The Use of Vitamin C with Chemotherapy in Cancer...

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IntroductionThere is an ongoing controversy over

the use of vitamin C in conjunction withchemotherapy. This writer has reviewed44 scientific and other articles on the ef-fectiveness of vitamin C alone, or withother vitamins, with chemotherapy. Thepurpose of this bibliography is to sum-marize these findings–international inscope–in chronological order. This paperpresents 24 positive studies, 12 positivereviews, one neutral study, one negativestudy, two negative reviews and four re-sponses to the latter. It then discussesthese findings.

It is necessary to point out that, al-though the first two studies reviewed in-volve terminal cancer patients not un-dergoing chemotherapy, they appearhere because they were the first, oramong the first, major clinical trialsconducted with high-dose vitamin C.

Positive Studies (Table 1)Study 1. 1976

Cameron E, Pauling, L: Supplemen-tal Ascorbate in the Supportive Treat-ment of Cancer: Prolongation of SurvivalTimes in Terminal Human Cancer. Pro-ceedings of the National Academy of Sci-ences, USA, Oct 1976; 73/10: 3685-3689.

SummaryCameron and Pauling wrote: “There is

increasing awareness that the progress ofhuman cancer is determined to some ex-tent by the natural resistance of the patientin his disease. Consequently there is grow-ing recognition that improvement in themanagement of these patients could comefrom the development of practical sup-portive measures specifically designed toenhance host resistance to malignant in-vasive growth.”

Since the authors believed “the freeavailability of ascorbic acid” to be an “im-portant factor in host resistance”, they con-ducted a clinical trial at the Vale of LevenDistrict General Hospital in Scotland totest this theory.

In the study, 100 terminal cancer pa-tients, many of whom had been treatedwith chemotherapy, were given supplemen-tal ascorbate as part of their routine man-agement. It was found that their survivaltimes were much greater than a controlledgroup of 1,000 similar patients who had notreceived the supplemental ascorbate. Themethod of treatment was through dailyhigh-dose (about 10g) intravenous admin-istration for about 10 days and then con-tinued orally. This treatment was appliedafter it had been considered by independ-ent clinicians that continued conventionaltreatment “would offer no further benefit”to the patients involved.

There was no indication in the studythat supplemental ascorbate did any harmto patients. On the contrary, life was bothprolonged and enhanced by the adminis-tration of ascorbate which would have apositive effect on “the natural mechanismsof resistance.” The treated group lived anaverage of more than 210 days comparedwith 50 days for the control group.

The Use of Vitamin C with Chemotherapy inCancer Treatment: An Annotated Bibliography

Judith O. Stoute1

“There are only three presently knownexamples in which an agent classifiable asan antioxidant has been shown to decreaseeffectiveness of ... chemotherapy in vivo. Thevast majority of both in vivo and in vitrostudies have shown enhanced effectivenessof standard cancer therapies or a neutraleffect on drug action.”

–D.W. Lamson and M.S. Brignall, 2000.

1. General Delivery, Saskatoon, SK S7K 2L5

Cameron and Pauling concluded “ thatthere is strong evidence that treatment ofpatients in Scotland with terminal (un-treatable) cancer with about 10 g of ascor-bate (ascorbic acid, vitamin C) per day in-creases the survival time by the factor ofabout 3 for most of them and by at least 20for a few (about 10%).”

Study 2. 1978Cameron E, Pauling L: Supplemental

Ascorbate in the Supportive Treatment ofCancer: Reevaluation of Prolongation ofSurvival Times in Terminal Human Cancer.Proceedings of the National Academy of Sci-ences, USA, Sept 1978; 75/9: 4538-4542.

SummaryIn this study, Cameron and Pauling

confirmed the results of their previous

clinical trial (1976) after “several experi-enced investigators in [the] field” hadraised questions about the selection of thecontrol and treatment groups.

Using a new control group, not onlywere the previous results reconfirmed, butthis study showed that “the increase in lifeexpectancy of ascorbate-treated patients …[was] found to be somewhat larger.” Indeed,eight of the terminal cancer patients whowere treated in 1976 were still living at thetime of this study.

Cameron and Pauling concluded“again that there is strong evidence thattreatment 1⁄4 with about 10g of ascorbateper day increases [the patients’] survivalsignificantly (by an average of about 300+days).” Likewise, the quality of life was en-hanced, and there was no indication of anyharm done to the patients.

1. Cameron E, Pauling L: Proc Natl Acad Sci, USA 1976; 73/10: 3685-3689.2. Cameron E, Pauling L: Proc Natl Acad Sci, USA 1978; 75/9: 4538-4542.3. Murata A, Morishige F, Yamaguchi H: Intl J Vit Nutr Res, Suppl 1982; 23: 101-113.4. Taper HS, De Gerlache J, Lans M, et al: Intl J Canc 1987; 40: 575-579.5. Hoffer A, Pauling L: J Orthomol Med 1990; 5/3: 143-154.6. Meadows GG, Pierson HF, Abdallah R: Am J Clin Nutr 1991; 54: 1284S-1291S.7. Skimpo K, Nagatsu T, Yamada K, et al: Am J Clin Nutr 1991; 54: 1298S-1301S.8. Hoffer A, Pauling L: J Orthomol Med 1993; Vol. 8, No. 3, pp. 157-167.9. De Loecker W, Janssens J, Bonte J et al: Anticanc Res 1993; 13: 103-106.10. Sarna S, Bhola RK: Archivum Immunol Ther Exper 1993; 41: 327-333.11. Prasad KN, Hernandez C et al: Nutri Canc 1994; 22/3: 233-245.12. Chiang CD, Song E, Yang VC, Chao CC: Biochem J 1994; 301: 759-764.13. Hoffer A: Townsend Lett Doct Patient 1996; Nov: 50-51.14. Kurbacher CM, Wagner U, Kolster B, et al: Canc Lett 1996; 103:183-189.15. Chen Y, Li C, Liu Y: Zhonghua Zhong Liu Za Zhi 1997; Sept19/5: 350-352.16. Roomi MW, House D, Eckert-Maksic M, et al: Canc Lett 1998, Jan; 122/1-2: 93-99.17. Nakagawa K: Cellular Mol Biol 2000; 46/8: 1375-1381.18. Reddy VG, Khanna N, Singh N: Biochem Biophys Res Comm 2001; 282: 409-415.19. Blasiak J, Gloc E, Wozniak K, et al: Chem-Biol Interact 2002; 140: 1-18.20. Catani MV, Costanzo A, Savini I, et al: Biochem J 2002; 364: 441-447.21. Calderon PB, Cadrobbi J, Marques C, et al: Medic Chem, 2002; 9/24: 2271-2285.22. Mantovani G, Maccio A, Madeddu C, et al: J Environ Pathol, Toxicol, Oncol 2003; 22/1:17-28.23. Drisko JA, Chapman J, Hunter VJ: J Am Coll Nutr 2003; 22/2: 118-123.24. Abdel Rehim WM, Sharaf IA, et al: Arzneim-Forsch./Drug Res 2003; 53/3: 214-220.

Table 1. Positive studies.

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Study 3. 1982Murata A, Morishige F, Yamaguchi H:

Prolongation of Survival Times of TerminalCancer Patients by Administration of LargeDoses of Ascorbate. International Journal forVitamin and Nutrition Research Supplement,1982, Vol. 23, pp. 101-113.

SummaryThis study by Murata et al. supports the

conclusions of Cameron and Pauling (1976and 1978) that high-dose ascorbic acid in-creases the life expectancy of terminal can-cer patients and to a certain extent enhancestheir quality of life.

The clinical trial at the first (large) hos-pital was conducted between January 1973and December 1977. It was involved of 99patients–48 male and 51 female in twogroups (high-dose and low-dose ascorbate)and without a control group. The high-dosegroup contained 55 patients who were pro-vided with “5 g per day or more” and thelow-dose group involved 44 patients whowere given “4 g per day or less” of ascorbate.Other criteria were age–the average age be-ing 60.5 years–and different types of cancerclassed as nine primary and other, withstomach, lung and bronchus and uterusbeing the main tumors.

With regard to average survival time,the results “to April 1, 1980, for those stillalive” were as follows: “None of the low-ascorbate patients survived more than 174days, whereas 18 (33%) of the high-ascor-bate patients” had an average of 620 days.“Three (6%) of the high-ascorbate patientswere still alive: ...with cancer of the uterus... breast and thymus .... These 3 patientswere clinically well, but with no significantprogression or regression in tumor; that is,the patients survived in symbiotic existencewith their tumors.”

These results were compared with anearlier period (1967-1972) when the patientseither received no ascorbate or the adminis-tration of ascorbate was low, and the averagesurvival time was also low.

For high-ascorbate patients who receivedbetween 5 and 29 g per day, the average sur-vival time was 246 days–“5.6 times as long asthe patients [who received] small doses ofascorbate.” This group’s average survival timewas 43 days. “Three of the high-ascorbatepatients were still alive, their average survivaltime being 1550 days on April 1, 1980.

Murata et al. concluded: “Ascorbate isespecially effective for cancer of the uterus,whereas it gives smaller increase in survivaltimes for cancer of the stomach and lung thanfor other kinds of cancer.”

The authors added: “In many cancerpatients, the administration of ascorbateseemed to improve the state of well-being,as measured by improved appetite, in-creased mental alertness, decreased require-ment for pain-controlling drugs, and otherclinical criteria.”

A second smaller clinical trial was con-ducted between January 1975 and December1979. It was comprised of 31 patients, withan average age of 66.8 years. The commonestcancer was that of the stomach. Fifteen maleand 16 female were divided into two groups(high-dose and low-dose). There was also acontrol group. Both of the treated groups hadsix participants, while the controls numbered19. The high-dose group was administered“5 to 30 g per day” of ascorbate and the low-dose group was given “0.5 to 3 g per day.”Other criteria were the same as those at thetrial at the large hospital.

Again Murata and coworkers notedascorbate improved survival times. “Noneof the control patients survived more than98 days, whereas 3 (50%) of the high-ascorbate patients (receiving 5 g per dayor more) survived longer than 98 days,their average being 158 days. One of thehigh-ascorbate patients was still alive,with a survival of 215 days.” The tumor(bladder) in this patient had decreased.

Average survival time for the controlswas 48 days, while for the high-ascorbatepatients it was 115 days - “2.4 times that ofthe controls.” No comparison was made of

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The Use of Vitamin C with Chemotherapy in Cancer Treatment

the average survival time for high-ascorbateand low-ascorbate patients and for low-ascorbate patients and controls, since theauthors believed that “the value obtainedwould have little statistical significance be-cause of [the] small numbers of the subjects.”

In reference to ascorbate and pain con-trol, the authors noted that pain controldrugs were given mainly to the control andlow-ascorbate groups as opposed to thehigh-ascorbate group.

Murata et al. concluded: “The resultsof the clinical trials conducted at the [twohospitals showed] that large doses of ascor-bate [offered] some degree of benefit toadvanced cancer patients, even thoughthere were some defects in the methods.”

The authors ended by explaining thereasons for their not conducting “a double-blind trial”. They mentioned the impossi-bility of finding “matched pairs for com-parison within” their small practice andcited “the effectiveness” of Cameron andPauling’s studies (1976 and 1978). “Moreo-ver,” they stated that as their “clinical ex-perience increased, [they] felt it to be ethi-cally wrong to withhold ascorbate in oth-erwise hopeless situations, merely for thesake of obtaining observations of dubioussignificance for statistical comparison.”Beyond this, “no harmful long-term sideeffect was observed among the patientswho received large doses of ascorbate.”

Study 4. 1987Taper HS, De Gerlache J, Lans M,

Roberfroid M: Non-Toxic Potentiation ofCancer Chemotherapy by Combined C andK3 Vitamin Pre-Treatment. InternationalJournal of Cancer, 1987; 40: 575-579.

SummaryTaper et al. investigated: “The influence

on the survival of ascitic liver tumor (TLT)-bearing mice of combined vitamin C and K3administered before or after a single i.p. doseof 6 different cytotoxic drugs, all commonlyused in human cancer therapy.”

The results of the study showed that(1) the vitamin treatment “produced a dis-tinct chemotherapy-potentiating effect forall drugs examined, especially when in-jected before chemotherapy”, and (2) the“treatment did not increase the general andorgan toxicity that accompanies cancerchemotherapy.”

“The main object of the potentiationof cancer therapy [as stated by Taper et al.was] to increase the cell-destructive actionof cytotoxic drugs or radiation, if possiblein a most selective, irreversible and non-toxic way. Such a potentiation might con-siderably increase the survival of cancerpatients.”

The authors continued: “Based on ourprevious observations, we hypothesizedthat DNase-reactivating compounds couldact as potentiators of cancer therapy....Among the different compounds examined,vitamin C (ascorbic acid or sodium ascor-bate) exclusively activates acid DNase in atransplantable hepatoma whereas K3 (me-nadione sodium bisulfite) selectively anddistinctly influences alkaline DNase.”

This acid-alkaline observation wasseen in an earlier study by Taper; still ear-lier, other investigators had made the sameobservation.

The test was conducted with 10 or 12ascitic transplantable mouse liver tumor(TLT)-bearing mice, six cytotoxic drugs ofvarying dosage, vitamin C (1g/kg), vitaminK3 (10 mg/kg) and controls, The vitaminswere administered i.p. before and after thechemotherapy. “Since the optimum timeof therapeutic efficiency was not known,both vitamins were administered twice, 24and 3 h[ours] before or after a single doseof chemotherapy.” The observations re:mortality etc. were made on mice “consid-ered as long-term survivors (LTS)–thesewere: “The mice which [had] survived 45to 59 days after tumor transplantation andexhibited no external signs of tumor [and]were killed and autopsied.”

The results were as follows: For CK3

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alone, the increase in life span was (% ILS45.79) as compared to the controls.

For CK3 and three drugs (cyclophos-phamide, procarbazine hydrochloride andasparaginase), the administration of thevitamins before the chemotherapy in-creased “the therapeutic effect of [the]drugs alone, thus indicating a synergisticeffect.” It was further noted that both meansurvival time (MST) and ILS were in-creased, with LTS only increasing for thefirst two mentioned drugs. Also, when CK3was administered after the first drug, the“treatment appeared less efficient”.

For CK3 and two drugs (vinblastine andadriamycin), the administration of the vita-mins before the chemotherapy produced ahigher effect than after the chemotherapywhich was “consistently lower.” In the case ofthe first drug, when the vitamins were admin-istered after the chemotherapy, there was “nosignificant effect in any parameter, except aslight increase in LTS (+16%).” In the case ofthe second drug, when the vitamins were ad-ministered after the chemotherapy, three ofthe parameters were “significantly increased”.The increases were: “MST (30.3), ILS (+70.2%)and LTS (40%).” On the other hand, when thevitamins were administered before both of thedrugs, the “treatment was highly potentiating,since the ILS [for the first drug was] +87%[and for the second drug] +88.8% ..., and 50%of mice were LTS after both drugs.”

For CK3 and 5-Fluorouracil, the admin-istration of the vitamins was most effectiveboth before and after the chemotherapy.When the drug was used alone, it “had aninsignificant effect (slight increase of all pa-rameters)”. When CK3 was administered af-ter the drug, the effect was “considerably in-creased.” The parameters were: “ILS +73.1%[and] LTS + 20%”. CK3 treatment before thedrug “produced the greatest potentiating ef-fect” which was plus or minus 143% ILS [and]plus or minus 60% LTS.”

Another experiment was conducted toconfirm the result that CK3 administered be-fore the chemotherapy produced a better ef-

fect. Taper et al. wrote: “It appeared impor-tant to evaluate whether combined adminis-tration of both vitamins was required to pro-duce the potentiation of tumor chemo-therapy” as described.

The authors continued: “In order to in-vestigate the effect of CK3 on the toxicityof the antineoplastic drugs, 2 more experi-ments were performed with cyclophospha-mide.” These experiments showed that“administration of CK3 before a single dose of80 mg/kg of the drug did not increase loss oftotal body weight as compared to treatmentwith the cytotoxic drug alone. Other experi-ments, using higher doses of cyclophospha-mide alone or together with CK3, gave similarresults.”

To conclude, Taper et al. stated: “Severalhypothetical mechanisms may be involved inthe action of vitamin C”, among them the gen-eration of H2O2 as reported by other investi-gators. Vitamin K3 may also generate H2O2 asreported by an investigator.

The authors continued: “The possiblegeneration of peroxides followed by mem-brane lipid alteration, DNase activation andDNA destruction by combined vitamin C andK3 in catalase-deficient cancer cells might beinvolved in the mechanisms of this selectivepotentiation.”

Finally, Taper et al. stated again: “Thepotentiating action of CK3 does not increasethe general toxicity of cancer chemotherapy”and they saw no need for objection in the useof vitamin C and vitamin K3 with chemo-therapy, although further research was needed.

Study 5. 1990Hoffer A, Pauling L: Hardin Jones

Biostatistical Analysis of Mortality Data forCohorts of Cancer Patients with a Large Frac-tion Surviving at the Termination of the Studyand a Comparison of Survival Times of Can-cer Patients Receiving Large Regular OralDoses of Vitamin C and Other Nutrients withSimilar Patients not Receiving Those Doses.Journal of Orthomolecular Medicine, 1990; 5/3: 143-154.

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SummaryHoffer and Pauling used “the

biostatistical analysis of mortality data forcohorts of cancer patients based on theHardin Jones principle” as developed by Dr.Pauling in their clinical test of 134 patients.These patients were from Dr. Hoffer’s prac-tice and most of them had received chemo-therapy.

The 134 patients were divided intothree groups. Two of the groups were ad-ministered 3 to 40 g but “mostly” 12 g dailyof vitamin C and other nutrients. The thirdgroup did not follow the regimen. The av-erage age of the patients was 53.1. The au-thors stated: “An important reason for car-rying out such a test is the determinationof the mean survival times of the homoge-neous subcohorts that compose the cohortbeing tested.”

Hoffer and Pauling concluded from theresults that “80% of the patients who fol-lowed the regimen [had] a probable survivaltime 21 times that of the controls ... or 13times that of the controls ..., or, for all 81patients, 16 times that of the 31 controls.”(Originally there were 33; Moss (1999) saidthat one died and one was very ill.)

In response to questions raised about“the validity of the results presented in [the]paper”, Hoffer and Pauling stated that al-though “the Hardin Jones principle hasbeen discussed briefly in several books andpapers during the last thirty years” only twowriters addressed “any significant discus-sion of its general validity for homogene-ous cohorts of cancer patients.” Moreover,other methods suggested for use have beensaid by the authors to be “less powerfulthan the method that [they had] used”.They believed that this method is an ac-ceptable one as evidenced by the numberof studies using it because of its “accuracyand reliability”.

In addition, the authors noted that theresults obtained in this study compare favour-ably with those associated with the use of high-dose ascorbic acid for terminal cancer patients

by Cameron and Pauling (1976 and 1978).Once again there was no indication of harmcaused by the administration of ascorbic acid.

Hoffer and Pauling concluded thattheir trial “will have value in calling to theattention of both physicians and patientsthe possibility that this regimen, as an ad-junct to appropriate conventional therapy,may have great value.”

Study 6. 1991Meadows GG, Pierson HF, Abdallah R:

Ascorbate in the Treatment of Experimen-tal Transplanted Melanoma. AmericanJournal of Clinical Nutrition, 1991; 54:1284S-1291S.

SummaryIn this study Meadows et al. showed:

“Sodium ascorbate supplementation indrinking water inhibited subcutaneoustumor growth, enhanced levodopa methyl-ester (LDME) chemotherapy, and in-creased survival of B16 melanoma-bear-ing mice.”

This study compared basal and re-stricted diets either with sodium ascorbateor LDME alone, or in combination. Thesegroups were matched to a control group.In mice on the basal diet:

(1) “Ascorbate had variable effects ontumor volume. Some tumors were sensi-tive whereas some were resistant to inhibi-tion by ascorbate.”

(2) “LDME treatment inhibited tumorgrowth during the treatment period and for8 d[ays] after treatment was stopped. Thetumor then began to grow, but the meantumor volume never reached the level of theuntreated group.”

(3) “The greatest suppression of tumorgrowth was observed in the LDME plusascorbate group, where ascorbate supple-mentation enhanced the growth-inhibitoryeffect of LDME.”

Results were better for mice on the re-stricted diet. To quote the authors directly:

“The most pronounced growth-inhibi-

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tory activity on B16 melanoma was ob-tained in mice fed the restricted diet. Thisdiet alone greatly inhibited tumor growth.Ascorbate alone and in combination withLDME was more effective than LDME aloneat retarding tumor growth, even though thedifferences were slight.” In addition theauthors noted that:

“Tumors generally were more invasivein untreated mice fed the basal diet than inmice fed the restricted diet.” Beyond this:“The primary tumor masses from both di-etary groups receiving ascorbate weresmaller, more well defined and less inva-sive. Secondary tumor masses were encap-sulated and the size of the tumors in micefed the restricted diet was smaller.”

Meadows and coworkers concluded:“The combination of LDME and ascor-

bate reduced the size and distribution ofsecondary tumors with the greatest effectobserved in mice fed the restricted diet.”

In reference to survival time, the re-sults for the basal diet group showed thatsurvival time was similar with LDME,ascorbate and LDME plus ascorbate treat-ments. This increase in survival was “sig-nificantly different” from the controls. Incontrast, the results for the restricted dietgroup showed that survival time was simi-lar and greater with LDME and ascorbatetreatment alone, but greatest for LDME andascorbate treatment. These increases insurvival time were also “significantly differ-ent” from the controls.

With regard to the mechanism thatwas involved in the activity of ascorbate,the authors stated: “Although the mecha-nism underlying this enhancement is un-known, it may be related in part to the al-most threefold greater accumulation ofascorbate in tumors from mice fed the re-stricted diet compared with mice fed thebasal diet.”

Meadows and colleagues pointed out:“An important effect of ascorbate in allstudies was the potentiation of the growth-inhibitory effects of LDME chemotherapy

in mice fed either basal or restricted dietsand bearing primary or experimental meta-static tumors. This modulating role is notwithout precedent and may be the most im-portant role for ascorbate in treatment ofmetastatic disease.”

The authors cautioned however:“Ascorbate should not be used indiscrimi-nately as an adjunct to chemotherapy be-cause it may abrogate the effect of somedrugs” as reported by other investigators.

Meadows and coworkers concluded:“In summary, ascorbate alone has some in-herent antitumor activity against primaryB16 melanoma in vivo; however, it exhibitedantimetastatic activity only in the presenceof tryosine and phenylalanine restrictionand/or LDME treatment. This adjuvant ac-tivity may also be important to the therapyof other cancers, and more studies areneeded to evaluate this role for ascorbate.”

Study 7. 1991Skimpo K, Nagatsu T, Yamada K, Sato

T, Niimi H, Shamoto M, Takeuchi T,Umezawa H, Fujita K: Ascorbic Acid andAdriamycin Toxicity, American Journal ofClinical Nutrition, 1991; 54: 1298S-1301S.

SummarySkimpo et al. wrote: “Adriamycin

(ADR) is effective against a wide range ofhuman neoplasms. However, its clinicaluse is compromised by serious cardiac tox-icity, possibly through induction ofperoxidation in cardiac lipids.”

In their study, the authors tested theeffectiveness of ascorbic acid and two de-rivatives “in reducing ADR toxicity in miceand guinea pigs.” At the same time, theyobserved the survival time of the animalsciting an interest in the clinical trial ofCameron and Pauling (1976 and 1978). Theresults of the tests showed that the ascor-bic acid and its derivatives can play a rolein increased survival and in preventingcardiac toxicity in mice with leukemia andcarcinoma. The tests were as follows:

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(1) Five leukemia-bearing mice wereadministered ADR 5 mg/kg and ascorbate 2g/kg for [12] days i.p. The test showed thatthe treatment “prolonged the life of [the]mice”, and toxicity of ADR was reduced.

(2) Five carcinoma-bearing mice weretested in three parts: (1) ADR 0.5 mg/kgand ascorbate 2 g/kg for 12 days i.p., (2)ADR as above and the derivative (CV-3611)50 mg/kg for the same time, and (3) theother derivative (ascorbyl palmitate) withthe same dose and time as above. The testsshowed that the treatment with both thederivatives also “prolonged the life of ...[the] mice”. The toxicity of ADR was alsoreduced. In addition, only “ascorbyl palmi-tate had a tendency to potentiate the anti-tumor effect of ADR.”

(3) Ten leukemia-bearing mice wereadministered two sets of ADR - “1 mg/kg”and 5 mg/kg and the same dose of ascor-bate as above through the same method.The test showed an increase in survival -the effect was most marked at the higherdose of ADR (5 mg/kg), and toxicity of ADRwas reduced

(4) Eleven carcinoma-bearing micewere tested in two parts: (1) ADR 15 mg/kg and CV-3611 430 mg/kg and (2) ADR asabove and ascorbyl palmitate 1240 mg/kg.These doses were administered subcutane-ously for seven days with the derivativesgiven before ADR and for 14 days after. ForCV-3611, the survival time increased “signifi-cantly” while for ascorbyl palmitate, survivaltime increased “only slightly”. Reduction intoxicity of ADR was observed for both.

(5) Another test was conducted on ten“normal guinea pigs, which, like humans,cannot synthesize ascorbic acid”. In thistest with ADR 0.5 mg/kg and ascorbate 143mg/kg, survival time increased “signifi-cantly”, and there was also a reduction intoxicity of ADR.

(6) With reference to lipid peroxide lev-els in mouse heart ADR toxicity, ascorbateor ascorbyl palmitate was used. “Ascorbate(2 g/kg) or ascorbyl palmitate (50 mg/kg)

was administered intraperitoneally for 5d[ays] before a single subcutaneous ADR (15mg/kg) administration, and ascorbate orascorbyl was continued for 5d[ays].” The testshowed that ADR plus ascorbate “decreasedthe elevated lipid peroxide levels by ADR,significantly in the heart.” ADR plusascorbyl palmitate showed “similar results”.

(7) The effects of ascorbate in cardiomy-opathy in guinea pigs were measured by elec-tron microscopy. This permitted the authorsto learn that: “The earliest alterations of dila-tion of sarcoplasmic recticulum and tranversetubular system and the appearance of a largenumber of cytoplasmic fat droplets, whichwere seen in cardiac tissue from guinea pigsreceiving ADR, were apparently reduced inanimals that were treated with ascorbate.”

Skimpo and colleagues concluded:“Our results suggest that ascorbate andthe derivatives may delay general toxicityof ADR and also prevent cardiac toxicity,possibly due to its activity as an antioxi-dant. Moreover, the ascorbate derivativesalone are likely to prolong the life oftumor-bearing animals.”

Study 8. 1993Hoffer A, Pauling L: Hardin Jones

Biostatistical Analysis of Mortality Data fora Second Set of Cohorts of Cancer Patientswith a Large Fraction Surviving at the Ter-mination of the Study and a Comparisonof Survival Times of Cancer Patients Receiv-ing Large Regular Oral Doses of Vitamin Cand Other Nutrients with Similar Patientsnot Receiving These Doses. Journal of Or-thomolecular Medicine, 1993, Vol. 8, No. 3,pp. 157-167.

SummaryThe purpose of this study was two-fold.

Firstly, it was an extension of the study byHoffer and Pauling (1990) but with a largenumber of cancer patients. Secondly, it wasdesigned to allow comparisons with thestudies of Cameron and Pauling (1976 and1978) on the produced effectiveness of vi-

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tamin C alone or in combination with othernutrients in the treatment of cancer.

This latter study involving 170 cancerpatients produced similar results to thefirst study with 134 cancer patients. Theparticipation rate in this second projectwas higher with 155 patients following theregimen and 15 choosing not to do so. Theresults showed that for the controlledgroup of 15, the mean survival time was 135days - the same for the 1990 study. Thetreated-group of 155 in the designated sub-group, that of four specific types of cancersand other cancers, were analysed as beingexcellent and good responders.

The mean survival time of about 50%of the first sub-group was “greater than 5years”, and for the other 50% it was 630days. The mean survival time for about 33%of the second sub-group was also “greaterthan 5 years” while for the remaining 67%it was 540 days.

According to the authors: “The maindifference between the results of the Hofferstudies and the Cameron studies is that thefraction of excellent responders is about 4times as great for the Hoffer regimen(50%..., 33%...) as for the Cameron regimen(10%). The good responders (about 60% forHoffer, 90% for Cameron) seem to bebenefitted by about the same amount(mean survival time 4 or 5 times the valuesfor the controls).” They continued: “Thesedifferences suggest that an additional 30%of patients with advanced cancer may be“cured”, (with survival times of five years,or more, after reaching an advanced stageof the disease) by following the more ex-tensive orthomolecular regimen prescribedby Hoffer rather than only the vitamin Cregimen prescribed by Cameron.”

Hoffer and Pauling concluded thatboth “regimens have some value, oftengreat value, for all cancer patients as anadjunct to appropriate conventionaltherapy.” They recommended “that all can-cer patients begin the orthomolecular regi-men as early in the course of the disease as

possible. The Hoffer regimen (varyingsomewhat from patient to patient), in ad-dition to including fruits and vegetables inthe diet, includes” the vitamins and miner-als described in the 1990 study.

Study 9. 1993De Loecker W, Janssens J, Bonte J, Ta-

per HS: Effects of Sodium Ascorbate (Vita-min C) and 2-Methyl-1,4-naphthoquinone(Vitamin K3) Treatment on Human TumorCell Growth in Vitro. Synergism with Com-bined Chemotherapy Action. AnticancerResearch, 1993; 13: 103-106.

SummaryDe Loecker et al. reported that when

vitamins C and K3 were combined withcertain chemotherapeutic agents, “in welldefined conditions” and dosage, the ap-plication resulted “in a synergistic effect ongrowth inhibition.” It was further noted thatwhen the vitamins reached “their ownsynergistic cytotoxicity levels [they] fre-quently [obscured] the additional synergisticlevels attributable to the chemotherapeu-tic agents.” However, it is believed that “lessdefined secondary mechanisms” than freeradicals both of the vitamins and thechemotherapy may be “responsible for theobserved stimulated cytotoxicity.”

The authors cited previous work on theincreased effectiveness of combined vita-mins and chemotherapy application onhepatoma-bearing mice. In their own studythe authors examined the “effects of a com-bined application of both vitamins togetherwith chemotherapy on a human en-dometrium adenocarcinoma cell line.”

This study consisted of a treated se-ries and a controlled series both of whichmet certain criteria but with the applica-tion process differing. For example, whenthe test material reached what was termed“50% confluence stage” for the treated se-ries, “the cells were exposed for 3 hours” tocertain chemo-therapeutic agents and thento a combination of the two vitamins. For

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the controlled series, after a certain con-fluence stage was reached, these cells “wereonly treated for 4 hours” with the chemo-therapeutic agents “and for 1 hr” with thevitamins but not with a combination of thevitamins and chemotherapy.

The results showed that the effective-ness of the chemotherapy together with thevitamins was considerably greater than thatof the chemotherapy alone.

De Loecker et al. concluded: “Althoughthe specific characteristics of the differentcytostatic drugs used have not been furtherexplored or analyzed, it appears that tovisualise any synergistic effects betweenchemotherapy and combined Vit C and K3treatment in vitro, the therapeutic doselevels have to be adequately proportionedand adjusted in function of actual cell den-sity to avoid either an insufficient effect oran undesired predominance of one kind oftreatment pattern.”

Study 10. 1993Sarna S, Bhola RK: Chemo-Immuno-

therapeutical Studies on Dalton’s Lymphomain Mice Using Cisplatin and Ascorbic Acid:Synergistic Antitumor Effect in Vivo and inVitro. Archivum Immunologiae et TherapiaeExperimentalis, 1993; 41: 327-333.

SummarySarna et al. noted “the serious side ef-

fects” of high dose cisplatin treatment asreported in a review of the drug. The ob-jective of the study then was “to find outthe effects of ascorbic acid on enhancementof tumor growth inhibition induced by [a]low dose of cisplatin.”

The method used was “direct treatmentof tumor cells in vivo and in vitro.” The testusing Dalton’s lymphoma mice treated withdifferent doses of either cisplatin andascorbic acid alone or in combination wasconducted in two parts; namely, chemo-therapeutical studies and chemoimmuno-therapeutical studies. A controlled group ofmice was used for comparison.

The results obtained from the chemo-therapeutical studies were as follows:

For ascorbic acid alone: “When tumorbearing mice were treated with ascorbic acid(20 or 40 mg/kg x 4) a slight increase in theirmean survival time compared to controlmice was observed. Animals treated with [a]high dose of ascorbic acid (60 mg/kg x 4)failed to show significant increase in theirlife span; however, 20-25% [of the] animalsappeared as tumor free survivors.”

For cisplatin alone: A “dose of cisplatin(3 mg/kg) was able to prolong the survivaltime of the ... mice (life span increased to166%)”-35 days without tumor free survivors.

For ascorbic acid and cisplatin: “Micetreated with cisplatin [as above] along withascorbic acid 20 or 40 mg/kg x 4) showedincreased mean survival time from 13 daysin control to 50 days in treated animals.”“Both [of] the concentrations of ascorbicacid in combination with cisplatin resultedin 40% tumor free survivors. Animals re-ceiving 60 mg/kg of ascorbic acid withcisplatin survived beyond 60 days, 50%appeared as tumor free survivors withoutany sign of tumor and its reappearance, therest of them died at a later stage prolong-ing their life span by 400%.” The life spanwith 20 mg/kg and 40 mg/kg was pro-longed by 287% and 275% respectively.

The results obtained from the chemo-immunotherapeutical studies were as follows:

For ascorbic acid alone: “Dalton’s lym-phoma cells ..., when incubated with dif-ferent concentrations of ascorbic acid andinjected into normal mice, developedtumor in all the animals similarly as incontrol mice. Mice receiving tumor cells,incubated with 25 μg/ml ascorbic acidshowed 10-15 day increase in their life span;however, innoculation of tumor cells incu-bated with 50 μg/ml of ascorbic acid re-sulted in mean survival time of mice simi-lar to the control.” The mean survival timewas: 20 days for the controls, 34.6 days forascorbic acid 25 μg/ml and 21.6 days forascorbic acid 50 μg/ml. “No tumor free as

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well as 60/more than 60 day survivors wereobserved with either concentration.”

For cisplatin alone: “Mice injected withcisplatin (5 or 10 μg/ml) incubated tumorcells showed significant increase in theirsurvival time compared to the control.” Thelatter concentration was more effective thatthe former resulting “in 70% 60-70 day sur-vivors with 204% increase in their life span.”The increase for the first concentration was110%. “Both [concentrations] of cisplatinsignificantly enhanced the mean survivaltime of mice to 43 and 62 days respectively.No tumor free survivors were observed ...with either dose.”

For ascorbic acid and cisplatin:“Tumor growth was significantly affectedafter injecting tumor cells incubated withcisplatin (5 μg/ml) along with 25 or 50 μg/ml of ascorbic acid. Up to 30% mice failedto develop tumor.... Even those mice whichdeveloped tumor exhibited significant in-crease in their mean survival time.”

The tests were as follows: “Tumors cellsincubated with cisplatin [as above] along with50 μg/ml of ascorbic acid, when injected inmice resulted in 30%, 60/more than 60 daysurvivors apart from tumor free survivors.”

“Mice injected ... with 10 μg/ml ofcisplatin along with 25 μg/ml of ascorbicacid resulted in 20% tumor free survivors,the rest of them developed tumor with anincrease in their mean survival time up to48 days including 20% of 60 day survivors.”

“Tumors cells incubated with cisplatin(10 μg/ml) along with ascorbic acid (50 μg/ml) when injected ... showed maximum sur-vival time of mice up to 70 days without anytumor free survivors.... The mean survivaltime in this [latter] group of mice was 58days which increased significantly comparedto the control mice.” As seen above, thecontrol mice survived for 20 days. The re-sult for cisplatin 5 μg/ml and ascorbic acid25 μg/ml was not recorded, but the increasein mean survival time was 42.2 days.

In summary, Sarna et al. observed thatin chemotherapeutical studies the “[m]ost

effective dose [of usage] of ascorbic acid incombination with cisplatin was found to be60 mg/kg which has given almost 100%tumor free survivors up to 65 days. About50% mice further survived indefinitely likenormal animals. Even low doses of ascor-bic acid (20 or 40 mg/kg) were found to beeffective in regressing tumor when com-bined with the subtherapeutical dose ofcisplatin. This finding shows that ascorbicacid somehow increases the therapeuticalpotential of the low dose of cisplatin result-ing in complete regression of tumor in mostof the animals. The subtherapeutical doseof cisplatin alone resulted in an increase inthe mean survival time of tumor bearingmice without any tumor free survivors.” Inchemo-immunotherapeutical studies:

“The tumor growth inhibition [bycisplatin alone] was further enhanced whenvitamin C was combined with the low doseof cisplatin in vitro.” The authors contin-ued: “One of the causes of the enhancementof cisplatin induced tumor inhibition byvitamin C ... might be an increased uptakeof cisplatin into the tumor cells” as re-ported “for vitamin E....”

In conclusion, Sarna et al. wrote thattheir present “studies suggest that cisplatinand ascorbic acid should be given togetherfor combination therapy of Dalton’s lym-phoma in mice. Treatment with ascorbic acidunder certain conditions enhances the tumorgrowth inhibition induced by cisplatin. Pos-sible causes of the enhancement ... are: (i)modulation of permeability of tumor cellmembrane by ascorbic acid which elevatesthe intratumor contents of ascorbic acid, (ii)increased uptake of cisplatin into tumor cells,(iii) increase of the efficiency of adduct for-mation in genomic DNA making less efficientthe DNA repair of cell, thus rendering thecisplatin more effective as an antitumoragent.” The authors ended by stating:

“In view of [their] studies the poten-tial usefulness of ascorbic acid in the pre-vention and treatment of cancer should notbe ignored.”

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Study 11. 1994Prasad KN, Hernandez C, Edwards-

Prasad J, Nelson J, Borus T, Robinson WA:Modification of the Effect of Tamoxifen,cisPlatin, DTIC, and Interferon-α2b onHuman Melanoma Cells in Culture by aMixture of Vitamins. Nutrition and Cancer,1994; 22/3: 233-245.

SummaryIn this study vitamin C was one of the

antioxidants used either alone or in combi-nation to test its effectiveness both on thereduction of growth and the enhancement ofthe growth-inhibition of certain chemothera-peutic agents for human melanoma cancer.

The results showed that vitamin C (so-dium ascorbate), when used alone “inhib-ited growth of melanoma cells ... withoutaffecting the morphology” while in combi-nation the growth inhibition was eithermore or significant.

With regard to the enhancement by vi-tamin C in conjunction with a chemothera-peutic agent, the results were as follows:

Vitamin Treatment with Tamoxifen:Vitamin C 100 μg/ml alone and vitamin C50 μg/ml with three vitamins “increased thegrowth-inhibitory effect of tamoxifen,” whilevitamin C 100 μg/ml with three vitaminsshowed no significant change.

Vitamin Treatment with cis-platin: Vi-tamin C 100 μg/ml alone “increased thegrowth-inhibitory effect of cis-platin”, vita-min C 100 μg/ml with three vitamins “en-hanced the cis-platin effect” while vitaminC 50 μg/ml with three vitamins “also in-creased the cis-platin effect.”

Vitamin Treatment with DTIC: VitaminC 100 μg/ml alone “enhanced the growth-inhibitory effect of DTIC,” vitamin C 100 μg/ml with three vitamins “did not result infurther suppression of growth” while vita-min C 50 μg/ml with three vitamins “mark-edly enhanced the DTIC effect.”Vitamin Treatment with Interferon α2b

Vitamin C 100 μg/ml alone “enhancedthe growth-inhibitory effect of interferon,”

vitamin C 100 μg/ml with three vitamins“enhanced the interferon effect” while vita-min C 50 μg/ml with three vitamins “signifi-cantly increased the interferon effect.”

In summary, vitamin C 100 μg/ml withthree vitamins and the four anti-canceragents “reduced growth of melanoma cellsby about 85%. This vitamin mixture in com-bination with cisplatin and interferon fur-ther reduced growth..., but in combinationwith DTIC or tamoxifen, no better effect wasnoted.” Vitamin C 50 μg/ml with the samenumber of vitamins “markedly enhanced thegrowth-inhibitory effect of all chemothera-peutic agents.”

The authors believed: “These resultssuggest that the addition of vitamin C, [andthe other vitamins] at nontoxic doses of eachvitamin may enhance the growth-inhibitoryeffect of currently used therapeutic agentson human melanoma cells in culture.”

Prasad et al. suggested: “Another scien-tific rationale for using vitamins in combina-tion with chemotherapeutic agents involvesthe reduction of toxicity of [these] agents onnormal cells by vitamins. This rationale can-not be tested in tissue culture systems. How-ever, several studies using individual vitaminsshowed that they can reduce tumor therapeu-tic agent-induced toxicity in animal models.... Vitamin C … has been shown to reducethe adverse effects of some chemotherapeu-tic agents on normal cells in animals” as re-ported by other investigators.

The authors ended by stating: “Themechanism of action of vitamins in tumortherapy is not totally clear”; they then ex-plained the mechanisms of action that maybe involved in the effectiveness of vitamin Cand other vitamins in cancer therapeuticagents’ activity.

Study 12. 1994Chiang CD, Song E, Yang VC, Chao CC:

Ascorbic Acid increases Drug Accumula-tion and reverses Vincristine Resistance ofHuman Non-Small-Cell Lung-Cancer Cells.Biochemical Journal, 1994; 301: 759-764.

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SummaryChiang et al. “established a [vincristine]

VCR-resistant subline from human lung-cancer PC-9 cells which displays a reduceddrug accumulation”. This resistant subline(PC-9/VCR) treated with cytotoxicity froma MTT dye assay showed a higher “increasein resistance to VCR” as opposed to theincreases of other anti-cancer agents; forexample, adriamycin and cisplatin. Theaddition of ascorbic acid enhanced thetreatment of PC-9/VCR.

The authors wrote: “A reduced accu-mulation of VCR was demonstrated. In-terestingly, the VCR resistance of the PC-9/VCR cell line was partially reversed byascorbic acid, and the drug uptake wasenhanced.”

The results were as follows: “The ef-fect of ascorbic acid on cellular responseto VCR was measured by the MTT-dye as-say. To eliminate complications from themodulating agent itself, a non-toxic or lowcytotoxic concentration of ascorbic acidwas used.” While low concentrations ofascorbic acid “had no profound effect” onresistant cells, a high concentration did. “At25 μg/ml, ascorbic acid slightly inhibitedcell growth.” In addition, a treatment with“25 μg/ml” ascorbic acid significantly low-ered the resistant-cell proliferation. Lowerconcentrations of ascorbic acid were alsoeffective in sensitizing VCR toxicity.”

Chiang et al. concluded that “ascorbicacid effectively inhibited the resistance ofPC-9/VCR cells to VCR” noting: “Althoughthe exact mechanism whereby ascorbicacid sensitizes PC-9/VCR cells to VCR isnot clear, it is possible that the drug-ac-cumulation-associated membrane activitydetected in this study is modulated byascorbic acid through an oxidationmechanism.”

The authors, after explaining the par-ticular mechanism, suggested: “This novelmechanism of drug resistance may be anadditional resistance pathway encoun-tered in clinical cancer therapy.”

Study 13. 1996Hoffer A: One Patient’s Recovery from

Lymphoma. Townsend Letter for Doctors &Patients, 1996; Nov: 50-51.

SummaryHoffer reported on the use of “megavi-

tamin therapy of which ascorbic acid wasthe main and most important compound.”

In this case of a man who had becomevery depressed as the result of “extremehardship, torture, and malnutrition” as wellas personal problems, and who developeda rare form of cancer, Hoffer administereda high dose of vitamin treatment.

The patient had undergone surgery, andchemotherapy had been started. At the sametime Hoffer “increased his ascorbic acid to12 grams daily”, along with another vitaminand two minerals. Over the course of time thedosage of ascorbic acid was increased to 24 gdaily” as radiation had also been applied. Thisvitamin treatment was effective in helping theregression of the “severe lymphoma”.Throughout the whole period, the patient’spersonal problems had remained and he hadcontinued to be depressed.

This patient survived “14 years after hefirst saw [Dr. Hoffer], 13 years after he wasdiagnosed.” Hoffer noted that since thisfirst case: He had “seen 19 patients withlymphoma ... who were treated by the samecancer clinic, and by [him], using the or-thomolecular program.”

The author continued: “Out of 13male patients, six were alive after fiveyears and two more will probably make it.An 80% five year cure rate is pretty good.One patient did not start the program. Helived 1.5 years. The six female lymphomacases did not do nearly as well. Only onelived for one year. The starting time wasalways from the date they first saw me.This is a small series and indicates a trend.I have not been able to find any factorwhich distinguishes the two sexes. Theyreceived similar orthodox treatment andthe same orthomolecular treatment.”

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Hoffer ended by noting:“In an earlier report with Linus Pauling

[1990 - described elsewhere in this presen-tation], we showed that in general everygroup of cancer patients given megavita-min treatment lived much longer than didtheir comparison group who were not giventhe benefit of these vitamins.”

Study14. 1996Kurbacher CM, Wagner U, Kolster B,

Andreotti PE, Krebs D, Bruckner HW:Ascorbic Acid (Vitamin C) improves theAntineoplastic Activity of Doxorubicin,Cisplatin, and Paclitaxel in Human BreastCarcinoma Cells in Vitro. Cancer Letters,1996; 103:183-189.

SummaryKurbacher et al. used vitamin C (ascor-

bic acid) and three antineoplastic agentsin a study of their effectiveness on “humanbreast carcinoma cell lines”. The vitaminand each agent were tested alone and incombination. Vitamin C at certain levels“improved the cytotoxicity” of the threeantineoplastic agents “significantly”.

In the test with doxorubicin (DOX), itwas found that vitamin C “both at non-toxic and at cytotoxic concentrations [pro-duced] a consistently synergistic antine-oplastic activity”. The authors noted that“this effect might be related to the genera-tion of free radicals which have been shownto have an impact on DOX-induced cell kill”in one of the cells tested as reported byother investigators.

It was found that the test with cisplatin(DDP) “produced synergistic cytotoxicitysolely when the [vitamin] was added atcytotoxic concentrations, [which] mightindicate that mechanisms other than thosemediated by oxyradicals are more impor-tant for DDP-activity compared to DOX, atleast in some breast tumors.”

The last test, that with paclitaxel (Tx),showed “a significant potentiation of Txactivity induced by Vit C.”

Kurbacher et al. ended by stating: “Inconclusion, we were able to demonstratethat ascorbic acid is likely to potentiatethree of the most active drugs for the treat-ment of [breast cancer]. Combination ef-fects mostly were synergistic or at leastadditive. The mechanism by which Vit C isable to improve the cytostatics studied isnot known at present and should be eluci-dated in further investigations. Due to thelow toxicity of Vit C even at very high con-centrations, combinations of ascorbic acidwith cisplatin, doxorubicin, or paclitaxelseem to be attractive for the future treat-ment of breast cancer.”

Study 15. 1997Chen Y, Li C, LiuY: [Effect of Ascorbate

on the Permeation and PhotosensitizingActivity of Hematoporphyrin Derivative(HPD) in Tumor]. Zhonghua Zhong Liu ZaZhi, Sept, 1997; 19/5: 350-352.

SummaryThe summary is extracted from an ab-

stract as the article was written in Chinese.Chen et al. tested “the depth of per-

meation and concentration” of the anti-cancer agent (HPD) alone or in combina-tion with ascorbic acid in their examina-tion of “photosensitizing effect.”

The test with mice tumor of a certainsize was conducted in three groups as follows:

In group I, HPD (PsD-007) 1 mg/mlwas administered to the mice.

In group II, HPD (PsD-007) 1 mg/mland ascorbic acid 20 mg/ml for 1 hour wasadministered to the mice.

Group III was used for comparisonwith HPD (PsD-007) 10 mg/ml alone, andthe treatment “was injected intravenouslyto mice bearing tumor of similar size”. Thetumor was removed 24 hours later.

The examination through the photo-sensitizing of the three tumors showed thatfor groups I and II, “red fluorescence wasmainly at the periphery of tumors that hadbeen immersed in HPD whereas the fluo-

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rescence was weaker and more evenly dis-tributed in tumors that had received HPDi.v.” A further comparison with HPD andother mixture and groups I and II of frozenmaterial showed similar features. For ex-ample, the concentration of the new mix-ture - malondialdehyde (nmol/L) - “washigher in tumors that had been immersedin [HPD] plus ascorbate than in tumorsimmersed in [HDP] alone. Tumors of micethat had received PsD-007 i.v. had the low-est concentration of both PsD-007 andmalondialdehyde.”

Chen et al. concluded: “Ascorbate fa-cilitates permeation of HPD into tumor andenhances the photodynamic effect of HPD.”

Study 16. 1998Roomi MW, House D, Eckert-Maksic

M, Maksic ZB, Tsao CS: Growth Suppres-sion of Malignant Leukemia Cell Line InVitro by Ascorbic Acid (Vitamin C) and ItsDerivatives. Cancer Letters, 1998; Jan; 122/1-2: 93-99.

SummaryRoomi et al. wrote: “Despite the vari-

ous reports on [ascorbic acid] toxicity, nowork has been reported underlying thecritical chemical structural features for itsactivity. The present study addresses thisquestion.” The authors described two “moi-eties” of ascorbic acid (AA), and these com-pounds were tested on a murine leukemiacell line.

In addition to investigating the mecha-nism which was involved in the cytotoxic-ity of ascorbic acid, Roomi et al. looked atthe “effect of modifying the structure toyield the maximum cytotoxic effect oftumor cell growth.”

An observation of one of the tests sug-gested “that the cytotoxic effect of ascor-bate was apparently not related to themetabolic or vitamin activities of ascorbateat the cellular level. Furthermore, studieson the viability of the treated cells indicatedthat the observed effect on cell growth was

not cytostatic in nature but was the resultof a direct cell killing action of ascorbate.”

The results of the study demonstrated“that the critical underlying feature for AAcytotoxicity [was] the dihydroxy γ-crotonolactone ring [moiety].” The othermoiety - ethylene glycol - was “not an im-portant feature for its toxicity.”

Roomi et al. concluded that the abovecompounds in addition to two others“could be potential candidates for humantrials.”

Study 17. 2000Nakagawa K: Effect of Chemotherapy

on Ascorbate and Ascorbyl Radical in Cer-ebrospinal Fluid and Serum of Acute Lym-phoblastic Leukemia. Cellular and Mo-lecular Biology, 2000; 46/8: 1375-1381.

SummaryThe purpose of this study on ascor-

bate (ASA) and ascorbyl (ASR) was two-fold. One section involved patients with“various human malaises” not havingchemotherapy, and the other involvedpatients with acute lymphoblasticleukemia (ALL) treated with chemo-therapy. This presentation reports onthe latter part.

Nakagawa described an action of vi-tamin C by stating that ascorbate “reactswith short-lived free radicals such as OHradical and forms ascorbyl radical(ASR).” He continued: “The propagationof chain reactions initiated by the short-lived free radical can be minimized dueto the relative stability of ASR. Steadystate concentration of ASR in serum canbe related to diseases and the treat-ments. Electron paramagnetic reso-nance (EPR) spectroscopy is a reliabletechnique to investigate free radicals.”The author pointed out that studies hadbeen done on “ASA or ASR” and “ASA incerebrospinal fluid (CSF)”. However, hestated: “details of ASR along with ASAin CSF and serum such as the effect of

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medical treatment and dynamic aspectsconcerning ASA and ASR are not yetknown.”

In this study “to examine the effect ofchemotherapy” on ASA and ASR in CSF andserum, the test comprised two groups of 73acute lymphoblastic leukemia (ALL) pa-tients. Group 1 with 57 ALL patients - 36male and 21 female - were undergoingchemotherapy. Group 2 with 16 ALL patients- 12 male and 4 female - had followed chemo-therapy. (This latter group was a type ofcontrol.) The average age of the groups was9.7 years and 8.7 years respectively.

The results for group 1 (undergoingchemotherapy) showed: “ASA concentrationin CSF was approximately two times higherthan that in serum. ASR concentration inCSF was also higher than that in serum.”Statistical analyses showed:

“The statistical values [were] consistentwith that of ASA, which is in blood at firstand becomes ASR. It [was] noted that ASRin CSF does not correlate with ASA in CSF.This correlation implies that oxidation ofASA in CSF may not interrelate with thesubjects studied. However, ASR in serum hasreasonable correlation with ASA in serum.This implies that oxidation of ASA in serummay be induced by the treatment.”

The results for group 2 (followingchemotherapy) showed: “Weak correlation ...[was] obtained for ASR in CSF and serum.No strong correlation for ASR and ASA inserum nor for ASA in CSF and serum wasobtained.”

The author continued: “These resultswere different from those for patients under-going the treatment and may be attributedto remission.”

In conclusion, Nakagawa stated: “Theanalyses showed that ASR and ASA in CSFand serum had good correlation for patientsundergoing chemotherapy but not for pa-tients after the therapy. The correlation forASR and ASA suggests that ascorbate mayplay an important role during chemo-therapy.”

Study 18. 2001Reddy VG, Khanna N, Singh N: Vita-

min C augments Chemotherapeutic Re-sponse of Cervical Carcinoma HeLa Cellsby stabilizing P53. Biochemical and Bio-physical Research Communications, 2001;282: 409-415.

SummaryReddy et al. wrote: “Human Papilloma

Virus (HPV) is associated in most instanceswith cervical cancer. The HPV oncoproteinstarget P53 protein [a tumour suppressorgene] for degradation, leading to deregulationof cell cycle.”

The authors found that vitamin Cthrough a downregulating action wasshown to decrease one of the functions ofHPV, and as a result stabilized P53. Theyalso observed: “Accumulation of P53 and itstarget gene bax then sensitized HeLa cellsto cell-cycle arrest, cell death/apoptosisinduced by cisplatin, and etoposide.”

For the downregulatng activity, lowdose vitamin C (1 μM) was administeredfor various time periods (6 - 36 hrs) to thecell culture of human cervical carcinomacell line (HeLa). This treatment was foundto be non-toxic.

The test using vitamin C with the twoanti-cancer agents showed that “cisplatintreatment (2-10 μM) for 48 h[ours] in Helacells primed with vitamin C (1 μM) for 24to 36 h[ours] resulted in increased celldeath.... Flow cytometric analysis showedthat the percentage apoptosis increasedfrom 13.7% with cisplatin alone, to 18.9,32.6, and 49.23% after vitamin C primingfor 12, 24, and 36 h[ours], respectively....”Similar results were observed with vita-min C (1 μM) and etoposide (2 μM) for36 hours.

In summary, Reddy et al. stated: “Thecause for poor responsiveness to chemo-therapy lies in the etiopathogenesis ofcervical cancer i.e., HPV infection andloss of tumor suppressor gene functiondue to inactivation of P53 [and another].

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The restoration of P53 levels could be a po-tential strategy to increase chemo-responsiveness. However, there are conflict-ing reports regarding the role of P53 andchemosensitivity” as reported by other inves-tigators. The authors continued: “Differentauthors have adopted different strategies...[to] stabilize P53 levels. We selected vitaminC based on the fact that it prevents the de-velopment of CIN to cervical cancer and de-creases methylcholanthrene (MCA) inducedcervical cancer in mice” as reported by otherinvestigators. Reddy et al. continued: “Vita-min C at low doses was seen to... increase inp53 protein... but was not sufficient to induceapoptosis”-thus its augmenting capability.

With regard to cisplatin, Reddy et al.stated: “Cisplatin, the single most activedrug against cervical cancer, was found toproduce maximum addictive affect in vitroon vitamin C pretreatment.” The authorsalso stated: “Another important finding ofour study was that the combination of highdoses of vitamin C and cisplatin could de-crease the effect of chemotherapy.” Theyadded: “Our findings suggest that primingwith low dose of vitamin C can have a sig-nificant additive effect particularly with lowdose of in vivo achievable chemotherapeu-tic drugs, as shown by increased apoptosis.”

In conclusion, Reddy et al. stated: “In-creasing drug sensitivity of cervical carci-noma cells by stabilizing P53 using vitaminC is a novel approach and has potential clini-cal relevance.”

Study 19. 2002Blasiak J, Gloc E, Wozniak K, Mlynarski

W, Stolarska M, Skorski T, Majsterek I:Genotoxicity of Idarubicin and its Modula-tion by Vitamins C and E and Amifostine.Chemico-Biological Interactions, 2002; 140: 1-18.

SummaryBlasiak et al. stated in this minireview of

treatment with antioxidants and chemo-therapy: “Genotoxicity of anticancer drugs in

non-tumor cells is of special significance dueto the possibility of inducing secondarytumors. It is therefore important to determinegenotoxic potential of a drug, which is to beused in chemotherapy.” They cited other in-vestigators in considering DNA damage “asessential markers of genotoxicity.”

The authors noted: “Idarubicin is ananthracycline anticancer drug used inhaematological malignancies. The main sideeffect of idarubicin is free-radicals basedcardiotoxicity.”

Blasiak et al. stated: “Because diet ofpatients receiving chemotherapy can be eas-ily supplemented with vitamins, it is reason-able to check whether these vitamins, ..., cansuppress the adverse effects of anticancerdrugs.” The authors cited studies which “in-dicated profitable activity of vitamins againstside effects of cisplatin, DOX and other anti-cancer drugs.”

For example, it was reported that (1) “vi-tamin C can promote the removal of oxidativeDNA damage from the DNA and/or nucleotidepool, through the upregulation of repair en-zymes,” and (2) it “can cause strand breaks andbase modifications in DNA via the productionof hydroxyl radicals or lipid alkoxyl radicals byreaction of the reduced metal ions with hy-drogen peroxide or lipid hydroxy-peroxides.”

Blasiak et al. stated that in their study, they“investigated DNA-damaging potential ofidarubicin in normal human peripheral bloodlymphocytes using the alkaline single cell gelelectrophoresis (comet assay).” A further studysought to discover “mechanisms underlyinggenotoxicity of idarubicin”, and to this end atest was conducted to check “the ability ofvitamins C and E and amifostine to modulateDNA-damaging effect exerted by the drug.”

The tests were conducted with normalhuman lymphocytes and murine transformed(cancer) cells.

With regard to normal humanlymphocytes, which were treated with thedrug in the presence and absence of the vita-mins, the result showed that vitamin C (so-dium ascorbate) 10 μM “significantly de-

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creased the mean % tail DNA of the cellsexposed to idarubicin at all tested concen-trations of the drug” - thus being effectivewith normal cells. On the other hand, thesame dose of sodium ascorbate “had no in-fluence on [the] murine ... transformed cells”- thus not being effective with cancer cells.The authors had noted that the latter cells“can be treated as model cells of human acutemyelogenous leukemia.” To conclude, Blasiaket al. stated:

(1) “Our experimental data [indicated]that idarubicin can generate damage to DNAin intact normal human peripheral bloodlymphocytes. It is likely, that the damage iscaused by oxygen radicals generated byidarubicin; DNA methylation by the drug canalso contribute to the damage.”

(2) “Our results [indicated] that not onlycardiotoxicity but also genotoxicity and inconsequence induction of secondary malig-nancies should be taken into account as di-verse side effects of idarubicin.”

(3) “Genotoxicity of idarubicin may beconsidered as the origin of its anticanceractivity, but the genotoxic effect exerted bythe drug on normal cells should not surpassthe effect on cancer cells.”

(4) “Vitamin C can be considered as pro-tective agents against DNA damage in nor-mal cells in persons receiving idarubicin-based chemotherapy, but the use of vitaminE cannot be recommended and at least needsfurther research.”

Study 20. 2002Catani MV, Costanzo A, Savini I,

Levrero M, De Laurenzi V, Wang JYJ, MelinoG, Avigliano L: Ascorbate Up-RegulatesMLH1 (Mut L Homologue-1) and P73: Im-plications for the Cellular Response to DNADamage. Biochemical Journal, 2002; 364:441-447.

SummaryCatani et al. stated as reported by other

investigators: “The cellular response toDNA damage requires activation of MLH1,

which can co-operate with the tumour-sup-pressor p53 gene to promote cell cycle ar-rest and cell death.”

In this study using cell culture, theauthors “investigated the ascorbate-medi-ated up-regulation of the MLH1 gene, as aninvolvement of ascorbate in the regulationof DNA repair enzymes [as] has been pos-tulated.”

Their results showed “for the first time,that this antioxidant vitamin positivelyregulates the apoptotic cascade primed byMLH1 in response to DNA damage” as re-ported by other investigators. MLH1 wasshown to modulate “the effectiveness” ofcisplatin when used in conjunction withascorbate. “Ascorbate, by increasing thecellular content of MLH1, improves thecellular response to DNA damage. Indeed,induction of increased MLH1 gene expres-sion by DNA damage allows faster c-Abl[pathway] activation; thereafter, increasedp73 activation (which is also regulated byascorbate) could be achieved.”

In conclusion, Catani et al. stated that“biochemical mechanisms accounting forthis activity are not fully understood.”However, the authors suggested that “boththe anti-carcinogenic and anti-cancer ac-tivities of ascorbate might be explained bymodulation of MLH1 gene expression. Thechemopreventive activity may be attributedto the ability of ascorbate to act as a radi-cal scavenger and also to prime, throughinduction of MLH1 and p73 gene expres-sion, the apoptotic programme in DNA-damaged cells, which otherwise would pro-ceed towards tumorigenic progression. Bymodulating MLH1 gene expression, ascor-bate can also enhance the anti-neoplasticactivity of several drugs: in our experimen-tal model, ascorbate, used in combinationwith cisplatin, increased the apoptosis oftumour cells.” Catani et al. noted that theirresults compared with the results of otherinvestigators; namely, Sarna and Bhola(1993) as seen elsewhere in this annotatedbibliography.

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Final ly the authors stated that“combined therapy with ascorbate andDNA-damaging drugs (such as cisplatin)may allow the same pharmacological ef-fectiveness to be attained with lowerdoses of the chemotherapeutic agent,with a consequent reduction in collat-eral effects.”

Study 21. 2002Calderon PB, Cadrobbi J, Marques C,

Hong-Ngoc N, Jamison JM, Gilloteaux J, Sum-mers JL, Taper HS: Potential TherapeuticApplication of the Association of Vitamins Cand K3 in Cancer Treatment. Current Medici-nal Chemistry, 2002; 9/24: 2271-2285.

SummaryCalderon et al. stated: “Oxidative

stress can stimulate growth, triggerapoptosis, or cause necrosis dependingupon the dose and the exposure time ofthe oxidizing agent.”

The authors continued: “A large bodyof evidence supports the idea thatoxidative stress induced by redox cyclingof vitamins C and K3 in association sur-passes cancer cellular defense systemsand results in cell death, The molecularmechanisms underlying such a processare, however, still unknown. Indeed, sev-eral types of cell death may be produced,namely autoschizis, apoptosis and necro-sis.”

The method which Calderon et al.studied in the treatment of cancer celldeath was the use of combined C-K3treatment with chemotherapy. Some ab-breviations are ILS–increase in life spanand MST -mean survival time.

The authors stated that “theoxidative stress induced by redox cyclingof these vitamins make cancer cells -which are deficient in antioxidants en-zymes [as reported by other investiga-tors]-more sensitive to the antitumoralcompound.” They continued: “Indeed, ithas been reported that the loss of redox

homeostasis either by vitamin C or byvitamin K3, results in cell death byapoptosis. Due to the close relationshipbetween apoptosis and oxidative stress,the increase in the intracellular levels ofhydrogen peroxide (H2O2) was thought tobe the explanation for the cytotoxicity ofthe combined vitamins”; vitamin K3 canalso “produce reactive oxygen species.”

One of the following tests was simi-lar to that described in Taper et al.(1987)– Taper, as indicated, is one of theauthors here. The results of the in vivotests are as follows:

(1) C and K3 alone and C plus K3:Twelve ascitic TLT-bearing mine were ad-ministered i.p. with C 1 g/kg and K3 10mg/kg alone or in combination. A con-trol group was used for comparison. Thetest showed that the combined treatmentof CK3 resulted in a mean survival timeof “23.1 days as compared to 15.8 days”for the control group. The vitamins alonedid not “have any significant effect on thelife span” of the mice.

(2) Cyclophosphamide alone andCK3 plus Cyclophosphamide: Thenumber of mice and the dose of the vita-mins were the same as above, and thedrug treatment was i.p. 80 mg/kg. Theresult for cyclophosphamide alone wassimilar to CK3 alone, whereas that forCK3 plus cyclophosphamide showed amuch higher increase in life span over thecontrols. “The cyclophosphamide aloneincreased the MST from 16.8 days in un-treated mice to 20.6 days (ILS=23%). Theeffect of CK3 on cyclophosphamide treat-ment resulted in an increased MST andILS of 26.8 days and 59.5% respectively.”

(3) Vincristine (Oncovin®) alone andCK3 plus Vincristine (Oncovin®): In thistest, the number of mice was ten and thedose of the vitamins was the same asabove. The drug treatment was i.p. 0.3mg/kg or 1.0 mg/kg. The result showedthat the first dose of oncovin had a “MSTof 19.0 days and CK3 alone a MST of 22.5

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days (as compared to 18.5 days in un-treated animals)”. In contrast “CK3 be-fore injection of oncovin [increased] theMST to 36.5 days, that is an ILS of 97.3%.”

In summary, “CK3-treatment selec-tively potentiated tumor chemotherapy,[and] produced sensitization of tumorsresistant to some drugs,” among other ef-fects not particular to this work.

With regard to the mechanism in-volved in CK3 activity, Calderon et al.noted: “One of the main questions raisedby the selective activity of CK3 againstcancer cells concerns the mechanismsconditioning the cell death.” Among themechanisms for this activity may be thegeneration of H2O2 by both vitamins asnoted in Taper et al. (1987). Here,Calderon et al. stated that they “have for-mulated the hypothesis that H2O2 is themajor reactive oxygen species involved inthe cell death by combined vitamins Cand K3. The experimental evidence sup-porting such hypothesis” was then ex-plained.

To conclude, Calderon et al. pro-posed “the association of vitamins C andK3 as an adjuvant cancer therapy whichmay be introduced into human cancertherapy without any change in the clas-sical anticancer protocols, and withoutany supplementary risk for patients.” Theauthors added: “Such adjuvant cancertherapy..., will not produce any supple-mentary risk ... but, on the contrary it willlead to beneficial effects of clinical can-cer treatment.”

Study 22. 2003Mantovani G, Maccio A, Madeddu C,

Mura L, Massa E, Gramignano G, LussoMR, Murgia V, Camboni P, Ferreli L: Reac-tive Oxygen Species, Antioxidant Mecha-nisms, and Serum Cytokine Levels in Can-cer Patients: Impact of an AntioxidantTreatment. Journal of Environmental Pa-thology, Toxicology and Oncology, 2003; 22/1:17-28.

Summary“The main goal” of this study by

Mantovani et al. “was to verify if the ad-ministration of different antioxidantagents, given either orally or i.v. to cancerpatients, is feasible and effective - that is,if it reduces the blood levels of ROS [reac-tive oxygen species] and increases antioxi-dant enzymes.”

“ROS play both positive and negativeroles in vivo.” The negative role is associ-ated among others with the production ofoxidative stress (OS), which in its turn isassociated with certain degenerative dis-eases such as cancer.

The measuring tool used in this studywas “the most important clinical index ofdisease progression - namely, the EasternCooperative Oncology Group (ECOG) Per-formance Status (PS).” The study of 28patients was conducted in five groupswith a selection of antioxidants adminis-tered individually for 10 days with limitedchemotherapy involvement. The resultsfor the group which was administered avitamin A-E-C mixture showed that thismixture was “effective in reducing reactiveoxygen species levels,” as well as having“the additional effect of increasing glu-tathione peroxidase activity” (GPx - anti-oxidant enzyme).

The test comprised of 28 advanced-stage cancer patients, 10 male and 18 fe-male, who had eight different tumors andwho met certain characteristics of age,height and weight. Two of the patients hadbeen on a chemotherapy regimen at leasttwo weeks prior to the study. A controlledgroup comprised 20 healthy individualswith similar physical characteristics. Themeasuring tool was the “WHO - approvedECOG-PS scale.” A number of tests usingdifferent parameters including thesingle antioxidants and the combinedvitamin mixture in the five groups wasconducted. The controlled group wasnot tested with the individual antioxi-dants. Of the five groups, the vitamin

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A-E-C group was termed Arm 5. This armwas comprised of four females only andwere designated by the number 1 of theECOG PS, classified as stage III (1) andIV (3) patients and had breast (1), lung(1), melanoma (1) and myeloma (1) can-cers. The treatment administered orallyper day for 10 days was vitamin A 30,000IU, vitamin E 70 mg and vitamin C500 mg.

The results of the test at baseline andafter for Arm 5 (A-E-C treatment)showed that the “blood levels of ROSdecreased significantly” with the treat-ment. (Three of the other arms alsoshowed this decrease.) With regard toGPx (antioxidant enzyme) activity, Arm5 showed the lowest increase of the arms.

With regard to safety (in the differenttests), Mantovani et al. stated: “The ad-ministration of antioxidant agents hasbeen proven safe: no adverse events wererecorded except in one patient who, af-ter amifostine administration, had ashort episode of orthostatic hypotension,which cleared up spontaneously in a fewminutes. The compliance to the antioxi-dant treatment was very high, and no pa-tient was withdrawn from or refused tocontinue treatment.”

In reference to Arm 5 (A-E-C treat-ment), Mantovani et al. stated that theseantioxidants “have ... been shown to beeffective at [their] institution and in sev-eral of the articles cited.” They noted thata further study on the impact of antioxi-dants on reactive oxygen species amongothers has been “accepted for publica-tion.” (A note pertaining to that studyfollows this summary.)

The authors continued that antioxidants“have different mechanisms of action”,and that “numerous recent data [have]demonstrated that antioxidant agents areeffective in reducing the OS [oxidativestress], and they even have an impact oncancer progression.” They referred to astudy with vitamin C alone or in combi-

nation where the effect on oxidativestress had been shown.

In their conclusion however, Mantovaniet al., based on the results of this studydid not suggest the vitamin combinationas a “best treatment” as they did for threeof the antioxidants. They had stated inthe same paragraph that a number of fac-tors was required to reach a “best anti-oxidant treatment”. Finally, the authorsstated that their “results warrant furtherinvestigation with an adequately largeclinical trial to test the hypothesis thatthe supplementation of antioxidantagents may mitigate oxidative stress incancer patients, occurring either sponta-neously or enhanced by treatment withcisplatin or other oxidative damage-in-ducing drugs” as reported by other inves-tigators.

A NoteThe anticipated follow-up on fur-

ther study of the A+C+E treatment wasnot forthcoming as that treatment wasnot among the combined antioxidanttreatments of the phase II study below.A phase III study mentioned in the ear-lier article “is soon to be activated at[the authors’] institution.”

Mantovani G, Maccio A, MadedduC, Mura L, Gramignano G, Lusso MR,Murgia V, Camboni P, Ferreli L, MocciM, Massa E: The Impact of DifferentAntioxidant Agents Alone or in Combi-nation on Reactive Oxygen Species,Antioxidant Enzymes and Cytokines ina Series of Advanced Cancer Patients atDifferent Sites: Correlation with DiseaseProgression. Free Radical Research,2003; 37/2: 213-223.

Study 23. 2003Drisko JA, Chapman J, Hunter VJ: The

Use of Antioxidants with First-LineChemotherapy in Two Cases of OvarianCancer. Journal of the American College ofNutrition, 2003; 22/2: 118-123.

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SummaryDrisko et al. stated: “Because of poor

overall survival in advanced ovarian malig-nancies, patients often turn to alternativetherapies despite controversy surroundingtheir use. Currently, the majority of cancerpatients combine some form of comple-mentary and alternative medicine withconventional therapies. Of these therapies,antioxidants, added to chemotherapy, area frequent choice.” Vitamin C is among theantioxidants used.

In this study, the authors reported on“two cases of advanced ovarian cancerwhere antioxidants were addedadjunctively to chemotherapy without ad-versely effecting outcome or survival.” Thestudy was observed as Case 1 and Case 2because as will be seen, the patients’ pro-cedures were not the same in all respects.

Case 1: This patient was 55 years old whohad undergone surgery and was found to havewhat is called Stage IIIC papillary serous ad-enocarcinoma of the ovary. After the surgery,the patient began a combined oral antioxi-dant treatment. This treatment “includedvitamin E (1,200 IU), coenzyme Q10 (300 mg),vitamin C (9,000 mg), beta-carotene (mixedcarotenoids, 25 mg), and vitamin A (10,000IU).” Then the patient received the first cycleof chemotherapy. This application consistedof “standard carboplatin (AUC 6) andpacilitaxel (175 mg/m2) chemotherapy for atotal of six cycles”. The next procedure wasa treatment of intravenous vitamin C. Thisapplication of ascorbic acid began with “15grams and increased to 60 grams per infu-sion given twice weekly.”

Drisko et al. continued: “The 60-gramascorbic acid infusions were given twotimes per week during the six cycles ofconsolidation chemotherapy, after whichthe patient continued the 60-gram ascor-bic acid infusion once per week. This doseand schedule was continued for one year,after which the patient chose to reduce thefrequency of the infusion to every 10 to 14days.” They continued: “The patient is cur-

rently over 40 months from initial diagno-sis and remains on ascorbic acid infusions.She has had several CT scans, as well as aPET scan, all of which remain negative fordisease. Her CA-125 remains normal at avalue of 8.8.”

Case 2: This patient was 60 years oldwho also had undergone surgery and wasfound to have what is called Stage IIICmixed papillary serous and seromucinousadenocarcinoma of the ovary. Threemonths after surgery, because of a prob-lem involving a respiratory condition, thispatient also began a combined oral anti-oxidant treatment. This treatment con-sisted of “ascorbic acid (3,000 mg/day),vitamin E (1,200 IU/day) and beta-caro-tene (25 mg/day) and vitamin A (5,000 IU/day)” but no coenzyme Q10. Then thepatient also received the first cycle ofchemotherapy. This application consistedof “carboplatin (AUC 6) and paclitaxel(135 mg/m2) for six cycles”. The next pro-cedure for this patient differed from thatof the other patient because:

“After the completion of her firstcourse of chemotherapy, the patient wasfound to have disease in the pelvis.... Thepatient declined consolidation chemo-therapy, instead opting for continuation oforal antioxidants and initiation ofparenteral ascorbic acid infusions.” Theintravenous ascorbic acid application wasthe same as for patient 1 - “15 grams andincreasing to 60 grams per infusion.”

Drisko et al. continued: “The patient[then] had daily 60-gram ascorbic acid in-fusions for one week and then began twiceweekly infusions, which continues to date36 months post-diagnosis. Although fur-ther diagnostic imaging was declined,physical examination has remained normal.Her most recent CA-125 is 5, and she is overthree years out from diagnosis.”

With regard to side effects of chemo-therapy, Drisko et al. observed from theresults:

(1) “Both patients were monitored for

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toxicity, and neither patient had grade threeor four toxicity that limited completion ofsix cycles of front-line chemotherapy.”

(2) “Both patients had mild, self-lim-ited nausea.”

(3) “Patient 1 noted the onset of numb-ness and tingling of both hands and feetduring the first course of chemotherapy,but prior to the institution of parenteralascorbic acid.”

(4) “Patient 1 also complained of theonset of fatigue, increased shortness ofbreath and peripheral edema during thefirst course of chemotherapy, but prior tothe introduction of intravenous ascorbicacid.”

(5) “Neither patient demonstratedhematologic toxicity, including neutrope-nia or thrombocytopenia” or “requiredcolony-stimulating factors. There was noevidence for febrile neutropenia or infec-tion.”

(6) Neither patient “demonstrated el-evated renal or liver enzymes.”

The only concern was the cardiac prob-lem which was resolved with other treatment.

Finally, Drisko et al. stated, after re-viewing a number of studies on the use ofantioxidants with chemotherapy:

“Despite the fact that chemotherapy-induced formation of free radicals is welldemonstrated, chemotherapy-induced cy-totoxicity in general does not seem to de-pend on formation of reactive oxygen spe-cies; thus, the concept that antioxidants arecontraindicated during most chemo-therapy regimens is no longer valid. In fact,as demonstrated with the reported cases,antioxidants when added adjunctively tochemotherapy may improve the efficacy ofchemotherapy and may prove to be safe.”The authors noted that a further studybased on “the positive results” of this studyis underway at their institution.

Study 24. 2003Abdel Rehim WM, Sharaf IA, Hishmat

M, El-Toukhy MA, Abo Rawash N, Fouad

HN: Antioxidant Capacity in Fasciolahepatica Patients Before and After Treat-ment with Triclabendazole Alone or in Com-bination with Ascorbic Acid (Vitamin C) andTocofersolan (Vitamin E). Arzneim.-Forsch./Drug Res., 2003; 53/3: 214-220.

SummaryAbdel Rehim et al. noted: “In Egypt, an

increasing prevalence of human fasciolia-sis was observed in the last 20 years”, andaccording to other investigators a newdrug, triclabendazole, “has recently beenregistered in Egypt for the treatment ofhuman fascioliasis.”

The authors stated: “The aim of thepresent study was to investigate the effect oftriclabendazole (...) therapy alone or in com-bination with ascorbic acid (vitamin C, ...) andtocofersolan (vitamin E, ...), in Fasciolahepatica patients, on Lipo-peroxidation(LPO) and blood antioxidant capacity.”

The clinical test was conducted with32 Fasciola hepatica patients both maleand female who had an average age of 28years old. They were grouped as 16 acuteand 16 chronic patients. These two groupsin turn were grouped in two subgroups ofeight patients each. It was in these sub-groups that the clinical test was observedalong with a controlled group of ten healthysubjects both male and female of the sameaverage age.

“One subgroup was given two consecu-tive oral doses each of 10 mg/kg bodyweight of trilabendazole suspension andthe other received vitamin C (1000 mg/day)and vitamin E (600 mg/day) for twomonths, together with the same dose oftriclabendazole given to the first subgroup.”

Five biochemical parameters were usedfor the test: (1) serum lipid peroxide, (2)erythrocyte lipid peroxide, (3) reduced glu-tathione (GSH), (4) glutathione peroxidase(GPx) and (5) superoxide dismutase (SOD).

The results showed that the combinedtreatment with the drug and vitamins wasmore effective than the drug alone. The

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test also showed that a statistical correla-tion between the biochemical parameterswas either positive or negative.

Abdel Rehim et al. observed the following:For Lipid Peroxides-“The results ob-

tained in the present study revealed a sig-nificant increase in the levels of lipidperoxides expressed as MDA [malonyldialdehyde] of both serum and erythrocytein chronic and acute Fasciola patients be-fore and after triclabendazole treatmentalone or in combination with vitamins ascompared to the corresponding control lev-els.” The authors also observed: “In thegroup of chronic Fasciola patients …, thelevels of MDA were significantly decreasedas compared to the corresponding valuesafter triclabendazole treatment”. They con-tinued, as reported by other investigators,that “this may be due to the reduction inoxidative stress induced by the free radicalscavenging effect of vitamins C and E witha consequent improvement of patient’s anti-oxidant capacity.”

For Reduced Glutathione-“In thepresent study, there was a significant de-crease in the level of glutathione contentin chronic and acute Fasciola patients be-fore and after triclabendazole alone or incombination with vitamins as compared tothe corresponding control level.” With re-gard to both groups of patients, the authorsobserved, as reported by an investigator:

“The significant decrease in blood glu-tathione peroxidase enzymatic activity inall Fasciola patients compared to controlscould be partly due to the reduction of glu-tathione itself where glutathione peroxi-dase (GPx) functions together with glutath-ione to exert its effect.”

For Glutathione Peroxidase andSuperoxide Dismutase-“The activities ofGPx and SOD were significantly higher inall Fasciola patients treated with tricla-bendazole and vitamins when comparedwith those of patients treated with tricla-bendazole alone.” The authors continued:“This could be explained on the basis of

increased antioxidant capacity of thesepatients exerted by vitamins C and E sup-plementation.”

Lastly, in reference to the statisticalcorrelation, Abdel Rehim et al. stated: “Ahighly positive correlation was observedbetween GSH and SOD, and between GSH,GPx and SOD and between serum and eryth-rocyte lipid peroxides ..., while a significantnegative correlation was found between li-pid peroxides and GSH, GPx and SOD....”

Finally, Abdel Rehim concluded: “Thesignificant improvement of SOD and GPxactivities and in lipid peroxide levels aftervitamins supplementation as compared totheir corresponding values after treatmentwith triclabendazole alone could be ex-plained on the basis of the potent actionof these vitamins in protection againstoxidative damage.”

This summary brings to an end thesection on positive studies.

Positive Reviews (Table 2)Review 1. 1993

Hoffer A: Orthomolecular Oncology. InQuillin P; Williams RW (eds.). AdjuvantNutrition in Cancer Treatment, 1992 Sym-posium Proceedings, Cancer TreatmentResearch Foundation, Arlington Heights,Illinois, USA, 1993.

SummaryHoffer wrote: “Orthomolecular oncol-

ogy is the treatment of cancer by the pro-vision of the optimal molecular environ-ment for the body, especially the optimalconcentrations of substances normallypresent in the human body. This does notmean that this treatment is an alternativeor is antagonistic to standard therapy us-ing toxic drugs in sublethal doses(xenobiotics). In my opinion, the optimumtreatment for cancer today, imperfect as itis, is orthomolecular therapy combinedwith xenobiotic therapy.”

In this article, Hoffer reported on the1990 Hoffer and Pauling study mentioned

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in the above section. Following thatstudy, as a result of a possible concernby “critics” regarding “validity”, anotherstudy was conducted for comparison.(The writer does not know the date of thestudy as it was not mentioned before.However, it may be 1990 or shortly there-after as the results were known before1992 as per below.) That study comprisedthe 101 original treated patients and 19untreated patients from the original 33controls (14 of whom had died).

With regard to survival time, the re-sult of this comparison study showed: “Thedifference in outcome between these twogroups [remained] large. In the first year,75% of the group not on the orthomolecu-lar program died, and at the end of fiveyears only 5% were alive. From the ortho-molecular group, 25% died by the end ofthe first year, and at the end of the 5th year39% were alive. By January 1, 1992, 41 pa-tients were still alive. The average dura-tion of life from the time I first saw themuntil this date was 49 months, comparedwith 15 months for the group treated with

xenobiotic therapy only.”These results supported the investiga-

tors’ “conclusion that orthomolecular treat-ment combined with xenobiotic treatmentis much superior to xenobiotic therapyalone.” However, Hoffer stated: “As a clini-cian who has worked with patients for 42years, I still think the original control group[of 33] is the sounder one to use scientifi-cally.” The author continued:

“Twenty patients out of 59 (34%) sur-vived 8 years. They were first seen be-tween 1978 and 1984. From the remain-ing 75, seen between 1985 and 1988, 22(29%) survived 4 years. This suggeststhat over the four years this group willalso yield a 25% 8-year survival.”

Finally, with regard to quality of life,the results of the 1990 study showed thatthe mineral-vitamin treatment enhancedthe life of the patients. Here, Hoffer elabo-rated on that enhancement. He stated:

“It is difficult to measure quality oflife, but it is relatively easy to find outwhether the patients and their familieswere more comfortable, suffered less

1. Hoffer A: Orthomolecular Oncology. AdjuvantNutrition in Cancer Treatment 1992 In Quillin, P and

Williams, RW (eds.).Symposium Proc, Cancer.Treatment Res Foundation.Illinois, USA, 1993.

2. Moss RW: Questioning Chemotherapy 1995; Equinox Press, NY.3. Prasad KN, Kumar A, Kochupillai V, et al: J Amer Coll Nutr 1999; 18/1: 13-25.4. Simone CB, Simone NL, et al: Intl J Integr Med 1999; 1: 20-24.5. Moss RW: Cancer Therapy: The Independent

Consumer’s Guide to Non-ToxicTreatment and Prevention 1999; Equinox Press, NY.

6. Lamson DW, Brignall MS: Altern Med Rev 1999; 4/5: 304-329.7. Conklin KA: Nutr Canc 2000; 37/1: 1-18.8. Hoffer A: Vitamin C and Cancer 2000; Quarry Press Inc., ON.9. Lamson DW, Brignall MS: Altern Med Rev 2000; 5/2: 152-163.10. Drisko JA, Chapman J, Hunter, VJ: Gynec Oncol 2003; 88/3: 434-439.11. Tamayo C, Richardson MA: Alternat Ther 2003; May/June/9/3: 94-102.12. Houston R: Townsend Lett Doctors Patients 2003; June/239: 104-106.

Table 2. Positive reviews.

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pain, and remained more functional.... Ihave not had a single complaint from mypatients that they suffered more pain anddiscomfort. This contrasts strongly withxenobiotic therapy, which is character-ized by severe discomfort of many kinds,nausea, fatigue of long duration, loss ofhair, etc. Orthomolecular therapy tendsto decrease the discomfort caused byxenobiotic therapy. This is also difficultto quantify, but I believe my patients weretelling me what really happened whenthey reported that they were able to tol-erate radiation and chemotherapy better.”Hoffer added: “Their surgeons often weresurprised by their rapid recovery fromsurgery.” He noted: “ They were dis-charged very quickly from the hospital.”

Review 2. 1995Moss RW: Questioning Chemotherapy.

Equinox Press, New York, 1995, chapter 9.

SummaryOne of the topics examined by this

book is the quality of life that results fromthe use of chemotherapy and non-toxicsubstances alone or in combination. Anti-oxidants, including vitamin C, used inconjunction with chemotherapy have beenfound to enhance the life of cancer pa-tients.

Moss cited two studies which showedvitamin C’s effectiveness:

(1) “vitamin C increased the cell-kill-ing ability of chemotherapy [Block 1991].”

(2) vitamin C “blocked heart damageassociated with the drugs doxorubicin(Adriamycin) and interleukin - 2 [Skimpo1991]” - seen elsewhere in this presenta-tion as well.

Moss quotes Linus Pauling [1987]: ‘Vi-tamin C ... controls to a considerable ex-tent the disagreeable side effects of thecytotoxic chemotherapeutic agents, such asnausea and loss of hair, and that benefitseems to add its value to that of the chemo-therapeutic agent.’

Finally, with regard to the concern ofsome doctors that “by reducing toxic sideeffects one may inadvertently decreasethe effectiveness of cytotoxic drugs”,Moss cited Simone (1994). The latterreported that there are “dozens of stud-ies suggesting an enhanced killing of can-cer cells by adding vitamin supplements,especially antioxidants to chemotherapy.”

Review 3. 1999Prasad KN, Kumar A, Kochupillai V,

Cole WC: High Doses of Multiple Antioxi-dant Vitamins: Essential Ingredients inImproving the Efficacy of Standard CancerTherapy. Journal of the American College ofNutrition, 1999; 18/1: 13-25.

SummaryPrasad et al. wrote: “Numerous articles

and several reviews have been published onthe role of antioxidants, and diet and life-style modifications in cancer prevention.However, the potential role of these factorsin the management of human cancer havebeen largely ignored.”

The authors also stated: “The efficacyof standard tumor therapy (...chemo-therapy...) has reached a plateau.” Theycontinued by noting: “The lack of enthusi-asm among clinical oncologists for usinghigh doses of antioxidant vitamins in com-bination with ... chemotherapy is primarilybased on fear that antioxidant vitaminsmay protect both normal and cancer cellsagainst free radicals which are generatedby ... most chemotherapeutic agents. Sev-eral in vitro and some in vivo studies sug-gest that such concerns are not valid.”

Prasad et al. continued: “Based on re-sults of our studies and others, we proposeda hypothesis that supplementation withhigh doses of multiple antioxidant vita-mins, together with diet modification andlifestyle changes may improve the efficacyof standard ... cancer therapies by reduc-ing their toxicity on normal cells and byenhancing their growth-inhibitory effects

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(...) on cancer cells.” The authors contin-ued: “This review will discuss whether ornot the above hypothesis can be supportedby published ... clinical results.”

With regard to the use of multiple anti-oxidants with chemotherapy, the authorsstated: “Several in vitro studies have re-vealed that vitamin C [as reported by manyinvestigators] ... enhance[s] the growth in-hibitory effect of most of the currently usedchemotherapeutic agents on some cancercells.” An example was cited with sodiumascorbate and 5-Fluorouracil which showedthat the vitamin enhanced the anti-tumoreffect of the chemotherapy. The authorsnoted: “The extent of [the] enhancementdepends on the dose and form of vitamin,the dose and type of chemotherapeuticagent and the type of tumor cells.”

Prasad et al. also noted: “The effect ofindividual antioxidant vitamins in com-bination with ... chemotherapeutic agentshas not been tested in human tumors invivo in a systematic manner.” The au-thors continued: “Most standard thera-peutic agents mediate their effects, inpart, by generating free radicals whichdamage both normal and cancer cells.Therefore, clinical oncologists fear thatthe use of high doses of antioxidant vita-mins during standard cancer therapymight be harmful since they might pro-tect both normal and cancer cells againstfree radical damage produced by tumortherapeutic agents. The available experi-mental data suggest that such fear hasno scientific basis.”

The authors cited examples includingthat of vitamin C above that demonstratedclearly: “ ... antioxidants do not protect can-cer cells against free radical and growth-inhibitory effects of standard therapy. Onthe contrary, they enhance its growth-inhibi-tory effects on tumor cells, but protect nor-mal cells against its adverse effects.” Thestudy by Prasad et al. (1994) with combinedvitamins and chemotherapy was also noted.

With reference to toxicity, Prasad et al.

stated: “The second part of our proposed hy-pothesis is that antioxidant vitamins in com-bination with standard therapeutic agentsmay reduce the toxicity of these agents onnormal cells. Several studies using animalmodels (...) support this hypothesis”- vita-min C is among them. For example, theauthors cited a study of vitamin C plusadriamycin (similar to Skimpo 1991) whichshowed that the vitamin reduced “the ad-verse effects of adriamycin on normal ani-mal cells.” While in combination with othervitamins, it reduced “bleomycin-inducedchromosomal breakage” as reported byother investigators.

“Based on the data ... and safety issues,”Prasad et al. recommended certain com-bined supplements for use “during and af-ter standard therapy”. The formula con-sisted of the following: “Multiple antioxi-dant vitamins including B-vitamins andappropriate minerals but without iron, cop-per and manganese, since these three min-erals interact with vitamin C to producefree radicals”.

“Additional 8 grams of vitamin C in theform of calcium ascorbate”, as the use of“10 g or more have been used in humancancer treatment without toxicity” as hasbeen reported. Extra vitamin E and B-caro-tene made up the formula.

The authors explained that calciumascorbate was selected over sodium ascor-bate because the latter at high doses hasbeen reported to have particular side ef-fects. They also explained the reasons forselecting the other nutrients and their par-ticular doses, and they described the treat-ment procedure.

In addition, Prasad and coworkerspoint out: “A low fat (...) and high fiber (...)diet should be continued during and afterstandard treatment.”

To conclude, Prasad et al. stated: “Theproposed recommendations ... will testour hypothesis that vitamin supplements,diet, and lifestyle modifications maymarkedly improve the efficacy of stand-

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ard . . . therapies by enhancing theirgrowth-inhibitory effects selectively ontumor cells, and by reducing their toxic-ity to normal cells.” The authors added:“The proposed recommendation ... mayalso reduce the risk of second malignan-cies, which are being detected at in-creased rates among survivors of stand-ard cancer treatment.”

Review 4. 1999Simone CB, Simone NL, Simone II CB:

Nutrients and Cancer Treatment. Interna-tional Journal of Integrative Medicine, 1999;1: 20-24.

SummarySimone et al. noted: “Cellular studies,

animal studies, and human studies dem-onstrate that vitamins A, E, C, and K, beta-carotene, and selenium, as single agentsor in combination, all protect against thetoxicity of adriamycin and enhance itscancer-killing effects.”

With regard to cellular and animalstudies, the authors continued: “In vitrocellular studies and animal studies haveused vitamins C [and other nutrients] - assingle agents or in combination - givenconcomitantly with chemotherapy, ortamoxifen, or interferon alpha-2b, or ra-diation, or combinations of thesemodalities. They all show the same effect:Increased tumor killing and increased pro-tection of normal tissues.”

In reference to the effectiveness ofantioxidants as anti-cancer agents,Simone et al. stated:

“Antioxidants protect normal cellsand other tissues by fighting free radicalsand the oxidative reaction that free radi-cals cause.” Vitamin C is among theseantioxidants.

Finally, the authors, as their contribu-tion to cancer treatment, recommend aprogram consisting of 22 vitamins, min-erals and other nutrients - “Dr. Simone’sRecommended Nutrients/Dosages.”

Review 5. 1999Moss RW: Cancer Therapy: The Inde-

pendent Consumer’s Guide to Non-ToxicTreatment and Prevention. Equinox Press,New York, 1999.

SummaryThe purpose of Moss’ book is two-fold:

(1) “to provide the person with cancer [andfuture cancer patients] with useful infor-mation on cancer alternatives”, and (2) “toaid the patient to better exercise freedomof choice in medical care.” To this end, theauthor presented “nearly 100 non-toxic andless-toxic treatments for cancer” and their“effectiveness and safety” as cited in “nearly1000 references” from international scien-tific journals. Treatment with vitamin Calone or in combination with chemo-therapy is among the methods used.

The following treatments using vitaminC alone or in combination were shown towork “well in conjunction with conventionaltreatments, by either enhancing their cell-killing power or decreasing toxic side effects.”

Moss cited studies by Hoffer andPauling 1990 and 1993 re: combined vita-min-mineral treatment and survival time,Meadows et al. 1991 re: vitamin C and cell-killing and side effects and Skimpo et. al.1991 re: vitamin C and toxicity ofadriamycin. All the cited studies are re-viewed elsewhere in this publication.

To conclude, Moss acknowledged thetoxicity of high dose vitamin C “under cer-tain circumstances” but noted that by reduc-ing the dosage or changing to another form,the “symptoms can be relieved”. Therefore,he continued, “vitamin C appears to be avery non-toxic substance, which most peo-ple can take in large amounts for long peri-ods of time without harm.”

Review 6. 1999Lamson DW, Brignall MS: Antioxidants

in Cancer Therapy: Their Actions and Inter-actions with Oncologic Therapies. Alterna-tive Medicine Review, 1999; 4/5: 304-329.

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SummaryIn this review, Lamson and Brignall

presented summaries of the use of antioxi-dants alone in cancer therapy and as anadjunct to chemotherapy. The authors ac-knowledged the concern of investigatorsthat antioxidants might “decrease the effec-tiveness” of chemotherapeutic agents. How-ever, they noted that it had been demon-strated - with a few exceptions - that cer-tain antioxidants including vitamin C wereeffective with chemotherapy. The reviewalso provided an extensive bibliography.

Lamson and Brignall reported on thefollowing studies: Taper et al. 1987 re: vita-min C plus vitamin K3 given before chemo-therapy which showed that the combinedvitamin treatment “increased survival andthe effect of several chemotherapeuticagents (...) in a murine ascitic liver tumormodel.” It was shown that the C+K3 treat-ment “did not increase the toxicity of theseagents to healthy tissue.” A certain charac-teristic of the models showed the antioxi-dants to be more effective than that of the“cytotoxic treatment alone, suggesting animmune-stimulating action of the vitamins.”

Skimpo et al. 1991 re: vitamin C plusdoxorubicin (adriamycin) which showedthat the combination “led to a reductionin the toxicity seen with doxorubicin alonein mice and guinea pigs”

Chiang et al. 1994 re: vitamin C plusvincristine whereby the vitamin was“shown to increase the drug accumulationand decrease resistance to [it] in humannon-small-cell lung cancer cells in vitro. Anascorbic acid-sensitive uptake mechanismwas theorized to explain these results.”

Wells et al. 1995 re: enhancement byvitamin C in “doxorubicin resistance inhuman breast cancer cell lines alreadyknown to be resistant” as opposed to thosethat are not.

Kurbacher et al. 1996 re: three chemo-therapeutic agents and vitamin C in whichthe vitamin “at non-cytotoxic concentra-tions (...) increased the activity of doxo-

rubicin, cisplatin, and paclitaxel in human-breast carcinoma cells in vitro.” Doxo-rubicin had the greatest activity. Lamsonand Brignall noted that from these results,the study’s authors noted “that since vita-min C has already shown an ability to re-duce the cardiotoxicity of doxorubicin,ascorbic acid and doxorubicin are an at-tractive future treatment for breast cancer.”

In conclusion, Lamson and Brignallrecommended that the time has come “toresearch the role of [antioxidants] in con-ventional oncologic treatment, rather thandismiss them as a class based on theoreti-cal concerns.”

Review 7. 2000Conklin KA: Dietary Antioxidants Dur-

ing Cancer Chemotherapy: Impact onChemotherapeutic Effectiveness and Devel-opment of Side Effects. Nutrition and Can-cer, 2000; 37/1: 1-18.

SummaryConklin wrote: “Chemotherapy has

long been a cornerstone of cancer therapy.Although extensive research is done on thedevelopment of more effective and lesstoxic antineoplastic agents, much less at-tention has been paid to factors that mayenhance the effectiveness of existing drugs.Nutritional factors may hold a key to en-hancing the anticancer effects of chemo-therapy and to reducing or preventing cer-tain chemotherapy-induced side effects.”

The author noted: “Administration ofantineoplastic agents results in oxidativestress, i.e., the production of free radicalsand other reactive oxygen species (ROS).Oxidative stress reduces the rate of cell pro-liferation, and that occurring duringchemotherapy may interfere with the cy-totoxic effects of antineoplastic drugs,which depend on rapid proliferation of can-cer cells for optimal activity. Antioxidantsdetoxify ROS and may enhance the antican-cer effects of chemotherapy.”

The author added: “ROS also contribute

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to side effects that occur only with individualagents, such as doxorubicin-induced cardio-toxicity, cisplatin-induced nephrotoxicity,and bleomycin-induced pulmonary fibrosis.Antioxidants can reduce or prevent many ofthese side effects, and for some supplementsthe protective effect results from activitiesother than their antioxidant properties.”

“ This review considers a limitednumber of dietary supplements that haveantioxidant properties or influence cellu-lar antioxidant systems. The emphasis ofthe review is on those antioxidant supple-ments that have been most studied withrespect to effects on antineoplastic respon-siveness or reduction of chemotherapy-in-duced side effects.” Vitamin C is amongthese supplements.

In reference to vitamin C and chemo-therapy, Conklin reported on several stud-ies, most of them described in this publi-cation.

For example the author cited in vitrostudies which showed that vitamin C (1) en-hanced “the cytotoxic activity of doxorubicin,cisplatin, paclitaxel, dacarbazine, andbleomycin.” (2) increased “drug accumula-tion” and “partially [reversed] vincristineresistance of human non-small-cell lungcancer cells.” (3) the author also noted:“Animal studies have shown that vitaminC at 500 mg/kg and 1,000 mg/kg [en-hanced] the chemotherapeutic effect of cy-clophosphamide, vinblastine, 5-FU,procarbazine, ... (BCNU), and doxorubicin,although other studies found that vitaminC was without effect on the activity ofdoxorubicin when vitamin C was adminis-tered at 2 g/kg/day to mice or 835 mg/kg/day to guinea pigs.” (4) “In mice and guineapigs, 2,000 mg/kg/day of vitamin C pre-vented doxorubicin-induced lipid perox-idation and reduced the acute cardiotoxiceffect of doxorubicin.” (5) “Protectionagainst chemotherapy-induced mutagen-esis by vitamin C has been demonstratedin cultured human lymphoblastoid celllines and peripheral blood lymphocytes and

after intraperitoneal administration of 3, 5,and 7 g/kg of vitamin C in mitomycin C-treated mice.”

The author also reported on a clinicalstudy that compared treatment with 100mg or 1,000 mg of vitamin C as follows:“Protection against chemotherapy-inducedmutagenesis has been found by Pohl andReddy [1989] after oral administration ofvitamin C to human volunteers. These in-vestigators cultured lymphocytes from 10volunteers two weeks before and two weeksafter daily administration of 100 or 1,000mg of vitamin C and assessed bleomycin-induced chromosomal damage in each ofthe cultures. Supplementation with 1,000mg of vitamin C significantly reduced thechromosomal damage, suggesting that vi-tamin C may reduce the risk of chemo-therapy-induced carcinogenesis. Althoughsupplementation with 100 mg of vitamin Creduced chromosomal damage, the differ-ence did not reach statistical significance.”

In conclusion, Conklin stated: “Dietarysupplementation with antioxidants mayprovide a safe and effective means of en-hancing the response to cancer chemo-therapy.” The author continued: “Vitamin Emay prove to be an important nutrient forenhancing antineoplastic activity because ofits role in preventing lipid peroxidation, thusmaintaining the rapid rate of proliferationof cancer cells. Other antioxidants may beimportant because of their antioxidantproperties”. With regard to vitamin C, theauthor did not mention it specifically, butas reported in the studies above, it seems tofit into the “other” category because of itsprotection “against lipid peroxidation” andits enhancing and reduction of toxicity ac-tivities as reported in the studies above.

Conklin also noted the probable im-proved quality of life with dietary supple-ments after chemotherapy. The authorwrote:

“Quality of life of patients after chemo-therapy may be improved by dietary sup-plementation with antioxidants that reduce

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or prevent chemotherapy-induced side ef-fects.” He continued: “Although approvedcytoprotectants are available” as reportedby another investigator, “these agents arenot without adverse effects.” He continued:“In contrast, certain dietary antioxidants,in doses that are without adverse effects,can ameliorate some side effects of cancerchemotherapy.” Only coenzyme Q10 in ref-erence to “cardiotoxicity” was mentionedfor this activity.

Conklin ended by stating that “muchmore work is needed to establish a clearrole for the use of dietary supplements asan adjunct to cancer chemotherapy.”

Review 8 . 2000Hoffer A: Vitamin C and Cancer.

Quarry Press Inc., Kingston, ON, 2000.

SummaryHoffer wrote that this book “is a col-

laborative work with Linus Pauling” whooriginated it, “because of his great interestin vitamin C and cancer”. However, theauthor stated:

“In spite of his immense prestige, LinusPauling could not find a publisher who wouldpublish our book.” He continued: “We shouldhave anticipated this response because theProceedings of the National Academy ofScience[s] ..., had rejected our first paper.”

The reason that Linus Pauling’s namewas not given as co-author is that, as Dr.Hoffer stated, by the time a publisher wasfound “it was too late to have Dr Paulingparticipate in the final editing of the book,for he died soon after. After he died I as-sumed that I could still co-author this bookwith him, but certain complications madethis impossible.”

The purpose of this book is to detailthe results of the 1990 Hoffer and Paulingstudy by “offering the reader the completecase histories” of that study. The authoralso elaborated on the quality of life of hiscancer patients. It is this latter that is sum-marized here.

The main parts of the presentation areset out under the following chapter headings:New Hope for Cancer Patients; ClinicalNutrition for Treating and Preventing Can-cer; Clinical Studies of the Value of Ortho-molecular Treatment; Case Histories.

Hoffer, in recognising “the fears ofsome critics,” stated that “this book is notan attack on the medical profession andthe use of the standard methods for treat-ing cancer, which include surgery, radia-tion, and chemotherapy. Rather, we haveattempted to redress the imbalance thatexists today between these xenobiotic ordrug treatments and nutritional or ortho-molecular therapy.” He continued:

“It is necessary to let the public knowthat complementary treatment is availableand to alert the press that they should payas much attention to the newer develop-ments in this field as they do to the stand-ard approaches. It is an attempt to bringnutrition back into medicine, restoring therole it played for hundred of years.”

The new hope is in the survival andquality of life of cancer patients through theuse of megavitamins including vitamin Calone, or in combination “as an adjunct toappropriate conventional therapy.” Hofferpointed out:

“An important word in this statementis the adjective ‘appropriate’. If there isgood evidence that the proposed conven-tional therapy has been found to be suffi-ciently effective in the treatment of otherpatients with the same kind of cancer tooutbalance the disagreeable side effects ofthe treatment, then the patient should giveserious consideration to the possibility ofaccepting the treatment, but if there is nosuch evidence, then the patient should re-ject the proposed therapy.”

Orthomolecular treatment as a com-plement to chemotherapy has been shownto increase survival time and reduce theside effects of some drugs for certain can-cers. The Hoffer regimen was outlined inthe 1993 Hoffer and Pauling study as de-

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scribed elsewhere in this document.Hoffer also pointed out: “Oncologists

are beginning to emphasize the impor-tance of considering duration and qual-ity of life in measuring response to treat-ment. Tumor shrinkage alone is nolonger considered an adequate measure”and he quoted a Toronto oncologist whoagreed with this view.

The author further expounded on thequality of life as seen in his patients bydetailing an example. Finally, he reiter-ated the benefits of orthomolecular treat-ment with regard to quality of life, sideeffects from chemotherapy and the pro-gram’s palatability. He noted that onlythose patients who were suffering fromsevere side effects of chemotherapy, orother associated condition could not fol-low the regimen.

In conclusion, Hoffer stated: “Ortho-molecular therapy provides a step for-ward in the battle against cancer whichmust be fully explored. There can be nological reason today why most of the re-search funds should go only toward theexamination of more chemotherapy andmore ways of giving radiation. Theremust be a major expansion into the useof orthomolecular therapy to sort out thevariables and to determine how to im-prove the therapeutic outcome of treat-ment.”

In Hoffer’s overall conclusion to thechapter (Clinical Studies of the Value ofOrthomolecular Treatment), the last wordwas for his friend, colleague and collabo-rator, Dr. Linus Pauling, when he wrote:

“Enterprising medical schools shouldestablish chairs in Orthomolecular On-cology, perhaps called the Linus PaulingChair of Orthomolecular Oncology.”

Review 9. 2000Lamson DW, Brignall MS: Antioxi-

dants and Cancer Therapy II: Quick Refer-ence Guide. Alternative Medicine Review,2000, Vol. 5, No. 2, pp. 152-163.

SummaryLamson and Brignall explained:“This guide is meant to be a compan-

ion to [their] previous review on effects ofantioxidant supplementation during can-cer therapy. Widespread use of antioxidantcompounds make this an area of increas-ing interest to oncologists as well as otherphysicians; hence, the attempt to reducethe findings of a lengthy report to a man-ageable guide.”

The authors continued: “Reducingcomplicated interactions to a single sen-tence can be an oversimplification. In mayinstances the effect of an antioxidant com-pound with a certain therapeutic agent maybe specific to a particular tumor type, ormay vary with dosage of both antioxidantand chemotherapy. This guide is best usedas a means of quickly identifying whichantioxidants are likely to be indicated orcontraindicated with a particular therapeu-tic agent.”

Lastly, the authors summarized in ta-bles a number of studies, some of which areseen elsewhere in this presentation.

Lamson and Brignall reported on sixstudies for vitamin C alone or in combina-tion with other vitamins in conjunctionwith chemotherapy: five studies were posi-tive and one study was negative. The re-sults were as follows:

Positive(1) Vitamin C in combination “in-

creased [the] therapeutic effect” of cyclo-phosphamide, doxorubicin, 5-fluorouraciland vincristine (Taper et al. 1987).

(2) Vitamin C “decreased [the] toxic-ity” of doxorubicin (Skimpo et al. 1991). Theauthors noted that ‘decreased toxicity’ re-ferred “to effect on healthy tissue.”

(3) Vitamin C “increased [the] cyto-toxic effect” of paclitaxel and cisplatin, aswell as in human breast CA [carcinoma]cells of doxorubicin (Kurbacher et al. 1996).

(4) Vitamin C “increased [the] cytotoxiceffect” of vincristine (Chiang et al. 1994).

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(5) Vitamins C in combination “in-creased [the] cytotoxic effect” of tamoxifen(Prasad et al. 1994).

Negative(1) Vitamin C - “ascorbic acid 2-phos-

phate found no change in drug-sensitivecells and decreased effect in resistant linesof doxorubicin (adriamycin)” (Wells et al.1995).

Lamson and Brignall concluded bystating:“There are only three presentlyknown examples in which an agent classi-fiable as an antioxidant has been shown todecrease effectiveness of ... chemotherapyin vivo. The vast majority of both in vivoand in vitro studies have shown enhancedeffectiveness of standard cancer therapiesor a neutral effect on drug action.”

Review 10. 2003Drisko JA, Chapman J, Hunter VJ: The

Use of Antioxidant Therapies DuringChemotherapy. Gynecologic Oncology,March 2003, Vol. 88, Issue 3, pp. 434-439.

SummaryDrisko et al. wrote: “At the present

time, many cancer patients combine someform of complementary and alternativemedicine therapies with their conventionaltherapies. The most common choice ofthese therapies is the use of antioxidants.”

This article is a review of four antioxi-dants including vitamin C.

The authors noted: “While it is ac-cepted that antioxidants are useful in the re-duction of adverse effects of chemotherapy,the prevailing opinion is that antioxidantsreduce the effectiveness of chemotherapyand radiation therapy’s neoplastic toxicity[five sources]. However, there is evidencethat antioxidants may also be a choice fortherapeutic intervention alongside chemo-therapy with demonstrated benefit in tumorsize reduction and/increased longevity[twelve sources].”

They continued: “Despite the theoreti-

cal concern that antioxidant therapies in-terfere with chemotherapy ... by loweringoxidative damage, evidence supporting thismechanism is currently lacking [onesource]. In fact, antioxidants act as thera-peutic biologic response modifiers and areable to directly induce apoptosis in alreadyestablished neoplastic cells [five sources].There is also supportive evidence that anti-oxidants enhance antitumor effects ofchemotherapy in vitro and in vivo [fivesources].” Lastly, the authors noted: “It isnow recognized that chemotherapy killstumor cells not by damaging essential bio-logical functions but by initiating pro-grammed cellular responses” and that “mu-tations that interfere with apoptosis mayproduce tumor chemotherapy resistance[two sources].”

In reference to vitamin C, Drisko et al.reported from 24 references on the vitaminwhich showed both positive and negativeresults of vitamin C alone, or in combina-tion with other vitamins used with chemo-therapy, among other descriptions. Threeof the studies are reviewed elsewhere in thisdocument.

Drisko et al. concluded: “Currently, evi-dence is growing that antioxidants mayprovide some benefit when combined withcertain types of chemotherapy. Because ofthe potential for positive benefits, arandomized controlled trial evaluating thesafety and efficacy of adding antioxidantsto chemotherapy in newly diagnosed ovar-ian cancer is underway at the University ofKansas Medical Center.”Review 11, 2003

Tamayo C, Richardson MA: Vitamin Cas a Cancer Treatment: State of the Scienceand Recommendations for Research. Alter-native Therapies, 2003; May/June/9/3: 94-102.

SummaryTamayo and Richardson stated: “The

rise in the use of dietary supplements andherbal medications by patients makes it

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imperative to reevaluate the past findingsof clinical studies. Among unconventionalapproaches, high-dose vitamin C is one ofthe most widely used and studied, yet con-troversial approaches.”

The authors continued: “High doses ofvitamin C and other naturally occurringsubstances are used in orthomolecularmedicine as described by the renownedchemist Linus Pauling.” They continued,according to one of the main proponentsof orthomolecular medicine: “The primaryaim of this approach is to establish an opti-mal molecular environment, yet the benefitsremain unproven and the approach discour-aged” by other authors.

“This paper summarizes the evidencefor the anti-tumor activity of vitamin C andreviews the biological plausibility support-ing the use of high dose vitamin C as acancer treatment.” Most of the material forthis study came from a 1999 Montrealworkshop, at which the objective amongothers, was to “assess the evidence ofmegadoses of vitamin C alone or with otheragents as a cancer treatment.” The find-ings of this assessment are described here.

By way of introduction, Tamayo et al.briefly recalled an early work by EwanCameron, MD, who “used high doses ofvitamin C to treat advanced, untreatablecancer in Scotland.”

The authors noted: “In 1971, Dr.Cameron conducted a Phase I-II study inpatients with advanced, untreatable malig-nancies and evaluated fifty consecutivecases for minimal/no response growth re-tardation, cytostasis, tumor regression, ortumor hemorrhage/necrosis” as reported inhis 1974 study with Linus Pauling.

Tamayo and Richardson continued:“Approximately 4% of patients had beenpreviously treated with chemotherapy andconsidered unlikely to respond to standardtreatment” as reported in a 1993 book byCameron and Pauling. This book also out-lined positive effects including “reducedtumor progression”.

The present authors continued: “Theclinical responses in Scotland suggesteda biological basis for further investigationin several cancers. Subsequently, two ret-rospective studies [1978 and l979 -Cameron and Pauling] compared survivalfor patients with vitamin C with that ofpatients treated with conventional treat-ment and who were matched on gender,age, tumor diagnosis, and clinical stage.Both studies demonstrated significantlyimproved survival with vitaminC.”Thereafter, Tamayo and Richardsoncontinued: “Increased interest in vitaminC resulted in two randomized, double-blind controlled trials of high dose oralvitamin C that were conducted at theMayo Clinic. The 1979 study included pa-tients with a variety of advanced cancers[Creagan et al.] and a 1985 trial includedpatients with advanced colon cancer[Moertel et al.]. Neither found vitamin Cbeneficial.” However, it was stated by theoriginal investigators (Cameron andPauling) that the two afore-mentionedstudies were not identical to theirs. Fol-lowing this controversy, “rational guide-lines for testing biological agents such asvitamin C have been developed, and newinformation has emerged [ten sources].”

Finally, by way of introduction andwith regard to safety and toxicity, Tamayoand Richardson noted:

“Although data about the effect of highvitamin C concentrations in modifying orenhancing biochemical or molecular func-tion in human tissues is limited, it seemsthat high doses are safe and lack deleteri-ous toxic effects.” Two authors reportedthat very high doses - in excess of 2,000 mg“may result in nausea and diarrhea.”

Tamayo and Richardson summarizedthe findings of the evidence of high dosevitamin C used alone or in combination withchemotherapy in point form. The materialfor the latter is presented in like manner.

The suggested “mechanisms of action forvitamin C ... with conventional chemotherapy”

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based on several studies were as follows:Enhanced cytotoxicity of conventionalchemotherapy [seven sources]Potentiation of chemotherapy ... with vita-min K3 [four sources][Modulation] and potentiation when com-bined with [other vitamins] of cytostaticagents (...) [one source]Increased cisplatin-induced apoptosis [onesource]Reduction of toxicity for select chemo-therapy (...) [three sources][P]revention of adriamycin cardiotoxicityin mice, [one source] and idarubicingenotoxicity and induction of secondarymalignancies [two sources]Reversal of cellular resistance to chemo-therapeutic agents [two sources] in MCF-7breast [one source] and melanoma cells[one source] Many of the above studies areseen elsewhere in this presentation.

Finally, Tamayo and Richardson citedthe 1990 Hoffer and Pauling study usingorthomolecular medicine, which is alsodetailed in this presentation, as appear-ing “to enhance the effectiveness of theconventional treatment [one source].”

To conclude, Tamayo and Richardsonstated: “The value of vitamin C as a can-cer treatment, alone or in combinationwith other nutrients, will only be estab-lished with scientific studies to deter-mine effectiveness, if any, and appropri-ate clinical indications and dosages.” Theauthors continued: Phase I and II stud-ies as well as Phase III investigations arenecessary given the plausible evidencefrom case reports, basic research, and thelimitations of prior Phase III research.The types of clinical studies and mecha-nism of action studies” to be investigatedwas then described.

Review 12, 2003Houston R: Two Anticancer Mecha-

nisms of Vitamins in Humans: A Review.Townsend Letter for Doctors & Patients,2003; June/239: 104-106.

SummaryIn this review Houston noted:“Recent literature explains why vita-

min C has been both successful and unsuc-cessful at extending the life of cancer pa-tients. Vitamin C at 10,000 mg/day waseffective in the form of sodium ascorbatebut not as dry ascorbic acid. The ascorbatesolution oxidizes to dehydroascorbate thatreadily and preferably enters cancer cellsand kills them.” The author continued:“However, Abram Hoffer achieved excel-lent results with ascorbic acid.”

Houston referred to a publication (2001),by a John Boik, which “lists seven traits thatdistinguish cancer.” Also listed were “somenatural compounds [including vitamin C]that are or probably are therapeutic.”

Houston quoted Boik in reference toHoffer and Pauling 1990, described in Hoffer2000: ‘My central thesis is that the most suc-cessful cancer therapies will be those thattarget all of these primary events involved incancer cell survival’.

The author also noted the clinical trialsof Cameron mentioned in Cameron andPauling’s book (1993) and Morishige et al.(1982) in the use of high dose vitamin C. Healso noted studies by Tsao et al. (1988) andAgus et al. (1999) with regard to the sodiumascorbate derivative, dehydroascorbate(DHK), and its activity in cancer cell-killing.“Normal cells can control the intake of vita-min C.” The author also mentioned the criti-cism by Creagan et al. (1979) and Moertel etal. (1985) of the 1976 Cameron and Paulingstudy. Lastly, Houston mentioned the posi-tive review of Lamson and Brignall (2000) ofthe use of vitamin C with chemotherapy. Theauthor reported:

“High-dose vitamin C can become anoxidizer and kill cancer by a free radicalmechanism. Radiation and chemotherapykill cancer by the same mechanism but alsokill normal cells.” Two of the above studiesand the review are presented elsewhere in thispublication.

In summary, Houston stated: “The sin-

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gle, non-randomized clinical test by Hoffer isnot scientific proof.” However he acknowl-edged that patients are concerned with us-ability, safety, contraindication and helpful-ness. He added:

“Hospitals and HMO’s might investigatethe possible savings by vitamin augmenta-tion. The vitamins are exceedingly safe com-pared to standard cancer therapies. The prob-ability of a more comfortable and longer lifeis high. Side effects and costs with vitaminsare low. Vitamins C in the form of oxidizedsodium ascorbate is economical and usefulbut less effective than the Hoffer regimen.”

To conclude Houston stated: “Currentcancer patients can consider using sodiumascorbate solution or Hoffer’s regimen undermedical supervision.”

Neutral Study (Table 3)Study 1, 2002

Lesperance ML, Olivotto IA, Forde N,Zhao Y, Speers C, Foster H, Tsao M,MacPherson N, Hoffer A: Mega-Dose Vita-mins and Minerals in the Treatment ofNon-Metastatic Breast Cancer: An Histori-cal Cohort Study. Breast Cancer Researchand Treatment, 2002; 2372-02: 1-7.

SummaryThis study by Lesperance et al. is de-

scribed as “an observational study” and itadmits that “other unknown factors” mayhave influenced its results. These showedthat high dose vitamin/mineral treatmentin combination with chemotherapy did notprovide a greater rate of survival or a lowerrate of recurrence for a treated group overa controlled group. The authors thereforesuggested “caution” when using high dosevitamin-mineral therapy for breast cancer.

Lesperance et al. described the back-ground to the test as follows: “Subjectswere women with unilateral, non-meta-static breast cancer diagnosed between1989 and 1998 inclusive and referred to theBritish Columbia Cancer Agency-Vancou-ver Island Centre (BCCA-VIC).... The BCAA

maintains a medical database containinginformation for all women diagnosed withbreast cancer in B.C; complete diagnosticand treatment data are recorded from 1989onwards.”

The authors continued: “The vitamin/mineral prescribed patients (cases) were seenby a single physician, not affiliated with theBCAA, who has treated over 900 cancer pa-tients with mega-doses of vitamins and min-erals in Victoria, British Columbia. Officerecords identified 271 patients with breastcancer.... Using the identity number, name,and date of birth, each case was linked to theBCCA medical database, and their recordretrieved.” The 90 most recent of the 271 pa-tients, all of whom were on the vitamin-min-eral treatment, were matched with the BCCApatients.

“The controls were drawn from 2360women ... referred to the BCCA-VIC over thesame time period. The cases were matchedto the controls (2:1)” using various criteria.

The determinants for the selection ofthe 90 patients in the treated group and the180 patients in the controlled group were:

“BCSS, the number of days from diag-nosis to death from breast cancer;” and“DFS, the number of days from diagnosis tosystemic relapse (regional or distant) ordeath from breast cancer.”

The results showed that both the sur-vival and the recurrence rates of the treatedgroup “were worse” than those of the con-trols. Lesperance et al. stated:

“Overall survival at 5 years was 72% (s.e.5%) and 81% (s.e. 3%) for the cases and con-trols, respectively. Ten-year survival was 65%(s.e. 7%) and 76% (s.e. 4%), respectively, forthe vitamin/mineral treated cases and thecontrols.”

The authors explained that the shortersurvival time of the treated group was de-termined after adjustment of certain crite-ria. They recognised that their “observation[contrasted] with an anticipation of survivalenhancements due to mega-doses of vita-mins and minerals” in the Hoffer and

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Pauling 1993 study, seen elsewhere in thispresentation. However, they suggested “cau-tion” when using high dose vitamin/min-eral treatment as an adjunct to chemo-therapy in the treatment of breast cancer.

Their general concern acknowledged:“Some oncologists believe that antioxidantscould interfere with the actions of somechemotherapy agents, however, the scientificdebate on this subject is still ongoing.”

Lesperance et al. stated: “A limitation ofthe study, however, was that the ultimate sam-ple size was not large enough to provide ad-equate power to discern small differences insurvival between the two groups.” They con-tinued: “Our initial working hypothesis wasthat the vitamin/mineral prescribed patientswould display a 25-30% increase [as reportedby Hoffer and Pauling as above] in BCSS andDFS over the controls.” In addition, the au-thors noted that “unknown factors” couldhave accounted for the shorter survival timeand unimproved recurrence of the treatedgroup over the controlled group.

In conclusion, Lesperance et al. stated:“The magnitude of the effects on survivalobserved in this study may be useful infor-mation, especially to groups planning to un-dertake controlled clinical trials of mega-dosevitamin/mineral regimes for the treatment ofbreast cancer. The results suggest that thevitamin/mineral regime prescribed is not acure for breast cancer.”

Negative Study (Table 3)Study 1, 1999

Agus DB, Vera JC, Golde DW: StromalCell Oxidation: A Mechanism by whichTumors obtain Vitamin C. Cancer Research,1999; 59: 4555-4558.

SummaryAgus et al. noted as reported by sev-

eral investigators: “Whereas much isknown about vitamin C and vitamin C de-ficiency states, there is little informationregarding the physiology of the vitamin incancer. Given the well-documented role ofvitamin C in the maintenance of normalimmune processes and host defense, it ispopularly believed that supplemental vita-min C ‘strengthens’ the immune system.Patients with cancer who take vitamin Cgenerally believe that it can enhance im-mune defense against the cancer. Thesenotions give little attention to the nutri-tional needs of the cancer itself. Cancercells readily take up vitamin C in vitro, andstudies have demonstrated high vitamin Cconcentrations in neoplasms comparedwith the adjacent normal tissue. Themechanism by which cancers accumulatevitamin C in vivo, however, is unknown.”

The authors continued: “Certain spe-cialized cells can transport ascorbic aciddirectly through a sodium ascorbatecotransporter, but in most cells, vitamin C

Table 3. Neutral study, negative study, negative reviews.

Neutral StudyLesperance ML, Olivotto IA, Forde N, et al: Breast Canc Res Treatment 2002; 2372-02: 1-7.

Negative StudyAgus DB, Vera JC, Golde DW: Cancer Research 1999; 59: 4555-4558.

Negative ReviewsLabriola D, Livingston R: Oncology 1999; July: 1003-1008.Labriola D: Townsend Lett Doctors Patients 1999; Nov: 120-121.

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enters through the facilitative glucose trans-porters (GLUTs) in the form of dehy-droascorbic acid, which is then reducedintracellularly and retained as ascorbic acid.”

A test observed: “Mice with xenografttumors were injected into the tail vein with[14C]ascorbic acid, [14C]dehydroascorbicacid, or [3H]sucrose and sacrificed 1[minute] after injection. Approximately 4%of the injected dehydroascorbic acid radio-activity (...) was found in the brain of thexenograft groups after 1 [minute], a resultconsistent with our previous work [1997].”These last square brackets are the writer’s- the earlier ones are those of the authorswho continued:

“Injected ascorbic acid and sucroseyielded only trace radioactivity in the brainhomogenate at 1 min, confirming thatascorbic did not readily pass the blood-brain barrier. Sucrose is not metabolized ortransported, and therefore it is used as amarker of plasma volume [according toother investigators]. The xenograft tumorsaccumulated injected dehydroascorbic acidat [various concentrations with different can-cers].” Agus et al. continued: “The results[showed] that the vitamin C accumulated inthe tumors was >86% ascorbic acid in ani-mals injected with dehydroascorbic acid aswell as those injected with ascorbic acid.”

From these results the authors con-cluded: “The involvement of the GLUTs invitamin C uptake by the xenograftedtumors was demonstrated by competitiveinitiation with D-glucose but not L-glucose.Because the malignant cells were not ca-pable of directly transporting ascorbic acid,we reasoned that the ascorbic acid wasoxidized to dehydroascorbic acid in thetumor microenvironment.”

The authors “hypothesized that ascor-bic acid was oxidized in the tumor micro-environment by superoxide anion. To test thisconcept, we coinjected animals bearingxenografts with ascorbic acid and SOD, cata-lase, or saline. The animals receiving SOD andradiolabeled ascorbic acid had an ~50% re-

duction in tumor vitamin C accumulation,whereas there was no change in the tumoraccumulation of vitamin C in animalscoinjected with dehydroascorbic acid andSOD. There was no effect of coadministrationof ascorbic acid and catalase, indicating thatperoxide likely did not play a role in oxidiz-ing ascorbic acid to dehydroascorbic acid.”

The authors also “tested the ability ofthe tumor cells themselves to generatesuperoxide anion.” They argued that: “Be-cause minced xenograft tumors, distinctfrom the cell lines, had a prominent abilityto generate superoxide anion, we concludedthat nonneoplastic cells in the tumorstroma were responsible for the superoxidegeneration.”

Agus and coworkers, as reported byother investigators, confirmed that: “A so-dium ascorbate cotransporter is present inmany organs”, but they did not find any“sodium-dependent ascorbic acid uptakein” the test materials of the present study.They continued: “Thus, the uptake of vita-min C in the form of dehydroascorbic acidthrough the GLUTs appears to be a generalmechanism for vitamin C uptake.” Theyadded that “the sodium ascorbatecotransporter may have a role in vitamin Cuptake of certain tumors.”

Agus and coauthors concluded by re-ferring to studies that dealt with positiveuse of vitamin C in anti-tumor therapy:“The increased intracellular concentrationof vitamin C may have effects on tumorgrowth and the tumor’s ability to respondto oxidative stress associated with chemo-therapy and radiation therapy.” However,they added:

“Although studies evaluating the role ofvitamin C supplementation in cancer pa-tients have generally shown no benefit withrespect to survival or tumor regression [asreported by investigators], it is not knownwhether high concentrations of vitamin Cin human tumors afford the malignant cellswith a metabolic advantage.” As seen in thisbibliography, subsequently published re-

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search have documented the effectivenessof vitamin C treatment with chemotherapy.

In conclusion, Agus and coworkerspointed out: “Our studies show the trans-port of dehydroascorbic acid by GLUTs isa means by which tumors acquire vitaminC and indicate the oxidation of ascorbic acidby superoxide anion produced by cells in thetumor stroma as a mechanism for generat-ing the transportable form of the vitamin.”

Negative Reviews (Table 3)Review 1, 1999

Labriola D, Livingston R: Possible In-teractions between Dietary Antioxidantsand Chemotherapy. Oncology, 1999; July:1003-1008.

SummaryLabriola and Livingston noted: “The

popularity of nonconventional therapies, fora myriad of diseases, has increased dramati-cally. Most patients use some form of al-ternative therapy, often concurrently withconventional treatment and frequentlywithout advising their conventional healthcare provider. Relying on media reports,Internet advertising, and industry market-ing, many patients believe thatnonconventional therapies offer cures forliterally every disease, including cancer; thatthey do not interfere with other treatments;and that they are uniformly free of toxicityat any dosage level” as reported by other in-vestigators.

They continued: “Since many patientstreat themselves with oral antioxidants dur-ing chemotherapy, clinicians need to formu-late a credible position on this subject ifthey are to provide their patients withtimely advice about the potential risks.”

Labriola and Livingston continued:“To date, no definitive human studieshave demonstrated the long-term effectsof combining chemotherapeutic agentsand oral antioxidants. Fortunately, themechanisms of action of both are under-stood well enough to predict the obvious

interactions and to suggest where cautionshould be exercised with respect to bothclinical decisions and study interpreta-tion” as reported by other investigators.

The objective of Labriola and Livingston’sreview was to “describe [the above] potentialinteractions and areas of concern, based onthe available data. It … also [suggested] sev-eral potential courses of action clinicians maytake when patients demonstrate an interestin alternative therapies.”

Labriola and Livingston discussed avail-able information under the following head-ings and sub-headings:

-Cytotoxic Actions of Chemotherapeutic Agents-Actions of Antioxidant Compounds-Predictable Mechanisms of Interaction-Factors that may predict Interactions-Fraction of Drug Effectiveness that de- pends on Reactive Oxygen Species-Nature of the Reactive Oxygen Species generated by the Chemotherapeutic Agent-Dosage and Concentration of Reactive Oxygen Species-Nature of the Antioxidant-Concentration of the Antioxidant-Temporal Relationship between the Antioxidant and Reactive Oxygen Species-Implications for Future Research-Implications for Clinical Practice-Options for the Patient interested in Nonconventional Therapies-Suggested Plan for Adjunctive Non- conventional Treatment-Warning Signs of Possible Interactions

ConclusionsLabriola and Livingston’s review made

no specific reference to vitamin C, except tonote that “[m]ost of the nonconventionaltreatments recommended for use with on-cology patients have antioxidant activity.The most common of these include: vita-mins A (including beta-carotene), B6, C, andE....” They stressed that: “One [of] the ob-jectives of this article is to increaseoncologists’ attention to potential interac-tions by articulating these mechanisms.”

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Review 2, 1999Labriola D: Guest Editorial-Antioxidants

and Chemotherapy: What You Need to KnowBefore Combining Them. Townsend Letter forDoctors & Patients, 1999; Nov: 120-121.

SummaryThis guest editorial responded to the

“considerable attention” which ensued fromthe 1999 Labriola and Livingston negativereview of the use of antioxidants duringchemotherapy.

In this editorial Labriola stated: “It isimportant to note that this paper [as above]does not address efficacy, even though itreferences a number of studies showing thepositive effects of nutritional supplemen-tation during chemotherapy. It does, how-ever, discuss those circumstances when theuse of antioxidants may interfere with thetumor killing actions of some chemothera-peutic agents. It also describes strategiesfor safely using both.”

The author then detailed a case whichinvolved the use of alternative treatments,including antioxidants, with chemotherapyto support his theory, and he referred thereader to a published account of this pa-tient’s case history.

Lastly, Labriola engaged “providersand patients” through questions and an-swers on four of what he called: “The mostcommon questions” asked.

This publication makes no specificmention of vitamin C.Positive Responses (Table 4)Response 1, 2000

Reilly P: Dr. Labriola’s Editorial onAntioxidants and Chemotherapy, TownsendLetter for Doctors & Patients, 2000; Feb/Mar: 90-91.

SummaryThis letter to the editor was a response to

the 1999 Labriola and Livingston article andGuest Editorial of Labriola (1999) as above.Reilly wrote that these publications have “leftmany readers confused and scared.”

He continued: “It is important toclarify that Dr. Labriola’s concern is basedupon a theory which has been shown to beunfounded when actually tested in clinicaltrials. Contrary to their statement, therehave been numerous studies including in-vitro experiments, animal trials and smallhuman trials which have consistentlyshown an enhancement of tumor kill andpatient survival when antioxidants are com-bined with conventional oncology care.”

The author then referred the reader tothree reviews that support the use of anti-oxidants with chemotherapy (Cole et al.1997, Prasad et al. 1999 and Lamson andBrignall 1999). Two of these references ap-pear in this bibliography.

Reilly noted: “Many of the references citedin [Labriola and Livingston 1999] are not evenrelevant to the discussion of combiningchemotherapy and antioxidants, but are re-view articles on the favorable use of antioxi-dants in the prevention of cancer, or generalarticles on the topic of complementarytherapy and its popularity (or totally irrelevantsuch as a discussion of antioxidants in myo-tonic dystrophy). The one reference which didspecifically examine the topic showed an en-hancement of in-vitro and in-vivo antitumoraction of [fluorouracil] and doxorubicin whencombined with antioxidants. The conclusionof the referenced article was ‘chemotherapeu-tic agents administered in the presence ofantioxidants may provide a novel therapy forcolorectal cancer.’ ”

The author described this article underdiscussion as “basically a pharmacology es-say”, and he stated: “Its conclusion is there-fore basically a biochemical theory basedupon other biochemical theories.” He con-tinued: “Frankly I am surprised that the au-thors seem to believe their own conclusionsin the face of a large body of actual clinicalresearch which contradicts them.”

After noting non-negative examples onside effects in Labriola and Livingston 1999,Reilly reported on six positive examples“published in peer reviewed literature that

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support the contention that antioxidantsnot only reduce the side effects of cancertreatments but also enhance tumor kill.”

With reference to vitamin C, the au-thor referred to Prasad et al. 1994, Skimpoet al. 1991 and Kurbacher et al. 1996 whichare reviewed elsewhere in this annotatedbibliography.

The author also noted an article -Hunter et al. 1994 - which described the useof antioxidants with chemotherapy as per-haps being “beneficial”.

Lastly, Reilly stated: “Meta-analysis ofchemotherapy shows it to be curative in afew tumor types, but to have much smallerbenefit in the most common cancers. Ifnutrition can reduce the side effects andperhaps even improve tumor kill, as moststudies suggest, then the cost benefit equa-tion for use of chemotherapy and radiationbegins to favor rational application of thesemodalities in situations where little else isavailable. Nutritional support clearly re-duces side effects of treatment. This ben-efit alone allows many patients to completetreatment who would otherwise discon-tinue due to side effects.”

In conclusion, he stated: “Theory is astarting point for research, but when theevidence contradicts the theory, then wemust recognize the primacy of evidence.The evidence at this point strongly favorsthe use of antioxidants to improve efficacyof treatment, reduce short term side effectsand hopefully reduce the incidence of sec-

ondary cancers caused by the treatment.The primary rule of medicine is first do noharm. [Medical practitioners] must look atthe harm we cause by ignoring data thatdoes not fit our expectations and denyingpatients access to protective factors.”

Reilly ended by stating: “The currentresearch does need to be expanded uponwith larger studies, both in vitro and in vivo.However to ignore the results of over 200studies showing benefit based upon thesame criteria used to judge other medica-tions is irrational. Using the same logic, taxolcould not be approved for use until 20 yearshad passed in order to prove that the initialbenefit was longstanding. The problem withthis logic is that cancer patients don’t have20 years to wait. If 180 articles agree a treat-ment can be beneficial, then we owe it toour patients to begin utilizing it while con-tinuing to support research to further clarifyany potential contraindications.”Response 2, 2000

Gignac MA: Antioxidants and Chemo-therapy: What You need to know beforefollowing Dr. Labriola’s Advice. TownsendLetter for Doctors & Patients, 2000; Feb/Mar: 88-89.

SummaryThis letter to the editor is a second

response to the 1999 Labriola andLivingston article and Guest Editorial ofLabriola (1999) as above. Gignac wrote thatthe former resulted in his “consulting with

1. Reilly P: Townsend Lett Doctors Patients 2000; Feb/Mar: 90-91.2. Gignac MA: Townsend Lett Doctors Patients 2000; Feb/Mar: 88-89.3. Hoffer A: Facts and Factoids: An Information

Sheet for Patients 2003; May: 1-9 http://www.doctor yourself. com/hoffer_factoids.html.

4. Prasad KN, Cole WC, Kumar B, et al: J Am Coll Nutr 2001; 20/5: 450S-463S.

Table 4. Positive responses.

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numerous confused and frightened cancerpatients”.

He continued: “The original article ref-erences 31 papers with no substantive datato support their contention that antioxi-dants interfere with chemotherapy. Whatis worse, this ‘scientific’ paper virtually ig-nores the fact that there are literally hun-dreds of articles (in vitro, in vivo, and hu-man studies) which support the positivebenefits of combination treatments. Inlight of the obvious bias of this article, onecan hardly justify its inclusion in a ‘scien-tific’ journal.”

Gignac stated that Labriola’s “centralpremise is that dietary antioxidants mostlikely undermine the effectiveness ofchemotherapy and that when in doubt, donot use any supplements while on chemo-therapy!”

He continued: “I am growing more andmore perplexed as to why a naturopathicphysician who purports to be a specialistin the treatment of cancer would ever writean article that is so clearly biased and one-sided. This article, and its aftermath, haddone more to harm the patient perceptionof ‘integrated’ oncology care than anythingelse that I can think of. How am I to un-derstand Dr. Labriola’s presumed objectiv-ity when he fails to even mention that wellover 100 scientific articles refute his con-tention that antioxidants interfere withchemotherapeutic effectiveness?”

The author then referred the reader tothe three reviews mentioned in Reilly abovethat support the use of antioxidants withchemotherapy (Prasad et al. 1999, Lamsonand Brignall 1999 and Cole et al. 1997).

Gignac then turned his attention to theGuest Editorial of Labriola (1999), statingthat the editorial was “so full of weak as-sumptions and faulty conclusions” that hewanted “to address them individually.” Thediscussion was in five parts including theexample of the case involving alternativetreatments, among them antioxidants, withchemotherapy.

In conclusion, Gignac stated: “The fu-ture of cancer treatment lies in the properintegration of conventional and comple-mentary treatments. Oncologists shouldnot be complacent about the fact that anestimated 40% of cancer patients die ofmalnutrition. According to Kern [1988]and Ollenschlager [1991], between 40 and80% of all cancer patients have clinicalsigns of malnutrition. Many responsiblephysicians believe that much of the toxic-ity symptoms from chemotherapy are di-rectly exacerbated by systemic nutrientdepletion, secondary to treatment. SomeGerman physicians are now openly recom-mending ‘high-dose supplementation ofessential antioxidants for patients under-going bone marrow transplantation’[Clemens 1989]. Until more research iscompleted, the preponderance of existingdata supports the concurrent use of anti-oxidants with chemotherapy.”

Response 3, 2000Hoffer A: Facts and Factoids: An In-

formation Sheet for Patients, http://www.doctoryourself.com/hoffer_factoids.html, May 2003; 1-9

SummaryIn this article Hoffer described the dif-

ference between a fact and a factoid, andhe also responded to the 1999 Labriola andLivingston review.

With regard to the discussion on factsand factoids the author wrote: “Fact: Some-thing that has really occurred or is the case:hence a datum of experience, as distinct fromconclusions. Loosely defined, something thatis alleged to be, or might be a ‘fact.’ ”

“Factoid: A factoid is a fact that neverexisted before it appeared in print, but hasbeen reprinted ever since. It is trulylaunched if it first appears in a reputablemedical journal like the Journal of theAmerican Medical Association and repub-lished in the New York Times which givesit international stature. A factoid, using

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simple Anglo Saxon terminology, is a lie,and like many lies and misconceptions,once it has been published develops a lifeof its own and is reprinted over and over,from textbook to textbook. The best ex-ample is the lie (factoid) that vitamin Ccauses kidney stones.”

Hoffer then elaborated on facts andfactoids in general and then under theheadings:

Evidence required to establish Facts inClinical Medicine

Evidence required to establish Factoidsin Clinical MedicineIn reference to Labriola and Livingston(1999), Hoffer noted the “rebuttals” by“Reilly, Gignac, and Lamson and Brignall”,but he did not report on the “arguments”.He stated however, that “it was evident thatDr. Labriola was not convinced by thepoints put forward by Reilly and Gignac”and said: “I think the factoid repeated byDr. Labriola would have a much betterchance of becoming a fact if he had con-sidered [certain] points.” These points wereoutlined in five parts thus:

What is the therapeutic value ofchemotherapy without any antioxidants?

The difference between possibility andprobability.

If he had not tried to bolster his argu-ment by referring so frequently to the peerreviewed journal in which his paper ap-peared.

Moss points out that oncologists haveno objection to using xenobiotic antioxi-dants during chemotherapy.

Dr. Labriola emphasizes that long termstudies must be used.

Hoffer stated: “In conclusion, as theproponents of the old paradigm [vitamins-as-prevention] see it, facts are facts onlyafter double blind controlled experimentsconducted by the right investigators fromthe correct school and published in thecorrect medical journals. Factoids can bethought up by anyone and immediatelybecome facts in the profession if the factoid

attacks the evidence against the new para-digm [vitamins-as-treatment].”

He continued: “These factoids arebased upon hypotheses. There is no clini-cal data to support any of them and almostall studies show that they are not true orreal. They are not supported by any stud-ies.” He then listed a number of currentfactoids about megadose vitamin C whichincluded that the vitamin “inhibits chemo-therapy” and “prevented Linus Paulingfrom living longer”.

Finally, Hoffer stated: “The opposite ofa factoid is a fact. The good news is that asnone of [the] factoids [in the list mentionedabove] are true, the opposite is true. Thissummary statement is based upon literallythousands of published papers in medicalliterature and hundreds of books that havebeen published in the past twenty years.”The author said that he could “not providereferences to these numerous clinical stud-ies, but readers of the Journal of Orthomo-lecular Medicine have ready access to thefacts and also to the book reviews of overone hundred of these books. The internetcontains a large number of excellent dis-cussions of vitamins and, of course, thefacts and factoids which are current.”

The author then listed some maladies,conditions and treatments for which vita-min C was used. Under the headings “Al-leged Toxicity”, “Factoid (lies)” and “Fact”,he noted what the factoid claims and whatthe fact is. These included, for the purposeof this bibliography, the use of vitamin Cwith chemotherapy and the factoid that thecombination “Decreases efficacy,” and thefact that it “Increases efficacy.” This list alsoincluded Linus Pauling’s use of vitamin Cas having “Shortened his life”, to whichHoffer remarked: “A ridiculous claim. Hedied age 94, fully mentally alert.”

As an overall conclusion, Hofferstated: “The factoids about vitamins,used in optimum doses when needed, arenot true, are not based upon clinical evi-dence, do not have any studies including

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double blind controlled clinical data tosupport them, and are used primarily toattack the new paradigm, the vitamins-as-treatment paradigm. Be wary offactoids whether they are in print, on theinternet, in the news media, on radio oron television....” The author ended bystating:

“The unfortunate result of these liesis that patients are made fearful, some willstop taking their vitamins, medical costswill increase since patients want to seetheir doctor again to discuss these mat-ters, and more patients will relapse. Theharm done by these factoids is immeas-urable, but fortunately is slowly decreas-ing as the population becomes moreknowledgeable and sophisticated aboutnutrition and nutrients. In the same waythat drug companies are not allowed tomake false therapeutic claims about theirproducts, we need a system which willneutralize the factoids as they are pro-posed. And above all we need the publicmedia to become much more intelligentand less subservient to major papers likethe New York Times.”

Response 4, 2001Prasad KN, Cole WC, Kumar B, Prasad

KC: Scientific Rationale for Using High-Dose Multiple Micronutrients as an Ad-junct to Standard and Experimental Can-cer Therapies. Journal of the American Col-lege of Nutrition, 2001; 20/5: 450S-463S.Summary

This review by Prasad et al. respondedto the negative review of Labriola andLivingston (1999).

Prasad et al. wrote: “Two opposing hy-potheses regarding the use of antioxidants asan adjunct to standard cancer therapy haverecently been proposed. We have suggestedthat high-dose multiple antioxidant supple-ments before and during standard or experi-mental cancer therapy may improve treat-ment efficacy by increasing tumor responseand decreasing toxicity [1999]. An alternative

hypothesis is that antioxidant supplementsshould not be used while treating cancerpatients with standard therapy because theywould protect both normal and cancer cellsagainst free radicals that are produced bymost of the anticancer agents [Labriola andLivingston 1999].”

The authors continued: “These two con-flicting hypotheses can be resolved if the fol-lowing scientific principles are followed: (a) theresults of the effects of low-dose (physiologi-cal range) antioxidants on cells are not ex-trapolated to those obtained with high-dose(pharmacologic, but non-toxic dose range)antioxidants; (b) data on the effects of a sin-gle antioxidant on cells are not extrapolatedto those obtained with multiple antioxidants;(c) results of the effects of antioxidants oncancer cells are not extrapolated to those onnormal cells; (d) data obtained on the effectsof short treatment duration with antioxidantsare not extrapolated to those obtained afterlong treatment duration; (e) all biological ob-servations on the effects of antioxidants oncells are not related to their action of scav-enging free radicals; and (f) all antioxidantsdo not produce similar effects on cells.”

Prasad et al. stated: “The purpose of thisreview [was] to analyze each of the abovescientific principles to demonstrate that cur-rent opinions opposing the use of antioxi-dants as an adjunct to standard cancertherapy have no scientific basis, and thatmicronutrient supplementation, includingantioxidants, under appropriate conditionsmay improve the efficacy of the current man-agement of human tumors.”

In reference to vitamin C or vitamin Cwith other vitamins and chemotherapy, a fewexamples were cited and explanations givenfor the principles (Cameron et al. 1979, Patiaket al. unpublished information and Prasad etal. 1979, 1994, 1999) - the last two referencesalso appear in this bibliography.

Lastly, the authors stated: “Another partof [their] proposed hypothesis is that antioxi-dant vitamins in combination with standardtherapeutic agents may reduce the toxicity of

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these agents on normal cells. Several studiesusing animal models (...) also support thispart of the hypothesis [Prasad et al. 1999].”The authors cited two examples of vitamin Cwhich showed that (1) the vitamin “reducesthe adverse effects of some chemotherapeu-tic agents on normal cells, such as those fromadriamycin [Fujita et al. 1982]”, and (2) vita-mins C+E+A “reduce bleomycin-inducedchromosomal breakage [Trinza et al. 1993].”

In conclusion, Prasad et al. stated: “Sub-stantial laboratory data and limited humanstudies indicate that supplementation withhigh-dose multiple micronutrients, includingappropriate antioxidants (vitamin C, ... ), asan adjunct to standard or experimentaltherapy (...), may improve their efficacy byincreasing tumor response and decreasingtoxicity. Clinical trials on this issue are inprogress. The responses of tumor cells toantioxidants differ from those of normal cells.Antioxidants, in part, have different mecha-nisms of action on tumor cells. In addition,some antioxidants, depending upon doses,can produce a bi-phasic effect on certaintumor cells. Additional mechanistic studieson antioxidants alone and in combinationwith standard tumor therapeutic agents areneeded.”

DiscussionThis annotated bibliography presents

research findings that assess the effective-ness of vitamin C alone, or with other vita-mins, when used during chemotherapy.

The summaries presented lead to thegeneral conclusion that vitamin C can playa safe and positive role in cancer treatmentas an adjunct to chemotherapy. This litera-ture review suggests that the use of vitaminC alone with chemotherapy results in:-an increase in survival time (Hoffer 1996,Meadows et al. 1991, Sarna et al. 1993,Skimpo et al. 1991)-enhancement of chemotherapy (Meadows etal. 1991, Prasad et al. 1994, Sarna et al. 1993)-inhibition of tumor growth (Chiang et al.1994, Meadows et al. 1991)

-a decrease in toxicity (Skimpo et al. 1991)-decreased elevated lipid peroxide (Skimpoet al. 1991)-modulation of genotoxicity of chemo-therapy (Blasiak et al. 2002)-an increase in cell death (Reddy et al. 2001)-When vitamins C and K3 were used withchemotherapy, results showed that the vi-tamin “did not increase the general andorgan toxicity that accompanies cancerchemotherapy” (Taper et al. 1987)-the vitamin treatment “produced a distinctchemotherapy-potentiating effect” for cer-tain drugs (Taper et al. 1987) and “selectivelypotentiated tumor chemotherapy [and] pro-duced sensitization of tumors resistant tosome drugs” (Calderon et al. 2002)-the application resulted “in a synergisticeffect on growth inhibition” (Kurbacher etal. 1996)-the combination was more effective thanthe chemotherapy alone (De Loecker et al.1993)-When vitamin C was given together withother vitamins or during chemotherapy,results showed that the mixture “markedlyenhanced the growth inhibitory effect” ofthe chemotherapy (Prasad et al. 1994)-“reduced growth of melanoma cells byabout 85%” (Prasad et al. 1994)-decreased side effects (Drisko et al. 2003)-increased survival time (Hoffer 1990)-enhanced quality of life (Hoffer 1990)-was “added adjunctively to chemotherapywithout adversely affecting outcome of sur-vival” (Drisko et al. 2003)-that combined treatment with chemo-therapy and vitamins was more effectivethan drug alone (Abdel Rehim et al. 2003)

All but one of the studies and reviewspresented in this bibliography support the useof vitamin C with chemotherapy. One neutralstudy, however, suggests “caution” when usinghigh dose vitamin-mineral therapy for breastcancer. The only negative review warned of“Possible Interactions between Dietary Anti-oxidants and Chemotherapy.” This stimulatedfour responses supporting the use.

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In conclusion, this annotated bibliog-raphy of literature on the effectiveness ofvitamin C alone, or with other vitamins,during chemotherapy confirms the conclu-sions of Prasad and coworkers (1999):

“... antioxidants [including vitamin C]do not protect cancer cells against freeradical and growth-inhibitory effects ofstandard therapy. On the contrary, theyenhance its growth-inhibitory effects ontumor cells, but protect normal cellsagainst its adverse effects.”

AcknowledgementsThis work was supported by a research

grant from the Lotte and John Hecht Me-morial Foundation. The writer is verygrateful to Dr. Harold D. Foster of the De-partment of Geography at the University ofVictoria, British Columbia, for his kindlyoffering the use of his computer and for hisvery valuable assistance, especially his ex-cellent editing of the document. The writershould also like to thank the office staff ofthe Department of Geography for helpfulcomputer assistance, the staff of theGreater Victoria Public Library and theUniversity of Victoria’s library for kindlysecuring interlibrary material and for pro-viding access to other information. Lastly,the writer thanks staff of the SaskatoonPublic Library, Saskatoon Board of Educa-tion and from the following at the Univer-sity of Saskatchewan: Department of Ge-ography, Information Technology, Libraryand Saskatchewan Population Health andEvaluation Research Unit, Inc. for kindlyproviding computer assistance or access.

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