is%mediated%by%the%mistletoe%lectins.%Cancer%Lett%99%(1):%59-72,1996.%[PUBMED%Abstract]

12.% Rentea%R,%Lyon%E,%Hunter%R:%Biologic%properties%of%iscador:%a%Viscum%album%preparation%I.Hyperplasia%of%the%thymic%cortex%and%accelerated%regeneration%of%hematopoietic%cellsfollowing%X-irradiation.%Lab%Invest%44%(1):%43-8,%1981.%[PUBMED%Abstract]

13.% Bloksma%N,%Schmiermann%P,%de%Reuver%M,%et%al.:%Stimulation%of%humoral%and%cellularimmunity%by%Viscum%preparations.%Planta%Med%46%(4):%221-7,%1982.%[PUBMED%Abstract]

14.% Hajto%T:%Immunomodulatory%effects%of%iscador:%a%Viscum%album%preparation.%Oncology%43(Suppl%1):%51-65,%1986.%[PUBMED%Abstract]

15.% Hajto%T,%Lanzrein%C:%Natural%killer%and%antibody-dependent%cell-mediated%cytotoxicity%activitiesand%large%granular%lymphocyte%frequencies%in%Viscum%album-treated%breast%cancer%patients.Oncology%43%(2):%93-7,%1986.%[PUBMED%Abstract]

16.% Hamprecht%K,%Handgretinger%R,%Voetsch%W,%et%al.:%Mediation%of%human%NK-activity%bycomponents%in%extracts%of%Viscum%album.%Int%J%Immunopharmacol%9%(2):%199-209,1987.%[PUBMED%Abstract]

17.% Hajto%T,%Hostanska%K,%Gabius%HJ:%Modulatory%potency%of%the%beta-galactoside-specific%lectinfrom%mistletoe%extract%(Iscador)%on%the%host%defense%system%in%vivo%in%rabbits%and%patients.Cancer%Res%49%(17):%4803-8,%1989.%[PUBMED%Abstract]

18.% Mueller%EA,%Hamprecht%K,%Anderer%FA:%Biochemical%characterization%of%a%component%inextracts%of%Viscum%album%enhancing%human%NK%cytotoxicity.%Immunopharmacology%17%(1):11-8,%1989%Jan-Feb.%[PUBMED%Abstract]

19.% Hajto%T,%Hostanska%K,%Frei%K,%et%al.:%Increased%secretion%of%tumor%necrosis%factors%alpha,interleukin%1,%and%interleukin%6%by%human%mononuclear%cells%exposed%to%beta-galactoside-specific%lectin%from%clinically%applied%mistletoe%extract.%Cancer%Res%50%(11):%3322-6,1990.%[PUBMED%Abstract]

20.% Beuth%J,%Ko%HL,%Gabius%HJ,%et%al.:%Behavior%of%lymphocyte%subsets%and%expression%of%activationmarkers%in%response%to%immunotherapy%with%galactoside-specific%lectin%from%mistletoe%inbreast%cancer%patients.%Clin%Investig%70%(8):%658-61,%1992.%[PUBMED%Abstract]

21.% Kuttan%G,%Kuttan%R:%Immunological%mechanism%of%action%of%the%tumor%reducing%peptide%frommistletoe%extract%(NSC%635089)%cellular%proliferation.%Cancer%Lett%66%(2):%123-30,1992.%[PUBMED%Abstract]

22.% Kuttan%G,%Kuttan%R:%Immunomodulatory%activity%of%a%peptide%isolated%from%Viscum%albumextract%(NSC%635%089).%Immunol%Invest%21%(4):%285-96,%1992.%[PUBMED%Abstract]

23.% Gabius%HJ,%Walzel%H,%Joshi%SS,%et%al.:%The%immunomodulatory%beta-galactoside-specific%lectinfrom%mistletoe:%partial%sequence%analysis,%cell%and%tissue%binding,%and%impact%on%intracellularbiosignalling%of%monocytic%leukemia%cells.%Anticancer%Res%12%(3):%669-75,%1992%May-Jun.%[PUBMED%Abstract]

24.% Beuth%J,%Ko%HL,%Tunggal%L,%et%al.:%Thymocyte%proliferation%and%maturation%in%response%togalactoside-specific%mistletoe%lectin-1.%In%Vivo%7%(5):%407-10,%1993%Sep-Oct.%[PUBMED%Abstract]

25.% Timoshenko%AV,%Gabius%HJ:%Efficient%induction%of%superoxide%release%from%human%neutrophilsby%the%galactoside-specific%lectin%from%Viscum%album.%Biol%Chem%Hoppe%Seyler%374%(4):%237-43,1993.%[PUBMED%Abstract]

26.% Timoshenko%AV,%Kayser%K,%Drings%P,%et%al.:%Modulation%of%lectin-triggered%superoxide%releasefrom%neutrophils%of%tumor%patients%with%and%without%chemotherapy.%Anticancer%Res%13%(5C):1789-92,%1993%Sep-Oct.%[PUBMED%Abstract]

27.% Kuttan%G:%Tumoricidal%activity%of%mouse%peritoneal%macrophages%treated%with%Viscum%albumextract.%Immunol%Invest%22%(6-7):%431-40,%1993%Aug-Oct.%[PUBMED%Abstract]

28.% Beuth%J,%Ko%HL,%Tunggal%L,%et%al.:%Immunoprotective%activity%of%the%galactoside-specificmistletoe%lectin%in%cortisone-treated%BALB/c-mice.%In%Vivo%8%(6):%989-92,%1994%Nov-Dec.%[PUBMED%Abstract]

29.% Heiny%BM,%Beuth%J:%Mistletoe%extract%standardized%for%the%galactoside-specific%lectin%(ML-1)induces%beta-endorphin%release%and%immunopotentiation%in%breast%cancer%patients.Anticancer%Res%14%(3B):%1339-42,%1994%May-Jun.%[PUBMED%Abstract]

30.% Stein%G,%Berg%PA:%Non-lectin%component%in%a%fermented%extract%from%Viscum%album%L.%grownon%pines%induces%proliferation%of%lymphocytes%from%healthy%and%allergic%individuals%in%vitro.Eur%J%Clin%Pharmacol%47%(1):%33-8,%1994.%[PUBMED%Abstract]

31.% Timoshenko%AV,%Gabius%HJ:%Influence%of%the%galactoside-specific%lectin%from%Viscum%album%andits%subunits%on%cell%aggregation%and%selected%intracellular%parameters%of%rat%thymocytes.Planta%Med%61%(2):%130-3,%1995.%[PUBMED%Abstract]

32.% Timoshenko%AV,%Cherenkevich%SN,%Gabius%HJ:%Viscum%album%agglutinin-induced%aggregationof%blood%cells%and%the%lectin%effects%on%neutrophil%function.%Biomed%Pharmacother%49%(3):%153-8,%1995.%[PUBMED%Abstract]

33.% Hostanska%K,%Hajto%T,%Spagnoli%GC,%et%al.:%A%plant%lectin%derived%from%Viscum%album%inducescytokine%gene%expression%and%protein%production%in%cultures%of%human%peripheral%blood

mononuclear%cells.%Nat%Immun%14%(5-6):%295-304,%1995.%[PUBMED%Abstract]

37.% Preisfeld%A:%Influence%of%aqueous%mistletoe%preparations%on%humoral%immune%parameterswith%emphasis%on%the%cytotoxicity%of%human%complement%in%breast%cancer%patients.%ForschKomplementarmed%4%(4):%224-8,%1997.

38.% Chernyshov%VP,%Omelchenko%LI,%Heusser%P,%et%al.:%Immunomodulatory%actions%of%Viscumalbum%(Iscador)%in%children%with%recurrent%respiratory%disease%as%a%result%of%the%Chernobylnuclear%accident.%Complement%Ther%Med%5%(3):%141-6,%1997.

39.% Heiny%BM,%Albrecht%V,%Beuth%J:%Correlation%of%immune%cell%activities%and%beta-endorphinrelease%in%breast%carcinoma%patients%treated%with%galactose-specific%lectin%standardizedmistletoe%extract.%Anticancer%Res%18%(1B):%583-6,%1998%Jan-Feb.%[PUBMED%Abstract]

43.% Bocci%V:%Mistletoe%(viscum%album)%lectins%as%cytokine%inducers%and%immunoadjuvant%in%tumortherapy.%A%review.%J%Biol%Regul%Homeost%Agents%7%(1):%1-6,%1993%Jan-Mar.%[PUBMED%Abstract]

44.% Gabius%HJ,%Gabius%S,%Joshi%SS,%et%al.:%From%ill-defined%extracts%to%the%immunomodulatory%lectin:will%there%be%a%reason%for%oncological%application%of%mistletoe?%Planta%Med%60%(1):%2-7,1994.%[PUBMED%Abstract]

47.% Lenartz%D,%Dott%U,%Menzel%J,%et%al.:%Survival%of%glioma%patients%after%complementary%treatmentwith%galactoside-specific%lectin%from%mistletoe.%Anticancer%Res%20%(3B):%2073-6,%2000%May-Jun.%[PUBMED%Abstract]

50.% Kunze%E,%Schulz%H,%Gabius%HJ:%Inability%of%galactoside-specific%mistletoe%lectin%to%inhibit%N-methyl-N-nitrosourea-induced%tumor%development%in%the%urinary%bladder%of%rats%and%tomediate%a%local%cellular%immune%response%after%long-term%administration.%J%Cancer%Res%ClinOncol%124%(2):%73-87,%1998.%[PUBMED%Abstract]

51.% Kunze%E,%Schulz%H,%Adamek%M,%et%al.:%Long-term%administration%of%galactoside-specificmistletoe%lectin%in%an%animal%model:%no%protection%against%N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced%urinary%bladder%carcinogenesis%in%rats%and%no%induction%of%a%relevantlocal%cellular%immune%response.%J%Cancer%Res%Clin%Oncol%126%(3):%125-38,%2000.%[PUBMEDAbstract]

52.% Mengs%U,%Schwarz%T,%Bulitta%M,%et%al.:%Antitumoral%effects%of%an%intravesically%applied%aqueousmistletoe%extract%on%urinary%bladder%carcinoma%MB49%in%mice.%Anticancer%Res%20%(5B):%3565-8,2000%Sep-%Oct.%[PUBMED%Abstract]

54.% Kleijnen%J,%Knipschild%P:%Mistletoe%treatment%for%cancer:%review%of%controlled%trials%in%humans.Phytomedicine%1:%255-60,%1994.

55.% Stirpe%F,%Sandvig%K,%Olsnes%S,%et%al.:%Action%of%viscumin,%a%toxic%lectin%from%mistletoe,%on%cells%inculture.%J%Biol%Chem%257%(22):%13271-7,%1982.%[PUBMED%Abstract]

56.% Walzel%H,%Jonas%L,%Rosin%T,%et%al.:%Relationship%between%internalization%kinetics%and%cytotoxicityof%mistletoe%lectin%I%to%L1210%leukaemia%cells.%Folia%Biol%(Praha)%36%(3-4):%181-8,%1990.%[PUBMEDAbstract]

57.% Franz%H:%Mistletoe%lectins%and%their%A%and%B%chains.%Oncology%43%(Suppl%1):%23-34,1986.%[PUBMED%Abstract]

58.% Sweeney%EC,%Palmer%RA,%Pfüller%U:%Crystallization%of%the%ribosome%inactivating%protein%ML1from%Viscum%album%(mistletoe)%complexed%with%beta-D-galactose.%J%Mol%Biol%234%(4):%1279-81,1993.%[PUBMED%Abstract]

59.% Jung%ML,%Baudino%S,%Ribéreau-Gayon%G,%et%al.:%Characterization%of%cytotoxic%proteins%frommistletoe%(Viscum%album%L.).%Cancer%Lett%51%(2):%103-8,%1990.%[PUBMED%Abstract]

61.% Dietrich%JB,%Ribéreau-Gayon%G,%Jung%ML,%et%al.:%Identity%of%the%N-terminal%sequences%of%thethree%A%chains%of%mistletoe%(Viscum%album%L.)%lectins:%homology%with%ricin-like%plant%toxinsand%single-chain%ribosome-inhibiting%proteins.%Anticancer%Drugs%3%(5):%507-11,%1992.%[PUBMEDAbstract]

63.% Burger%AM,%Mengs%U,%Schüler%JB,%et%al.:%Anticancer%activity%of%an%aqueous%mistletoe%extract(AME)%in%syngeneic%murine%tumor%models.%Anticancer%Res%21%(3B):%1965-8,%2001%May-Jun.%[PUBMED%Abstract]

64.% Janssen%O,%Scheffler%A,%Kabelitz%D:%In%vitro%effects%of%mistletoe%extracts%and%mistletoe%lectins.Cytotoxicity%towards%tumor%cells%due%to%the%induction%of%programmed%cell%death%(apoptosis).Arzneimittelforschung%43%(11):%1221-7,%1993.%[PUBMED%Abstract]

66.% Maier%G,%Fiebig%HH:%Absence%of%tumor%growth%stimulation%in%a%panel%of%16%human%tumor%celllines%by%mistletoe%extracts%in%vitro.%Anticancer%Drugs%13%(4):%373-9,%2002.%[PUBMED%Abstract]

67.% Mueller%EA,%Anderer%FA:%Chemical%specificity%of%effector%cell/tumor%cell%bridging%by%a%Viscumalbum%rhamnogalacturonan%enhancing%cytotoxicity%of%human%NK%cells.Immunopharmacology%19%(1):%69-77,%1990%Jan-Feb.%[PUBMED%Abstract]

Laboratory/Animal/Preclinical StudiesThe%immune-system%-stimulating%and%cytotoxic%properties%of%mistletoe%have%been%investigated%inlaboratory%and%animal%studies.

Viscotoxins%and%lectins%have%been%investigated%as%active%components%in%mistletoe;%most%researchhas%focused%on%the%lectins.[1-9]%Purified%mistletoe%lectins%have%demonstrated%cytotoxic%andimmune-system-stimulating%activities.%To%date,%four%different%lectins:%ML-1,%ML-2,%ML-3,%and%Viscumalbum%chitin%-binding%agglutinin%have%been%identified%in%mistletoe%extracts.%ML-1%(or%viscumin)may%be%responsible%for%many%of%mistletoe’s%biological%effects.%When%a%laboratory%method%wasused%to%selectively%deplete%ML-1%from%Viscum album%extracts,%their%cytotoxic%and%immune-system-stimulating%properties%were%markedly%reduced.[10,11]%It%should%be%noted%that%fermentationeliminates%most%of%the%ML-1%in%mistletoe%extracts.[12-14]%Polysaccharide%and%oligosaccharidecomponents%of%mistletoe%extracts%with%substantial%immune-stimulating%properties%have%beenreviewed.[15,16]

The%molecular%structure%of%ML-1%consists%of%an%alpha%chain%and%a%beta%chain,%which%can%beseparated%from%one%another.[1,1,6-9,13,17,18]%Each%chain%type%appears%to%mediate%a%subset%of%theactivities%described%for%the%intact%lectin.%Cytotoxicity%is%associated%mainly%with%the%alpha%chain.%Inlaboratory%studies,%the%ML-1%alpha%chain%has%been%coupled%to%monoclonal%antibodies%to%produceimmunotoxins%that%target%and%kill%specific%cell%types.[19-21]

Recombinant%ML-1,%rML%(also%known%as%rViscunim%or%aviscumin)%appears%to%have%the%sameefficacy%as%plant-based%ML-1%in%laboratory%studies.[22]%Since%this%is%not%an%extract%of%mistletoe,%it%isout%of%the%purview%of%this%summary.

The%beta%chain%of%ML-1%is%responsible%for%binding%to%the%surface%of%a%target%cell.[23]%Studies%ofmistletoe%lectin%binding%to%cancer%cells%have%examined%whether%the%extent%of%cell%binding%canpredict%disease%outcome%or%survival.%Studies%show%that%the%prognostic%value%of%ML-1%bindingdepends%on%the%type%of%cancer.[24]%For%human%breast%cancer%cells,%the%amount%of%lectin-boundcells%correlates%positively%with%disease%outcome.%However,%for%human%adenocarcinoma%of%thelung,%there%is%no%correlation%between%the%amount%of%lectin-bound%cells%and%disease%survival.[25]Though%much%research%has%looked%at%this%particular%aspect,%there%have%not%been%studies%thatdirectly%link%the%concentration%of%that%component%to%any%clinical%activity%of%mistletoe.

Laboratory%studies%have%shown%that%mistletoe%extracts%can%stimulate%the%activity%of%white%bloodcells%in vitro and%cause%them%to%release%molecules%thought%to%be%important%for%anticancer%immuneresponses.%[4,6,8,9,17,26-33]%In%addition,%mistletoe%extracts%have%demonstrated%cytotoxic%activityagainst%a%variety%of%mouse,%rat,%and%human%cancer%cells%in vitro.[1,8,23,34-37]

There%are%conflicting%reports%concerning%the%stimulation%of%cancer%cell%growth%in vitro.%In%one

study,%the%in vitro%growth%of%several%types%of%human%cancer%cells%was%stimulated%by%treatment%withlow%doses%of%the%purified%lectin%ML-1.[1]%However,%various%other%studies%found%that%ML-1%andmistletoe%extracts%did%not%induce%cell%proliferation.[38,39]

A%2004%in vitro%study%of%IscadorQu,%a%fermented%aqueous%extract%from%European%mistletoe%grownon%oaks,%against%various%cell%lines%demonstrated%that%sensitivity%to%this%extract%varies%greatlyamong%cell%lines.%In%sensitive%cell%lines,%a%strong%effect%was%seen%in%epidermal%(HaCaT),%lungadenocarcinoma%(NCI-H125),%and%breast%adenocarcinoma%(MCF-7)%cell%lines%whereas,%little%or%noeffect%was%seen%in%lung%squamous%cell%carcinoma%(MR65)%and%colon%carcinoma%(Cac0-2,%HT-29).Some%cells%lines%were%responsive%to%high%or%low%concentrations%of%IscadorQu.%IscadorQu%showedearly%cell%cycle%inhibition%followed%by%apoptosis%in%a%dose-dependent%manner.[40]

Studies%of%the%ability%of%mistletoe%to%inhibit%cancer%cell%growth%in%animals%have%yielded%mixed%andinconsistent%results.[5-9,36,41-49]%In%most%of%these%studies,%mistletoe%extracts%were%administeredeither%by%subcutaneous%injection%or%by%intraperitoneal%injection.

In%one%animal%study,%treatment%with%IscadorM%increased%the%survival%time%of%mice%that%had%beenimplanted%with%Ehrlich%ascites%mouse%cancer%cells,%but%not%L1210%leukemia%or%B16%melanomacancer%cells.[50]%The%effect%of%IscadorM%on%the%growth%of%tumors%formed%in%mice%by%threeadditional%types%of%mouse%cancer%cells%(i.e.,%Lewis%lung%carcinoma,%colon%adenocarcinoma%38,%andC3H%mammary%adenocarcinoma)%was%also%assessed%in%this%study.%Treatment%with%IscadorMsubstantially%reduced%the%growth%rate%of%all%three%types%of%tumors.

In%another%animal%study,%mice%were%administered%IscadorM%before,%during,%or%after%injection%witheither%of%two%types%of%mouse%cancer%cells%(i.e.,%Dalton%lymphoma%or%Ehrlich%ascites).[51]%In%thisstudy,%all%groups%of%mice%treated%with%mistletoe%showed%substantially%slower%tumor%growth%thanthe%control%groups.

No%antitumor%effect%or%improvement%in%survival%was%observed%when%IscadorM%was%used%to%treatrats%bearing%chemically%induced%mammary%carcinomas%or%tumors%formed%from%rat%Walker%256carcinosarcoma%cells.[52]%In%this%study,%IscadorM%was%also%not%effective%in%treating%mice%that%hadbeen%injected%with%Ehrlich%ascites%cells.%In%addition,%IscadorP%was%found%ineffective%in%treating%ratswith%tumors%formed%from%rat%L5222%leukemia%cells.

In%another%study,%intratumoral%injections%of%mistletoe%extract%(abnobaVISCUM%Fraxini-2)demonstrated%more%antitumor%activity%than%intravenous%gemcitabine%when%injected%into%mousexenografts%of%human%pancreatic%cancer.[53]

Treatment%with%the%mistletoe%extract%Lektinol%(also%sold%as%Plenosol;%refer%to%the%GeneralInformation%section%of%this%summary%for%more%information)%has%likewise%yielded%mixed%results%inanimal%experiments.[7]%Treatment%with%Lektinol%slowed%the%growth%of%tumors%formed%in%micefrom%implants%of%three%types%of%mouse%cancer%(i.e.,%colon%adenocarcinoma%38,%Renca%renal%cell

carcinoma,%and%F9%testicular%carcinoma)%but%not%in%two%other%mouse%cancers%(i.e.,%B16%melanomaand%Lewis%lung%carcinoma).

The%anticancer%effects%of%Isorel%(also%sold%as%Vysorel;%refer%to%the%General%Information%section%ofthis%summary%for%more%information)%have%been%examined%in%at%least%two%animal%studies.[36,54]%Inone%study,%IsorelM%was%used%alone%or%in%combination%with%local%x-ray%therapy%in%mice%bearingmouse%CMC-2%fibrosarcoma%tumors.[54]%When%IsorelM%was%used%alone,%no%effect%on%either%tumorgrowth%or%animal%survival%was%observed.%When%IsorelM%injections%were%combined%with%local%x-raytherapy%of%tumors,%substantial%improvements%in%survival%were%found%in%comparison%with%thesurvival%of%mice%treated%with%local%x-ray%therapy%alone.%With%local%x-ray%therapy%alone,%22%%of%micewere%cured%of%their%tumors.%When%local%x-ray%therapy%was%combined%with%IsorelM%injections,administered%before%or%after%the%x-ray%treatment,%the%cure%rate%increased%to%43%.%When%IsorelMwas%administered%both%before%and%after%local%x-ray%therapy,%the%proportion%of%cured%miceincreased%to%67%.

In%another%study,%IsorelM%showed%antitumor%and%antimetastatic%effects%in%mice%that%had%beeninjected%with%mouse%mammary%carcinoma%cells.[36]%The%antitumor%effects%appeared%mostpronounced%when%IsorelM%was%injected%in%the%vicinity%of%tumors.

The%ability%of%purified%or%recombinant%lectin%ML-1%to%inhibit%the%formation%of%chemically%inducedbladder%tumors%in%rats%has%been%evaluated%in%three%studies.[5,8,48,55]%In%two%of%the%studies,purified%ML-1%was%administered%by%subcutaneous%injection.[5,8,55]%Treatment%with%ML-1%did%notreduce%the%frequency%of%bladder%tumor%formation%or%increase%immune%system%activity%in%thebladder%wall%in%either%study.%In%the%third%study,%recombinant%ML-1%was%introduced%directly%into%thebladder%through%a%process%known%as%intravesical%instillation.[8,48]%In%this%study,%the%frequency%ofbladder%tumor%formation%was%reduced%by%approximately%50%%in%ML-1-treated%animals.%As%in%theother%two%studies,%immune%system%activity%in%the%bladder%wall%was%not%increased%substantially.%Itwas%concluded%that%the%antitumor%effect%observed%in%this%study%was%the%result%of%direct%cytotoxicaction%by%the%recombinant%lectin%against%malignant%cells.[48]

A%few%animal%studies%have%suggested%that%mistletoe%is%beneficial%in%decreasing%the%side%effects%ofconventional%anticancer%therapy%(e.g.,%chemotherapy%and%radiation%therapy)%and%that%itcounteracts%the%effects%of%drugs%used%to%suppress%the%immune%system.[56-59]%In%one%study,IscadorM%was%shown%to%increase%the%number%of%white%blood%cells%in%mice%treated%withcyclophosphamide%chemotherapy%or%radiation%therapy%and%to%decrease%the%amount%of%weight%lossdue%to%radiation,%but%not%during%cyclophosphamide%treatment.[58]%In%another%study,%IscadorMwas%shown%to%accelerate%the%recovery%of%hematopoietic%tissue%in%the%bone%marrow%and%spleens%ofirradiated%rats%and%mice.[56]%In%another%study,%the%mistletoe%product%Eurixor%was%shown%tocounteract%the%immunosuppressive%effects%of%treatment%with%the%drug%cortisone.[57]%In%this%invitro%study,%mistletoe%(Viscum album L.)%did%not%inhibit%chemotherapy-induced%cytostasis%or

cytotoxicity.[60]

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19.% Wiedłocha%A,%Sandvig%K,%Walzel%H,%et%al.:%Internalization%and%action%of%an%immunotoxincontaining%mistletoe%lectin%A-chain.%Cancer%Res%51%(3):%916-20,%1991.%[PUBMED%Abstract]

20.% Tonevitsky%AG,%Toptygin%AYu,%Pfuller%U,%et%al.:%Immunotoxin%with%mistletoe%lectin%I%A-chain%andricin%A-chain%directed%against%CD5%antigen%of%human%T-lymphocytes;%comparison%of%efficiencyand%specificity.%Int%J%Immunopharmacol%13%(7):%1037-41,%1991.%[PUBMED%Abstract]

21.% Bocci%V:%Mistletoe%(viscum%album)%lectins%as%cytokine%inducers%and%immunoadjuvant%in%tumortherapy.%A%review.%J%Biol%Regul%Homeost%Agents%7%(1):%1-6,%1993%Jan-Mar.%[PUBMED%Abstract]

22.% Habeck%M:%Mistletoe%compound%enters%clinical%trials.%Drug%Discov%Today%8%(2):%52-3,2003.%[PUBMED%Abstract]

23.% Müthing%J,%Meisen%I,%Kniep%B,%et%al.:%Tumor-associated%CD75s%gangliosides%and%CD75s-bearing

glycoproteins%with%Neu5Acalpha2-6Galbeta1-4GlcNAc-residues%are%receptors%for%theanticancer%drug%rViscumin.%FASEB%J%19%(1):%103-5,%2005.%[PUBMED%Abstract]

24.% Fritz%P,%Dippon%J,%Kierschke%T,%et%al.:%Impact%of%mistletoe%lectin%binding%in%breast%cancer.Anticancer%Res%24%(2C):%1187-92,%2004%Mar-Apr.%[PUBMED%Abstract]

25.% Blonski%K,%Schumacher%U,%Burkholder%I,%et%al.:%Binding%of%recombinant%mistletoe%lectin(aviscumine)%to%resected%human%adenocarcinoma%of%the%lung.%Anticancer%Res%25%(5):%3303-7,2005%Sep-Oct.%[PUBMED%Abstract]

26.% Timoshenko%AV,%Kayser%K,%Drings%P,%et%al.:%Modulation%of%lectin-triggered%superoxide%releasefrom%neutrophils%of%tumor%patients%with%and%without%chemotherapy.%Anticancer%Res%13%(5C):1789-92,%1993%Sep-Oct.%[PUBMED%Abstract]

27.% Timoshenko%AV,%Gabius%HJ:%Influence%of%the%galactoside-specific%lectin%from%Viscum%album%andits%subunits%on%cell%aggregation%and%selected%intracellular%parameters%of%rat%thymocytes.Planta%Med%61%(2):%130-3,%1995.%[PUBMED%Abstract]

28.% Timoshenko%AV,%Cherenkevich%SN,%Gabius%HJ:%Viscum%album%agglutinin-induced%aggregationof%blood%cells%and%the%lectin%effects%on%neutrophil%function.%Biomed%Pharmacother%49%(3):%153-8,%1995.%[PUBMED%Abstract]

29.% Hostanska%K,%Hajto%T,%Spagnoli%GC,%et%al.:%A%plant%lectin%derived%from%Viscum%album%inducescytokine%gene%expression%and%protein%production%in%cultures%of%human%peripheral%bloodmononuclear%cells.%Nat%Immun%14%(5-6):%295-304,%1995.%[PUBMED%Abstract]

33.% Hallek%M:%Interleukin-6-mediated%cell%growth%in%multiple%myeloma--a%role%for%Viscum%albumextracts?%Onkologie%28%(8-9):%387,%2005.%[PUBMED%Abstract]

34.% Schaller%G,%Urech%K,%Giannattasio%M:%Cytotoxicity%of%different%viscotoxins%and%extracts%from%theEuropean%subspecies%Viscum%album%L.%Phytother%Res%10%(6):%473-7,%1996.

35.% Maier%G,%Fiebig%HH:%Absence%of%tumor%growth%stimulation%in%a%panel%of%16%human%tumor%cell

lines%by%mistletoe%extracts%in%vitro.%Anticancer%Drugs%13%(4):%373-9,%2002.%[PUBMED%Abstract]

37.% Zuzak%TJ,%Rist%L,%Eggenschwiler%J,%et%al.:%Paediatric%medulloblastoma%cells%are%susceptible%toViscum%album%(Mistletoe)%preparations.%Anticancer%Res%26%(5A):%3485-92,%2006%Sep-Oct.%[PUBMED%Abstract]

38.% Kelter%G,%Fiebig%HH:%Absence%of%tumor%growth%stimulation%in%a%panel%of%26%human%tumor%celllines%by%mistletoe%(Viscum%album%L.)%extracts%Iscador%in%vitro.%Arzneimittelforschung%56%(6A):435-40,%2006.%[PUBMED%Abstract]

39.% Kelter%G,%Schierholz%JM,%Fischer%IU,%et%al.:%Cytotoxic%activity%and%absence%of%tumor%growthstimulation%of%standardized%mistletoe%extracts%in%human%tumor%models%in%vitro.%AnticancerRes%27%(1A):%223-33,%2007%Jan-Feb.%[PUBMED%Abstract]

40.% Harmsma%M,%Grommé%M,%Ummelen%M,%et%al.:%Differential%effects%of%Viscum%album%extractIscadorQu%on%cell%cycle%progression%and%apoptosis%in%cancer%cells.%Int%J%Oncol%25%(6):%1521-9,2004.%[PUBMED%Abstract]

41.% Cebović%T,%Spasić%S,%Popović%M:%Cytotoxic%effects%of%the%Viscum%album%L.%extract%on%Ehrlichtumour%cells%in%vivo.%Phytother%Res%22%(8):%1097-103,%2008.%[PUBMED%Abstract]

42.% Seifert%G,%Jesse%P,%Laengler%A,%et%al.:%Molecular%mechanisms%of%mistletoe%plant%extract-inducedapoptosis%in%acute%lymphoblastic%leukemia%in%vivo%and%in%vitro.%Cancer%Lett%264%(2):%218-28,2008.%[PUBMED%Abstract]

43.% Thies%A,%Dautel%P,%Meyer%A,%et%al.:%Low-dose%mistletoe%lectin-I%reduces%melanoma%growth%andspread%in%a%scid%mouse%xenograft%model.%Br%J%Cancer%98%(1):%106-12,%2008.%[PUBMED%Abstract]

44.% Van%Huyen%JP,%Delignat%S,%Bayry%J,%et%al.:%Interleukin-12%is%associated%with%the%in%vivo%anti-tumor%effect%of%mistletoe%extracts%in%B16%mouse%melanoma.%Cancer%Lett%243%(1):%32-7,2006.%[PUBMED%Abstract]

45.% Beuth%J,%Ko%HL,%Schneider%H,%et%al.:%Intratumoral%application%of%standardized%mistletoe%extractsdown%regulates%tumor%weight%via%decreased%cell%proliferation,%increased%apoptosis%andnecrosis%in%a%murine%model.%Anticancer%Res%26%(6B):%4451-6,%2006%Nov-Dec.%[PUBMED%Abstract]

46.% Braun%JM,%Ko%HL,%Schierholz%JM,%et%al.:%Standardized%mistletoe%extract%augments%immuneresponse%and%down-regulates%local%and%metastatic%tumor%growth%in%murine%models.Anticancer%Res%22%(6C):%4187-90,%2002%Nov-Dec.%[PUBMED%Abstract]

47.% Pryme%IF,%Bardocz%S,%Pusztai%A,%et%al.:%Dietary%mistletoe%lectin%supplementation%and%reducedgrowth%of%a%murine%non-Hodgkin%lymphoma.%Histol%Histopathol%17%(1):%261-71,

48.% Elsässer-Beile%U,%Ruhnau%T,%Freudenberg%N,%et%al.:%Antitumoral%effect%of%recombinantmistletoe%lectin%on%chemically%induced%urinary%bladder%carcinogenesis%in%a%rat%model.%Cancer91%(5):%998-1004,%2001.%[PUBMED%Abstract]

50.% Khwaja%TA,%Dias%CB,%Pentecost%S:%Recent%studies%on%the%anticancer%activities%of%mistletoe(Viscum%album)%and%its%alkaloids.%Oncology%43%(Suppl%1):%42-50,%1986.%[PUBMED%Abstract]

51.% Kuttan%G,%Vasudevan%DM,%Kuttan%R:%Effect%of%a%preparation%from%Viscum%album%on%tumordevelopment%in%vitro%and%in%mice.%J%Ethnopharmacol%29%(1):%35-41,%1990.%[PUBMED%Abstract]

52.% Berger%M,%Schmähl%D:%Studies%on%the%tumor-inhibiting%efficacy%of%Iscador%in%experimentalanimal%tumors.%J%Cancer%Res%Clin%Oncol%105%(3):%262-5,%1983.%[PUBMED%Abstract]

53.% Rostock%M,%Huber%R,%Greiner%T,%et%al.:%Anticancer%activity%of%a%lectin-rich%mistletoe%extractinjected%intratumorally%into%human%pancreatic%cancer%xenografts.%Anticancer%Res%25%(3B):1969-75,%2005%May-Jun.%[PUBMED%Abstract]

54.% Jurin%M,%Zarković%N,%Hrzenjak%M,%et%al.:%Antitumorous%and%immunomodulatory%effects%of%theViscum%album%L.%preparation%Isorel.%Oncology%50%(6):%393-8,%1993%Nov-Dec.%[PUBMED%Abstract]

55.% Kunze%E,%Schulz%H,%Gabius%HJ:%Inability%of%galactoside-specific%mistletoe%lectin%to%inhibit%N-methyl-N-nitrosourea-induced%tumor%development%in%the%urinary%bladder%of%rats%and%tomediate%a%local%cellular%immune%response%after%long-term%administration.%J%Cancer%Res%ClinOncol%124%(2):%73-87,%1998.%[PUBMED%Abstract]

56.% Rentea%R,%Lyon%E,%Hunter%R:%Biologic%properties%of%iscador:%a%Viscum%album%preparation%I.Hyperplasia%of%the%thymic%cortex%and%accelerated%regeneration%of%hematopoietic%cellsfollowing%X-irradiation.%Lab%Invest%44%(1):%43-8,%1981.%[PUBMED%Abstract]

57.% Beuth%J,%Ko%HL,%Tunggal%L,%et%al.:%Immunoprotective%activity%of%the%galactoside-specificmistletoe%lectin%in%cortisone-treated%BALB/c-mice.%In%Vivo%8%(6):%989-92,%1994%Nov-Dec.%[PUBMED%Abstract]

58.% Kuttan%G,%Kuttan%R:%Reduction%of%leukopenia%in%mice%by%"viscum%album"%administration%duringradiation%and%chemotherapy.%Tumori%79%(1):%74-6,%1993.%[PUBMED%Abstract]

60.% Weissenstein%U,%Kunz%M,%Urech%K,%et%al.:%Interaction%of%standardized%mistletoe%(Viscum%album)

extracts%with%chemotherapeutic%drugs%regarding%cytostatic%and%cytotoxic%effects%in%vitro.%BMCComplement%Altern%Med%14:%6,%2014.%[PUBMED%Abstract]

Human/Clinical StudiesMistletoe%has%been%evaluated%as%a%treatment%for%people%with%cancer%in%numerous%clinical%studies.[1-20]

The%mistletoe%extracts%and%products%studied%in%clinical%trials%were%Iscador,%Eurixor,%Helixor,Lektinol,%Isorel,%abnobaVISCUM,[21]%and%recombinant%lectin%ML-1%(refer%to%the%appropriatesections%and%tables%at%the%end%of%this%section%for%more%information).

The%findings%from%more%than%50%clinical%trials%of%mistletoe%extracts%in%patients%with%cancer%havebeen%published,%and%several%systematic%reviews%and%meta-analyses%of%the%results%of%these%studieshave%been%performed.%Three%of%the%most%recent%systematic%reviews%addressed%quality%of%life(QOL),%survival,%and%symptom%relief%in%patients%with%various%cancer%types.[18,20,22]%Most%studiesreported%an%improvement%in%QOL.

In%one%systematic%review%that%examined%26%randomized%controlled%trials%(RCTs),%22%trials%reportedan%improvement%in%QOL.%All%10%of%the%nonrandomized%controlled%trials%also%reported%the%samebenefit.%Improvement%in%fatigue,%nausea%and%vomiting,%depression,%emotional%well-being,%andconcentration%were%reported.%Some%of%the%studies%were%well%designed,%while%others%reportedweaknesses.[22]

Tumor%response,%QOL,%and%psychological%distress%were%measured%in%a%review%of%21%RCTs%of%variouscancers%in%which%different%mistletoe%preparations%were%used%either%alone,%with%chemotherapy,%orwith%radiation%therapy.[18]%Survival%times%were%included%in%13%of%the%studies.%Most%of%the%studiesreported%benefits%for%patients,%although%this%review%was%limited%by%small%sample%size%andmethodological%weaknesses.%Thus,%the%authors%were%unable%to%suggest%practice%guidelines%for%theuse%of%mistletoe.

The%oldest%of%these%three%reviews%investigated%the%results%of%10%RCTs%that%used%a%variety%ofmistletoe%extracts%in%patients%with%various%malignancies.%There%was%no%difference%in%survival%orother%benefits%for%cancer%patients%who%received%mistletoe.%Therefore,%mistletoe%was%notrecommended%as%a%curative%or%supportive%care%therapy.[20]

A%systematic%review%of%all%controlled%clinical%studies%of%mistletoe%found%consistent%improvement%inchemotherapy-associated%fatigue%as%well%as%other%QOL%measures.[22]

Although%mistletoe%was%found%to%be%therapeutically%effective%in%most%of%the%reported%studies,many%of%the%studies%had%one%or%more%major%design%weaknesses%as%mentioned%above%that%raiseddoubts%about%the%reliability%of%the%findings.%These%weaknesses%include%registration%of%small

numbers%of%patients;%presence%of%large%numbers%of%patients%who%either%were%not%evaluable%orwere%otherwise%excluded%from%the%analyses;%failure%to%adequately%document%mistletoe%use,mistletoe%dose,%and/or%interruptions%of%mistletoe%use;%absence%of%control%subjects%or%use%ofhistorical%control%subjects;%use%of%inadequate%randomization%procedures;%absence%of%treatmentblinding;%extensive%use%of%subset%analysis;%and%the%measurement%of%mean%as%opposed%to%mediansurvival.%(Note:%In%studies%with%small%numbers%of%patients,%the%mean%survival%time%can%be%greatlyexaggerated%if%one%or%more%patients%exhibit%unusually%long%survival;%median%survival,%therefore,%isa%less%biased%measure.)%In%addition,%evaluation%of%the%studies%is%often%hindered%by%incompletedescriptions%of%the%study%design%and%by%incomplete%reporting%of%clinical%data,%including%data%aboutprevious%and%concurrent%therapies%received%by%the%patients.%A%selection%of%studies%is%discussedbelow,%organized%by%the%type%of%mistletoe%extract%used.%Eurixor,%Isorel,%and%Vysorel%are%no%longeravailable%on%the%market%for%sale.

Iscador

An%interim%analysis%of%a%randomized%phase%III%trial%reported%on%220%patients%with%locally%advancedor%metastatic%pancreatic%cancer.[23]%Patients%received%best%supportive%care%and%were%randomlyassigned%to%receive%either%IscadorQu%or%no%antineoplastic%therapy%(control).%Patients%werestratified%according%to%tumor%stage,%age,%and%performance%status.%Iscador%was%administeredsubcutaneously%in%a%dose-escalating%manner%from%0.01%mg%to%10%mg%three%times%per%week.Treatment%with%Iscador%demonstrated%a%significant%enhancement%of%overall%survival%(OS)%(4.8months%vs.%2.7%months%for%IscadorQu%patients%vs.%control%patients,%respectively;%prognosis-adjusted%hazard%ratio%[HR],%0.49;%P%<%.0001).%Patients%were%further%stratified%into%two%groups%basedon%their%expected%prognostic%factors:

Poor%prognosis—patients%who%met%at%least%two%of%the%three%following%criteria:

1.% Union%for%International%Cancer%Control%class%of%stage%IV.

2.% Older%than%65%years.

3.% Eastern%Cooperative%Oncology%Group%score%greater%than%2.

Good%prognosis—all%other%patients.

Subgroup%analysis%demonstrated%clinically%relevant%enhancement%in%the%survival%of%both%groups%ofpatients%who%received%Iscador.%The%median%OS%in%patients%who%were%classified%as%having%a%goodprognosis%was%6.6%months%for%the%Iscador%group%versus%3.2%months%for%controls%(HR,%0.43;%P%<.0001).%Patients%classified%with%a%poor%prognosis%had%a%median%OS%of%3.4%months%for%the%Iscadorgroup%versus%2.0%months%for%controls%(HR,%0.55;%P%=%.0031).%For%patients%who%received%Iscador,%thefrequency%and%severity%of%post%baseline%disease-related%symptoms%were%also%significantly%lower

•

for%the%following:

Pain.

Weight%loss.

Fatigue.

Nausea/emesis%(P%<%.0001%for%all%parameters).

Diarrhea%(P%=%.0033).

Anxiety%(P%=%.046).

The%independent%data%monitoring%committee%that%reviewed%the%interim%analysis%resultsrecommended%termination%of%the%trial%because%of%statistically%significant%superiority%of%survival%inthe%treatment%group,%compared%with%the%control%group.

A%three-arm,%randomized%phase%III%trial%that%involved%408%patients%with%previously%untreated,inoperable%non-small%cell%lung%cancer%was%conducted%between%1978%and%1987.[24]%Patients%wererandomly%assigned%to%one%of%the%following%treatments:

Subcutaneous%injection%3%times%a%week%with%IscadorU%or%IscadorQu%(refer%to%the%GeneralInformation%section%of%this%summary%for%more%information);%the%concentration%of%mistletoewas%increased%during%a%seven-injection%sequence%or%cycle,%followed%by%a%3-day%pause,%andthen%the%process%was%repeated;%IscadorU%was%administered%for%two%cycles,%followed%by%twocycles%of%IscadorQu;%both%mistletoe%preparations%contained%mercury).

Intramuscular%injection%once%a%week%with%Polyerga%Neu,%which%is%a%sheep%spleen%glycopeptidethat%is%reported%to%be%an%immunostimulant%and%an%inhibitor%of%tumor%cell%glycolysis.

Intramuscular%injection%once%a%week%with%a%vitamin%B%mixture,%which%served%as%a%placebo.

Complete%follow-up%information%was%available%for%337%patients,%and%312%patients%(105%Iscadortreated,%100%Polyerga%Neu%treated,%and%107%placebo%treated)%were%included%in%the%survival%analysis.No%statistically%significant%differences%in%survival%were%found%between%the%three%groups.%Mediansurvival%for%the%Iscador%group%was%9.1%months;%for%the%Polyerga%Neu%group,%it%was%9.0%months;%andfor%the%placebo%group,%it%was%7.6%months.%The%researchers%reported%that%11.5%%of%the%patients%inthe%Iscador%group%survived%2%years%from%the%time%they%entered%the%trial;%the%correspondingsurvival%values%for%the%Polyerga%Neu%and%the%placebo%groups%were%13.9%%and%10.1%,%respectively.In%addition,%no%differences%were%found%between%the%three%groups%with%respect%to%tumor%response,median%body%weight,%blood%chemistry%values,%Karnofsky%Performance%Status,%and%quality%of%life.However,%more%patients%in%the%Iscador%group%than%in%the%Polyerga%Neu%or%the%placebo%groupsreported%subjective%improvement%in%feelings%of%well-being%(59.4%%vs.%43.2%%and%44.8%,

••••••

•

respectively).

Another%randomized%phase%III%trial%of%mistletoe%as%a%treatment%for%people%with%cancer%involved830%patients%with%high-risk%melanoma%(i.e.,%a%primary%tumor%>3%mm%in%diameter%and%no%regionallymph%nodes%positive%for%cancer%or%a%primary%tumor%of%any%size,%one%or%two%regional%lymph%nodespositive%for%cancer,%and%no%distant%metastases)%who%were%randomly%assigned%to%one%of%thefollowing%four%groups%after%potentially%curative%surgery:%(1)%treatment%with%low-dose%interferon%-alpha,%(2)%treatment%with%low-dose%interferon-gamma,%(3)%treatment%with%IscadorM,%or%(4)%nofurther%treatment.%Both%types%of%interferon%and%IscadorM%were%administered%by%subcutaneousinjection%for%a%period%of%1%year.[5]%The%interferon%injections%were%administered%every%other%day,whereas%IscadorM%was%administered%3%times%a%week%for%up%to%1%year.%After%8%years%of%follow-up,%noincrease%in%survival%time%or%increase%in%time%until%melanoma%recurrence%was%demonstrated%formistletoe%treatment%or%treatment%with%either%type%of%interferon.

In%another%retrospective%multicenter%cohort%study%that%determined%the%safety%and%efficacy%ofIscador%as%an%adjuvant%long-term%treatment%after%surgery%for%malignant%melanoma,%686%patientrecords%were%examined%(357%untreated%controls%and%329%treated%with%Iscador).%Safety,%efficacy,and%a%cluster%of%survival%endpoints%(tumor%related,%disease%free,%brain%metastases%free,%and%OS)were%measured.%The%use%of%additional%adjuvant%chemotherapy%was%more%frequent%in%the%Iscador-treated%group,%while%the%use%of%immunotherapy%was%more%frequent%in%the%control%group.%Onlymild%to%intermediate%adverse%drug%reactions%were%seen%in%the%treated%group.%The%tumor-relatedmortality%rate%was%8.9%%in%the%Iscador%group,%compared%with%10.7%%in%the%control%group%(P%=%.017).[25]

Three%other%studies%of%mistletoe%were%described%in%a%single%published%report.[4]%One%of%the%threestudies%was%a%large%cohort%study%on%the%effectiveness%of%Iscador%as%a%treatment%for%people%withrectal%cancer,%colon%cancer,%breast%cancer,%stomach%cancer,%or%lung%cancer.[4]%The%second%andthird%studies%were%small,%prospective,%randomized,%matched-pair%studies%(one%randomized,%onenonrandomized)%that%involved%patients%who%were%selected%from%a%group%of%8,475%individuals%whohad%not%been%treated%with%mistletoe.[4]

These%studies%are%summarized%in%Table%1.%The%overall%conclusion%of%the%authors%in%the%report%ofthese%three%studies%was%that%Iscador%treatment%can%produce%a%clinically%significant%increase%insurvival%in%cancer%patients.%However,%there%were%several%weaknesses%in%the%design%and%executionof%these%studies.%In%a%large%cohort%study,%the%investigators%were%unable%to%find%matched%cohortsfor%61%%of%eligible%patients,%and%even%among%the%patients%for%whom%matches%were%found,%fewerthan%two-thirds%were%judged%to%adhere%strictly%to%the%matching%criteria;%thus,%the%final%analysiscontained%fewer%than%25%%of%eligible%patients.%In%the%two%small%prospective%studies,%no%records%ofthe%amount%or%duration%of%Iscador%use%were%kept.

The%use%of%Iscador%as%an%adjuvant%treatment%has%been%examined%in%several%studies.%In%thefollowing%studies,%Iscador%proved%safe%and%effective%and%also%showed%a%significant%survivaladvantage%over%untreated%controls.

A%retrospective%multicenter%cohort%study%of%parallel%groups%examined%Iscador%as%a%postoperativeadjuvant%using%safety%and%efficacy%as%the%main%endpoints.%A%total%of%1,442%patient%records%(710treated%patients%and%732%untreated%controls)%were%randomly%selected%from%medical%institutionsthat%provided%both%standard%and%alternative%treatments.%Safety%and%efficacy%were%measured%bythe%number%and%severity%of%adverse%drug%reactions.%The%treatment%group%showed%significantlyless%adverse%reactions%(confidence%interval%=%95%;%P%=%<%.001)%compared%with%the%controls.[26,27]

A%multicenter,%controlled,%retrospective%observational%cohort%study%that%involved%nonmetastaticcolorectal%cancer%patients%treated%between%1993%and%2002%was%conducted%to%evaluate%safety%andefficacy%measures%with%Iscador.%Eight%hundred%and%four%consecutive%colorectal%patients%(429treated%with%Iscador%and%375%controls)%from%26%hospitals%and%practices%were%included.%Iscador%waswell%tolerated,%with%a%significant%reduction%in%adverse%events,%a%higher%rate%of%symptom%relief,%andimproved%disease-free%survival%compared%with%the%control%group.%The%study%concluded%the%use%ofIscador%has%a%beneficial%effect%as%an%adjuvant%therapy%and%long-term%treatment%for%patients%withstage%I%to%III%colorectal%cancer.[28]

A%randomized%phase%II%study%of%Iscador%combined%with%carboplatin-containing%regimens%wasconducted%in%chemotherapy-naïve%patients%with%advanced%non-small%cell%lung%cancer.[29]Seventy-two%patients%were%randomly%assigned%to%receive%either%chemotherapy%alone%withcarboplatin%combined%with%gemcitabine%or%pemetrexed%(39%patients)%or%chemotherapy%plusIscador%(33%patients)%3%times%a%week%until%tumor%progression.%Time%to%progression%(4.8%months%vs.6%months)%and%OS%(11%months)%were%similar%in%both%treatment%groups.%There%were%no%differencesin%QOL%observed%between%the%treatment%groups,%although%chemotherapy%dose%reductions,nonhematologic%toxicities,%and%hospitalizations%were%less%frequent%in%patients%treated%with%Iscadorin%this%nonblinded%study.

Another%U.S.%trial%(NCT00283478)%of%the%mistletoe%extract%Iscar%with%gemcitabine%versusgemcitabine%alone%as%a%second-line%therapy%for%non-small%cell%lung%cancer%patients%who%havefailed%one%prior%line%of%chemotherapy%has%been%completed%but%not%yet%published.

Table 1. Use of Iscador in Cancer Treatment: Clinical

Reports Describing Therapeutic Endpointsa

Reference'Citation(s) Type'of'Study Type(s)'of'Cancer

[24] Randomized%trial Lung,%non-small%cell,%inoperable

[30] Randomized%trial Lung,%non-small%cell,%stages%I–IV

[5] Randomized%trial Melanoma,%stages%II–III

[23] Randomized%trial Pancreatic,%advanced%or%metastatic

[26] Comparative,%retrolective,cohort%study

Breast,%stages%I–IV

[25] Comparative,%retrolective,cohort%study

Melanoma,%stages%II–III

[4] Cohort%study Breast,%stage%III

[4] Cohort%study Various%types,%stages%I–IV

[28] Retrospective,%observationalcohort%study

Nonmetastatic%colorectal

[31] Nonconsecutive%case%series Pancreatic

[32] Case%report Lung,%small%cell,%stage%IV

Other Mistletoe Preparations

Eurixor

Five%randomized%controlled%trials%of%Eurixor%have%been%published%as%peer-reviewed%articles.%Thelargest%of%these%studies%involved%477%patients%with%squamous%cell%carcinoma%of%the%head%and%neck.[2,15]%These%patients%were%randomly%assigned%to%treatment%with%surgery%or%surgery%and%radiationtherapy,%and%they%were%randomly%assigned%again%to%either%no%additional%treatment%or%treatmentwith%Eurixor.%This%double%randomization%produced%the%following%four%groups:%(1)%105%patientstreated%with%surgery%alone;%(2)%97%patients%treated%with%surgery%and%Eurixor;%(3)%137%patientstreated%with%surgery%and%radiation%therapy;%and%(4)%138%patients%treated%with%surgery,%radiationtherapy,%and%Eurixor.%Eurixor%was%administered%in%four%treatment%cycles%over%a%60-week%period.Each%treatment%cycle%lasted%12%weeks%and%was%followed%by%a%4-week%break%period.%During%eachcycle,%Eurixor%was%administered%by%subcutaneous%injection%twice%a%week.%Each%injection%containedenough%standardized%mistletoe%extract%to%yield%a%dose%of%1%nanogram%of%ML-1%lectin%per%kilogramof%body%weight.%The%results%of%this%randomized%trial%showed%that%treatment%with%Eurixor%did%not

LN+%=%lymph%node–positive%disease;%No.%=%number.

Refer%to%text%and%the%NCI%Dictionary%of%Cancer%Terms%for%additional%information%and%definition%of%terms.

Number%of%patients%treated%plus%number%of%patients%controlled%may%not%equal%number%of%patients%enrolled;%number%of%patients%enrolled%=%number%of%patients%initially%recruited/considered%by%the%researchers%who%conducted%a%study;%number%of%patients%treated%=number%of%enrolled%patients%who%were%administered%the%treatment%being%studied%and%for%whom%results%were%reported;%historical%control%subjects%are%not%included%in%number%of%patients%enrolled.

Chemotherapy,%radiation%therapy,%hormonal%therapy,%or%cytokine%therapy%administered/allowed%at%the%same%time%as%mistletoe%therapy.

For%information%about%levels%of%evidence%analysis%and%an%explanation%of%the%level%of%evidence%scores,%refer%to%Levels%of%Evidence%for%Human%Studies%of%Cancer%Complementary%and%Alternative%Medicine

Control%patients%were%treated%with%a%vitamin%B%mixture%as%a%placebo;%100%additional%evaluable%patients%were%treated%with%Polyerga%Neu,%a%sheep%spleen%glycopeptide%reported%to%be%an%immunostimulant%and%an%inhibitor%of%tumor%cell%glycolysis;%treatment%with%PolyergaNeu%was%not%found%to%be%beneficial.

Radiation%therapy%for%metastases%distant%from%the%site%of%the%primary%tumor%was%permitted;%radiation%therapy%to%the%primary%tumor%site%or%use%of%other%anticancer%treatment%was%not%permitted.

Among%10,226%cancer%patients%enrolled%in%a%retrospective%matched-pair,%case-control%study,%1,751%had%been%treated%with%Iscador%or%another%mistletoe%product%and%8,475%had%not%been%treated%with%mistletoe;%from%the%8,475%untreated%patients,%two%sets%of%matchedpairs%were%formed%for%prospective%studies;%in%the%prospective%studies,%one%member%of%each%pair%was%randomly%assigned%to%be%treated%with%Iscador%and%the%other%member%served%as%a%control%subject.

Patients%were%strictly%matched%according%to%gender,%year%of%birth%±%3%years,%year%of%diagnosis%±%3%years,%type%of%tumor,%stage%of%disease,%and%conventional%therapy%received.

a

b

c

d

e

f

g

h

i

improve%either%5-year%disease-free%survival%or%5-year%disease-specific%survival.%In%addition,%nostimulation%of%the%immune%system%or%improvement%in%quality%of%life%was%found%with%Eurixortreatment.

It%has%been%suggested%that%a%less-than-optimum%dose%of%mistletoe%was%administered%to%patients%inthis%trial.[4]%The%same%dose%of%Eurixor,%however,%has%been%used%in%other%clinical%studies,%includingstudies%in%which%benefit%was%reported.[1,33]%In%addition,%both%the%dose%and%the%duration%of%Eurixortreatment%in%this%trial%are%consistent%with%those%recommended%by%the%manufacturer.[2]

A%prospective,%randomized%phase%II%trial%involved%45%patients%who%had%noninvasive%bladdercancer.[3]%After%surgery,%the%patients%were%randomly%assigned%to%receive%either%three%cycles%oftreatment%with%Eurixor%or%no%further%therapy.%The%goal%of%the%study%was%to%determine%whetherEurixor%treatment%could%reduce%bladder%cancer%recurrence.%Twenty-three%patients%were%randomlyassigned%to%the%treatment%group,%and%22%were%randomly%assigned%to%the%control%group.%Each%cycleof%Eurixor%treatment%consisted%of%3%months%of%subcutaneous%injections,%administered%twice%aweek,%followed%by%a%3-month%break%period.%One%milliliter%of%Eurixor%was%administered%at%eachinjection.%After%18%months%of%follow-up,%11%recurrences%were%observed%in%the%treatment%group,%and8%were%observed%in%the%control%group.%The%average%time%of%recurrence%for%the%treatment%groupwas%6.3%months;%for%the%control%group,%it%was%6.4%months.%The%median%disease-free%interval%for%thetreatment%group%was%9%months;%for%the%control%group,%it%was%10.5%months.%None%of%thesedifferences%was%considered%significant.

A%major%concern%about%this%study,%however,%is%that%the%dose%of%lectin%ML-1%administered%topatients%was%not%adjusted%for%body%weight.

Eurixor%is%no%longer%available%on%the%market%for%sale.

Isorel

Only%two%trials%of%Isorel%have%been%reported%in%the%publicly%available,%online%indexed%peer-reviewed%medical%literature.%In%one%study,%64%patients%with%advanced%colorectal%cancer%(Dukes%Cand%D)%were%randomly%assigned%to%three%groups:%(1)%surgery%and%chemotherapy;%(2)%surgery%andchemotherapy%plus%Isorel;%and%(3)%surgery%alone.%Patients%receiving%treatment%with%Isorel%had%asignificantly%better%median%survival%advantage%and%a%better%cumulative%survival%advantage%thanpatients%in%the%other%two%groups.%In%addition%there%were%no%side%effects%to%treatment%in%the%Isorelgroup.[34]

Another%study%showed%that%perioperative%use%of%Isorel%in%patients%with%cancer%of%the%digestivetract%resulted%in%an%increase%in%lymphocytes%through%14%days%of%drug%administration.

Isorel%is%no%longer%available%on%the%market%for%sale.

Helixor

In%a%three-arm%randomized%trial,%breast%cancer%patients%were%randomly%assigned%to%one%of%thefollowing%groups%after%surgery:%Helixor,%chemotherapy,%or%control.%Some%patients%in%each%groupwere%also%treated%with%local%radiation%therapy.%The%number%of%evaluable%patients%in%thechemotherapy%group%was%177,%with%survival%in%the%chemotherapy%group%superior%to%that%in%thecontrol%group%and%equivalent%to%that%in%the%Helixor%group.[35]%In%another%three-arm%randomizedtrial,%metastatic%colorectal%cancer%patients%were%randomly%assigned%to%receive%chemotherapy%only(n%=%20),%chemotherapy%plus%Helixor%(n%=%20),%or%chemotherapy%plus%Ney-Tumorin%(n%=%20).%Ney-Tumorin%is%a%mixture%of%peptides%and%proteins%from%15%different%organs%of%fetal%and%young%pigs%orcows%that%is%reported%to%have%both%antitumor%and%immunostimulatory%properties.%The%meansurvival%time%(in%months)%of%patients%treated%with%either%Helixor%or%Ney-Tumorin%wasapproximately%twice%that%of%patients%treated%with%chemotherapy%only.[36]%The%use%of%Helixor%hasalso%been%examined%in%other%studies.[37-40]

Most%studies%have%been%conducted%in%Europe,%primarily%in%Germany%and%Austria.%However,%theNational%Center%for%Complementary%and%Integrative%Health%in%cooperation%with%the%NationalCancer%Institute%(NCI)%conducted%a%phase%I%trial%(NCCAM-02-AT-260)%of%mistletoe%(Helixor%A)%andgemcitabine%in%patients%with%advanced%solid%tumors.%The%Helixor%A%and%gemcitabine%combinationshowed%limited%toxicity,%and%no%botanical-drug%interactions%were%reported.[41]

abnobaVISCUM

No%tumor%response%was%seen%in%any%of%the%25%patients%in%a%phase%ll%trial%that%examined%the%effectof%a%mistletoe%extract,%known%as%abnobaVISCUM,%in%metastatic%colorectal%cancer%resistant%tostandard%treatment%(5-fluorouracil%and%leucovorin%chemotherapy).%The%endpoint%of%the%study%wasobjective%tumor%response.%Patients%were%administered%a%gradually%increasing%daily%dose%of%0.15mg%to%15%mg.%Treatment%duration%ranged%from%4%weeks%to%66%weeks.%Toxicity%levels%were%mild.Some%patients%reported%relief%of%disease%symptoms.[42]%A%small,%randomized,%nonblinded%trial%ofabnobaVISCUM,%given%postoperatively%to%15%patients%with%resected%stage%IB%or%II%gastric%cancer,showed%improved%quality%of%life%among%patients%who%received%the%mistletoe%extract%comparedwith%16%untreated%controls.[43]

Table 2. Use of Other Mistletoe Products in Cancer

Treatment: Clinical Reports Describing Therapeutic

Endpointsa

Reference'Citation(s) Type'of'Study Product'Tested

[3] Randomized%trial Eurixor

[1,33] Randomized%trial Eurixor

[44,45] Randomized%trial Eurixor

[2] Randomized%trial Eurixor

[35] Randomized%trial Helixor

[36] Randomized%trial Helixor

[13] Randomized%controlled%trial PS76A%(Lektin)

[34] Randomized%trial Isorel

[46] Nonrandomized%controlledtrial

Isorel

abnobaVISCUM%Quercus

Check%NCI’s%list%of%cancer%clinical%trials%for%cancer%CAM%clinical%trials%on%mistletoe%extract%that%areactively%enrolling%patients.

References

3.% Goebell%PJ,%Otto%T,%Suhr%J,%et%al.:%Evaluation%of%an%unconventional%treatment%modality%withmistletoe%lectin%to%prevent%recurrence%of%superficial%bladder%cancer:%a%randomized%phase%II

No.%=%number.

Refer%to%text%and%the%NCI%Dictionary%of%Cancer%Terms%for%additional%information%and%definition%of%terms.

Number%of%patients%treated%plus%number%of%patients%controlled%may%not%equal%number%of%patients%enrolled;%number%of%patients%enrolled%=%number%of%patients%initially%number%of%enrolled%patients%who%were%administered%the%treatment%being%studied%and%for%whom%results%were%reported;%historical%control%subjects%are%not%included%in%number%of%patients%enrolled.

Chemotherapy,%radiation%therapy,%hormonal%therapy,%or%cytokine%therapy%administered/allowed%at%the%same%time%as%mistletoe%therapy.

For%information%about%levels%of%evidence%analysis%and%an%explanation%of%the%level%of%evidence%scores,%refer%to%Levels%of%Evidence%for%Human%Studies%of%Cancer%Complementary%and%Alternative%Medicine

This%trial%was%a%four-arm%trial;%patients%were%randomly%assigned%to%surgery%only%or%to%surgery%plus%radiation%therapy,%followed%by%a%second%randomization%to%no%mistletoe%treatment%or%to%treatment%with%Eurixor;%the%resulting%treatment%groups%contained%the%followingnumbers%of%evaluable%patients:%surgery%only%=%105,%surgery%plus%Eurixor%=%97,%surgery%plus%radiation%therapy%=%137,%and%surgery%plus%radiation%therapy%plus%terms%of%disease-free%survival,%disease-specific%survival,%improvement%in%quality%of%life,%or%stimulation%of%the%immune%system;%in%the%table,%mistletoe-treated%and%nontreated%(control)%patients%were%grouped%(i.e.,%number%treated%=%97%+%138%=%235,%and%number%control%=105%+%137%=%242).

Viscum%fraxini-2

a

b

c

d

e

f

trial.%J%Urol%168%(1):%72-5,%2002.%[PUBMED%Abstract]

4.% Grossarth-Maticek%R,%Kiene%H,%Baumgartner%SM,%et%al.:%Use%of%Iscador,%an%extract%of%Europeanmistletoe%(Viscum%album),%in%cancer%treatment:%prospective%nonrandomized%and%randomizedmatched-pair%studies%nested%within%a%cohort%study.%Altern%Ther%Health%Med%7%(3):%57-66,%68-72,74-6%passim,%2001%May-Jun.%[PUBMED%Abstract]

5.% Kleeberg%UR,%Suciu%S,%Bröcker%EB,%et%al.:%Final%results%of%the%EORTC%18871/DKG%80-1randomised%phase%III%trial.%rIFN-alpha2b%versus%rIFN-gamma%versus%ISCADOR%M%versusobservation%after%surgery%in%melanoma%patients%with%either%high-risk%primary%(thickness%>3mm)%or%regional%lymph%node%metastasis.%Eur%J%Cancer%40%(3):%390-402,%2004.%[PUBMEDAbstract]

6.% Viscum%album.%In:%Homoeopathic%Pharmacopoeia%Convention%of%the%United%States:Homoeopathic%Pharmacopoeia%of%the%United%States.%Washington,%DC:%2002,%Monograph%9444Visc.

7.% Tröger%W,%Jezdić%S,%Ždrale%Z,%et%al.:%Quality%of%life%and%neutropenia%in%patients%with%early%stagebreast%cancer:%a%randomized%pilot%study%comparing%additional%treatment%with%mistletoeextract%to%chemotherapy%alone%.%Breast%Cancer:%Basic%and%Clinical%Research%3:%35-45,%2009.

8.% Grossarth-Maticek%R,%Ziegler%R:%Prospective%controlled%cohort%studies%on%long-term%therapy%ofbreast%cancer%patients%with%a%mistletoe%preparation%(Iscador).%Forsch%Komplementmed%13%(5):285-92,%2006.%[PUBMED%Abstract]

9.% Grossarth-Maticek%R,%Ziegler%R:%Prospective%controlled%cohort%studies%on%long-term%therapy%ofcervical%cancer%patients%with%a%mistletoe%preparation%(Iscador).%Forsch%Komplementmed%14(3):%140-7,%2007.%[PUBMED%Abstract]

10.% Grossarth-Maticek%R,%Ziegler%R:%Randomized%and%non-randomized%prospective%controlledcohort%studies%in%matched%pair%design%for%the%long-term%therapy%of%corpus%uteri%cancerpatients%with%a%mistletoe%preparation%(Iscador).%Eur%J%Med%Res%13%(3):%107-20,%2008.%[PUBMEDAbstract]

11.% Grossarth-Maticek%R,%Ziegler%R:%Prospective%controlled%cohort%studies%on%long-term%therapy%ofovairian%cancer%patients%with%mistletoe%(Viscum%album%L.)%extracts%iscador.Arzneimittelforschung%57%(10):%665-78,%2007.%[PUBMED%Abstract]

12.% Bar-Sela%G,%Goldberg%H,%Beck%D,%et%al.:%Reducing%malignant%ascites%accumulation%by%repeatedintraperitoneal%administrations%of%a%Viscum%album%extract.%Anticancer%Res%26%(1B):%709-13,2006%Jan-Feb.%[PUBMED%Abstract]

13.% Wetzel%D,%Schäfer%M:%Results%of%a%randomised%placebo-controlled%multicentre%study%withPS76A2%(standardised%mistletoe%preparation)%in%patients%with%breast%cancer%receiving

adjuvant%chemotherapy.%[Abstract]%Phytomedicine%7%(Suppl%2):%A-SL-66,%2000.

14.% Schöffski%P,%Riggert%S,%Fumoleau%P,%et%al.:%Phase%I%trial%of%intravenous%aviscumine%(rViscumin)in%patients%with%solid%tumors:%a%study%of%the%European%Organization%for%Research%andTreatment%of%Cancer%New%Drug%Development%Group.%Ann%Oncol%15%(12):%1816-24,2004.%[PUBMED%Abstract]

16.% Kienle%GS,%Berrino%F,%Büssing%A,%et%al.:%Mistletoe%in%cancer%-%a%systematic%review%on%controlledclinical%trials.%Eur%J%Med%Res%8%(3):%109-19,%2003.%[PUBMED%Abstract]

17.% Kienle%GS,%Glockmann%A,%Schink%M,%et%al.:%Viscum%album%L.%extracts%in%breast%andgynaecological%cancers:%a%systematic%review%of%clinical%and%preclinical%research.%J%Exp%ClinCancer%Res%28:%79,%2009.%[PUBMED%Abstract]

19.% Kienle%GS,%Kiene%H:%Complementary%cancer%therapy:%a%systematic%review%of%prospective%clinicaltrials%on%anthroposophic%mistletoe%extracts.%Eur%J%Med%Res%12%(3):%103-19,%2007.%[PUBMEDAbstract]

20.% Ernst%E,%Schmidt%K,%Steuer-Vogt%MK:%Mistletoe%for%cancer?%A%systematic%review%of%randomisedclinical%trials.%Int%J%Cancer%107%(2):%262-7,%2003.%[PUBMED%Abstract]

21.% Mabed%M,%El-Helw%L,%Shamaa%S:%Phase%II%study%of%viscum%fraxini-2%in%patients%with%advancedhepatocellular%carcinoma.%Br%J%Cancer%90%(1):%65-9,%2004.%[PUBMED%Abstract]

22.% Kienle%GS,%Kiene%H:%Review%article:%Influence%of%Viscum%album%L%(European%mistletoe)%extractson%quality%of%life%in%cancer%patients:%a%systematic%review%of%controlled%clinical%studies.%IntegrCancer%Ther%9%(2):%142-57,%2010.%[PUBMED%Abstract]

23.% Tröger%W,%Galun%D,%Reif%M,%et%al.:%Viscum%album%[L.]%extract%therapy%in%patients%with%locallyadvanced%or%metastatic%pancreatic%cancer:%a%randomised%clinical%trial%on%overall%survival.%Eur%JCancer%49%(18):%3788-97,%2013.%[PUBMED%Abstract]

24.% Dold%U,%Edler%L,%Mäurer%HCh,%et%al.,%eds.:%[Adjuvant%Cancer%Therapy%in%Advanced%Non-SmallCell%Bronchial%Cancer:%Multicentric%Controlled%Studies%To%Test%the%Efficacy%of%Iscador%andPolyerga].%Stuttgart,%Germany:%Georg%Thieme%Verlag,%1991.

25.% Augustin%M,%Bock%PR,%Hanisch%J,%et%al.:%Safety%and%efficacy%of%the%long-term%adjuvant%treatmentof%primary%intermediate-%to%high-risk%malignant%melanoma%(UICC/AJCC%stage%II%and%III)%with%a

standardized%fermented%European%mistletoe%(Viscum%album%L.)%extract.%Results%from%amulticenter,%comparative,%epidemiological%cohort%study%in%Germany%and%Switzerland.Arzneimittelforschung%55%(1):%38-49,%2005.%[PUBMED%Abstract]

26.% Bock%PR,%Friedel%WE,%Hanisch%J,%et%al.:%Retrolective,%comparative,%epidemiological%cohort%studywith%parallel%groups%design%for%evaluation%of%efficacy%and%safety%of%drugs%with%"well-established%use".%Forsch%Komplementarmed%Klass%Naturheilkd%11%(Suppl%1):%23-9,2004.%[PUBMED%Abstract]

27.% Bock%PR,%Friedel%WE,%Hanisch%J,%et%al.:%[Efficacy%and%safety%of%long-term%complementarytreatment%with%standardized%European%mistletoe%extract%(Viscum%album%L.)%in%addition%to%theconventional%adjuvant%oncologic%therapy%in%patients%with%primary%non-metastasizedmammary%carcinoma.%Results%of%a%multi-center,%comparative,%epidemiological%cohort%study%inGermany%and%Switzerland]%Arzneimittelforschung%54%(8):%456-66,%2004.%[PUBMED%Abstract]

28.% Friedel%WE,%Matthes%H,%Bock%PR,%et%al.:%Systematic%evaluation%of%the%clinical%effects%ofsupportive%mistletoe%treatment%within%chemo-%and/or%radiotherapy%protocols%and%long-termmistletoe%application%in%nonmetastatic%colorectal%carcinoma:%multicenter,%controlled,observational%cohort%study.%J%Soc%Integr%Oncol%7%(4):%137-45,%2009.%[PUBMED%Abstract]

29.% Bar-Sela%G,%Wollner%M,%Hammer%L,%et%al.:%Mistletoe%as%complementary%treatment%in%patientswith%advanced%non-small-cell%lung%cancer%treated%with%carboplatin-based%combinations:%arandomised%phase%II%study.%Eur%J%Cancer%49%(5):%1058-64,%2013.%[PUBMED%Abstract]

30.% Salzer%G,%Danmayr%E,%Wutzholfer%F,%et%al.:%[Adjuvant%Iscador®%treatment%of%non-small%cellbronchial%carcinoma.%Results%of%a%randomized%study].%Dtsch%Z%Onkol%23%(4):%93-8,%1991.

32.% Bradley%GW,%Clover%A:%Apparent%response%of%small%cell%lung%cancer%to%an%extract%of%mistletoeand%homoeopathic%treatment.%Thorax%44%(12):%1047-8,%1989.%[PUBMED%Abstract]

34.% Cazacu%M,%Oniu%T,%Lungoci%C,%et%al.:%The%influence%of%isorel%on%the%advanced%colorectal%cancer.Cancer%Biother%Radiopharm%18%(1):%27-34,%2003.%[PUBMED%Abstract]

35.% Gutsch%J,%Berger%H,%Scholz%G,%et%al.:%[Prospective%study%in%radically%operated%breast%cancer%withpolychemotherapy,%Helixor®%and%untreated%controls].%Dtsch%Z%Onkol%21:%94-101,%1988.

36.% Douwes%FR,%Wolfrum%DI,%Migeod%F:%[Results%of%a%prospective%randomized%study:chemotherapy%versus%chemotherapy%plus%"biological%response%modifier"%in%metastasizingcolorectal%carcinoma].%Dtsch%Z%Onkol%18%(6):%155-64,%1986.

37.% Piao%BK,%Wang%YX,%Xie%GR,%et%al.:%Impact%of%complementary%mistletoe%extract%treatment%onquality%of%life%in%breast,%ovarian%and%non-small%cell%lung%cancer%patients.%A%prospectiverandomized%controlled%clinical%trial.%Anticancer%Res%24%(1):%303-9,%2004%Jan-Feb.%[PUBMEDAbstract]

38.% Auerbach%L,%Dostal%V,%Václavik-Fleck%I,%et%al.:%Signifikant%höherer%anteil%aktivierter%NK-Zellendurch%additive%misteltherapie%bei%chemotherapierten%mamma-Ca-patientinnen%in%einerprospektiven%randomisierten%doppelblinden%studie.%In:%Scheer%R,%Bauer%R,%Becker%H,%et%al.:Fortschritte%in%der%Misteltherapie.%Aktueller%Stand%der%Forschung%und%klinischen%Anwendung.Essen,%Germany:%KCV-Verlag,%2005,%pp%543-54.

39.% Matthes%HF,%Schad%F,%Buchwald%D,%et%al.:%Endoscopic%ultrasound-guided%fine-needle%Injectionof%Viscum%album%L.%(mistletoe;%Helixor%M)%in%the%therapy%of%primary%inoperable%pancreascancer:%a%pilot%study.%[Abstract]%Gastroenterology%128%(Suppl%2):%A-T988,%A433-A434,%2005.

40.% Beuth%J,%Schneider%B,%Schierholz%JM:%Impact%of%complementary%treatment%of%breast%cancerpatients%with%standardized%mistletoe%extract%during%aftercare:%a%controlled%multicentercomparative%epidemiological%cohort%study.%Anticancer%Res%28%(1B):%523-7,%2008%Jan-Feb.%[PUBMED%Abstract]

41.% Mansky%PJ,%Wallerstedt%DB,%Sannes%TS,%et%al.:%NCCAM/NCI%Phase%1%Study%of%Mistletoe%Extractand%Gemcitabine%in%Patients%with%Advanced%Solid%Tumors.%Evid%Based%Complement%AlternatMed%2013:%964592,%2013.%[PUBMED%Abstract]

42.% Bar-Sela%G,%Haim%N:%Abnoba-viscum%(mistletoe%extract)%in%metastatic%colorectal%carcinomaresistant%to%5-fluorouracil%and%leucovorin-based%chemotherapy.%Med%Oncol%21%(3):%251-4,2004.%[PUBMED%Abstract]

43.% Kim%KC,%Yook%JH,%Eisenbraun%J,%et%al.:%Quality%of%life,%immunomodulation%and%safety%of%adjuvantmistletoe%treatment%in%patients%with%gastric%carcinoma%-%a%randomized,%controlled%pilot%study.BMC%Complement%Altern%Med%12:%172,%2012.%[PUBMED%Abstract]

44.% Heiny%BM,%Albrecht%V,%Beuth%J:%Stabilization%of%quality%of%life%with%mistletoe%lectin-1-standardized%extract%in%advanced%colorectal%carcinoma.%Onkologe%4%(Suppl%1):%S35-9,%1998.

45.% Sauer%H:%Quality%of%life%stabilization%with%mistletoe-1-standardized%extract%in%advancedcolorectal%carcinoma%[Letter].%Onkologe%4:%1180,%1998.

46.% Enesel%MB,%Acalovschi%I,%Grosu%V,%et%al.:%Perioperative%application%of%the%Viscum%album%extractIsorel%in%digestive%tract%cancer%patients.%Anticancer%Res%25%(6C):%4583-90,%2005%Nov-

Dec.%[PUBMED%Abstract]

Adverse EffectsAlthough%a%number%of%different%mistletoe%extracts%have%been%used%in%human%studies,%the%reportedside%effects%have%generally%been%minimal%and%not%life%threatening.%Common%side%effects%includesoreness%and%inflammation%at%injection%sites,%headache,%fever,%and%chills.[1-3]

One%meta-analysis%using%Viscum album L.%and%isolated%mistletoe%lectins%included%both%animal%andhuman%studies.%Doses%and%application%forms%varied.%No%immunosuppressive%effects%werereported.%Side%effects%included%local%reactions%at%the%injection%site%and%flu-like%symptoms%such%asfever,%chills,%fatigue,%mild%gastrointestinal%symptoms,%and%headache.%High%doses%of%mistletoelectins%resulted%in%reversible%hepatotoxicity%in%some%cases.[4]%Another%review%reported%adversereactions%that%included%local%reactions%at%the%injection%site,%fever,%increased%intracerebral%pressure,headache,%circulatory%problems,%thrombophlebitis,%swelling%of%lymph%nodes,%and%allergicreactions.[5]

A%few%cases%of%severe%allergic%reactions,%including%anaphylactic%shock,%have%been%reported.[2]

References

2.% Hutt%N,%Kopferschmitt-Kubler%M,%Cabalion%J,%et%al.:%Anaphylactic%reactions%after%therapeuticinjection%of%mistletoe%(Viscum%album%L.).%Allergol%Immunopathol%(Madr)%29%(5):%201-3,%2001Sep-Oct.%[PUBMED%Abstract]

4.% Kienle%GS,%Kiene%H:%Review%article:%Influence%of%Viscum%album%L%(European%mistletoe)%extractson%quality%of%life%in%cancer%patients:%a%systematic%review%of%controlled%clinical%studies.%IntegrCancer%Ther%9%(2):%142-57,%2010.%[PUBMED%Abstract]

5.% Ernst%E,%Schmidt%K,%Steuer-Vogt%MK:%Mistletoe%for%cancer?%A%systematic%review%of%randomisedclinical%trials.%Int%J%Cancer%107%(2):%262-7,%2003.%[PUBMED%Abstract]

Summary of the Evidence for Mistletoe Extracts

Mistletoe%is%one%of%the%most%widely%studied%complementary%and%alternative%medicine%therapies%forcancer.%In%certain%European%countries,%the%preparations%made%from%European%mistletoe%(Viscumalbum%L.)%are%among%the%most%prescribed%drugs%offered%to%cancer%patients.%Mistletoe%extractshave%been%evaluated%in%numerous%clinical%studies%and%improvements%in%survival,%quality%of%life,and/or%stimulation%of%the%immune%system%have%been%frequently%reported.%However,%most%clinicalstudies%conducted%to%date%have%had%one%or%more%major%weaknesses%that%raise%doubts%about%thereliability%of%the%findings.%In%addition,%no%evidence%exists%to%support%the%notion%that%stimulation%ofthe%immune%system%by%mistletoe%leads%to%an%improved%ability%to%fight%cancer.%Because%all%patientsin%the%reported%clinical%studies%appear%to%have%been%adults,%no%information%is%available%about%theuse%of%mistletoe%as%a%treatment%for%children%with%cancer.

Separate%levels%of%evidence%scores%are%assigned%to%qualifying%human%studies%on%the%basis%ofstatistical%strength%of%the%study%design%and%scientific%strength%of%the%treatment%outcomes%(i.e.,endpoints)%measured.%The%resulting%two%scores%are%then%combined%to%produce%an%overall%score.For%additional%information%about%levels%of%evidence%analysis,%refer%to%Levels%of%Evidence%forHuman%Studies%of%Cancer%Complementary%and%Alternative%Medicine.

This%PDQ%cancer%information%summary%for%health%professionals%provides%comprehensive,%peer-reviewed,%evidence-based%information%about%the%use%of%mistletoe%extracts%in%the%treatment%ofpeople%with%cancer.%It%is%intended%as%a%resource%to%inform%and%assist%clinicians%who%care%for%cancer

http://www.cancer.gov/about-cancer/treatment/cam/hp/mistletoe-pdq/#link/_AboutThis_1

patients.%It%does%not%provide%formal%guidelines%or%recommendations%for%making%health%caredecisions.

The%lead%reviewers%for%Mistletoe%Extracts%are:

Channing%J%Paller,%MD%(Johns%Hopkins%Hospital)

Levels of Evidence

•••

••

National%Cancer%Institute:%PDQ®%Mistletoe%Extracts.%Bethesda,%MD:%National%Cancer%Institute.%Datelast%modified%<MM/DD/YYYY>.%Available%at:%http://www.cancer.gov/about-cancer/treatment/cam/hp/mistletoe-pdq.%Accessed%<MM/DD/YYYY>.

Disclaimer

Contact Us

Updated:%March%24,%2015

http://www.cancer.gov/about-cancer/treatment/cam/hp/mistletoe-pdq

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