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Adriamycin cardiom yopathy: pathophysiology andprevention

PAWAN K SINGAL, NATASHA ILISKOVIC, TIMAO U , AND DINENDER KUMARInstitute of Cardiovascular Sciences, S t. Boniface General Hospital Research Centre and Departmentof Physiology, Faculty of M edicine, University of Manitoba, W innipeg, Canada

ABSTRACT Current know ledge about adriamycincardiomyopathy indicates that the major cause of th iscondition is increased oxidative stress although thedrugs antitumor action in patients m ay involve otherm echanism s. Controversies about the d ifferent anti-oxidants in preventing cardiomyopathy likely stemfrom the fact that antioxidants must be effective inboth the lip id an d w ater p hases, an d the dose mustbe optim al, in order to be protective. Probucol, anantioxidant an d promoter of endogenous antioxi-dants, is one such agent. Conducting clinical trialsw ith an op tim al dose of probucol is the next step an dshould make th is grea t an tican cer drug safer an dmore efficient in the fight against t he c an ce r. -S in -gal, P . K , iliskovic, N ., L i, T ., Kumar, D . Adriamycincardiomyopathy: pathophysiology and prevention .FASEBJ . 11, 931-936 (1997)

Key Words : o xid ative slress heart failure . antioxidants -p ro b uc ol

DISCOVERY OF ADRIAMYCIN (DOXORUBICIN), an a ntitu -mor antib io tic, in the early 1960s represented a majoradvancement in the fight against cancer, as the drugwas found to be very effectivein a varietyof softandsolid human malignancies (1, 2). This enthusiasmq ui ck ly w a ne d, h ow ev er , w he n it became obvious thata dri amy cin had t he very serious side effect of causingcardiornyopathy leading to congestive heart fa ilure(CHF)2 (3-6). In thisreview,we discusscurrent con-cepts about the pathophysiology of adriamycin car-diomyopathy and different approaches for itsprevention.

During earlyclinicaltrials ith adriam ycin, electro-cardiogram (EKG) modifications including tachycar-dia, ST segment depression, and T wave changesw er e o bs er ve d (7). But ittook a retrospectiveanalysisof 399 patient charts to firm ly establish the occur-rence of CHF due to adriamycin (3). This study alsomade it c lear that CHF was a dose-dependent phe-nomenon. An incidence of >5% was seen at a 501-550 mg/m2 body surface area, increasing to >30%a t o ve r 6 01 mg/rn2 (3).Thus, the dose of 500mg wasc on si de re d t he u pp er l im it in o rd er t o m in im iz e th eri sk of adr iam yci n c ard iom yop ath y and CH F. Su bse -

quent studies showed that cardiornyopathy could oc-cur at a much smaller dose of adriamycin in patientsw ith risk factors such as age, some underlying heartconditions, previous or concurrent radiation therapy(5), and concom itant chemotherapy (8).

More rec ent ly, a lon g-t erm fol low -up s tud y re -vealed that patients who were asymptomatic of car-diac toxicity at the tim e of complete rem ission ofcancer after treatm ent w ith adriamycin showedwithin the next 4 to 20 years an unusually high inci-dence of cardiovascular complications typical of ad-riamycin cardiornyopathy (9). Because of its highantitumor efficacy, adriamycin, despite the risk, hasremained in use. A lthough the use of adriarnycin asa single agent has been restricted, i tf or ms a v al ua bl ecomponent of various regimens of chemotherapy.Th ere for e, th ere i ssti ll ne ed t o f ind w ays t o av oidor minim ize the cardiotoxic side effects of adriamy-cm in the treatment of cancer patients.

One approach ha s been to optimize the way inw hic h th e dr ug isad min ist ere d i n ord er t o re duc e i tspeak concentrations in the plasma. S low infusion ofth e drug over 6-96 h in contrast to a rapid infusionover a few m inutes has significantly decreased the in-cidence of cardiotoxicity (10, 11), but th is approachincreases hospital stay and adds to the cost. Anotherapproach has been to synthesize analogs of adria-m yc in t ha t w ou ld be effectively cytotoxic against can-cer but not cardiotoxic. However, a better analog ofadriamycin w ith the same or improved therapeutici nd ex a nd l es sc ar di ot ox ic it yha s not been found yet(12). A third focus of the research has been to de-velop an effective combination therapy that wouldprevent cardiotoxicity but not in terfere w ith antitu-mo r pro per tie s of adriamycin (13). There has beensome success with the firstwo a pp ro ac he s, b ut t heoccurrence of cardiovascular events has not beenelim inated . Nevertheless, a better understanding oft he e ff ec tsof adriamycin and a clear differentiationo f t he a nt it um or a ct io n f ro m t he c ar di ot ox ic e ff ec ts

Correspondence: St. Boniface General Hospital R esearchCentre, 351 Tache Ave., Room R3022, W innipeg, M anitoba,Canada R2H 2A6.

2Abbrev iations: CHF , congestive heart failure; EKG , electro -card iogram ; HDL, high-density lipopro tein .


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h av e r es ul te d i n g re at er s uc ce ss w it h c om bi na ti ontherapies in subclinicalstudies (13-15).

CUNICAL CHARACTERISTICSThe effects of adriamycin on the cardiovascular sys-tem can be categorized as acute and chronic. Acuteeffects include tachycardia, hypotension, and variousE KG c ha ng es ( 3, 1 6 -1 8) . T he se e ff ec tsu su al ly oc cu rduring or soon after adnamycin administration.However, the acute effects of adriamycin are never ofmaj or c onc ern b eca use th ese are generally reversib lea nd /o r c li ni ca ll ya na ge ab le . C hr on ic e ff ec ts ,n t heother hand, are irreversible cardiomyopathicchanges leading to congestive heart failure w ith graveprognosis (3, 6). Although improvement of de-creased ventricular function can be seen in somecases w ith conventional heart fa ilure therapy, it istem por ary and the se pat ien ts us ual ly go in to he artfailureeven years later (9). Thus, patients generallya re r ef ra ct or y t o c on ve nt io na l t he ra pi es , an d h ea rttransplantation is the only option available. Adria-mycin cardiomyopathy can occur w ithin months orsometim es years after the treatm ent has been com -pleted (3, 9). Typical clin ical characteristics of ad-vanced adriamycin cardiomyopathy are a profounddecrease in blood pressure and markedly elevatedh ea rt r at e, a d ec re as e i n e je ct io n f r ac ti on ,a nd v en -triculardilationwith subsequent failure(3).The car-diomyopathy is also characterized by a specificultrastructural pathology. The main features in car-diac biopsies from patients are cytoplasm ic vacuoli-z at io n d ue t o d il at io no f t he s ar co tu bu le s a nd l os so fmyofibrils (3, 19). The severity of adriamycin-in-duced heart damage can be determ ined by quantifi-cation of these ultrastructural changes according tot he Bi ll in gh am s ca le ( 20 , 2 1) .

ANIMAL MODELA po wer ful too l to s tud y d iff ere nt a spec ts of ad ria -mycin cardiotoxicity and its prevention was madea va il ab leb y t he d ev el op me nt o f d if fe re nt sm al l a ni -mal models (13, 22). Adriamycin-induced cardiacc ha ng es i n r at s cl os el ym im ic s ev er al f ea tu re s o f t hecardiomyopathy seen in humans (23-25). The ratmodel is considered suitable because it emulatess tr uc tu ra la s w el l a s f un ct io na l c ha ng es o bs er ve d i np at ie nt s a nd i sh ig hl y r ep ro du ci bl e ( 24 , 2 6) .

MECHANISMSThe subcellular basis for adriamycin-induced cardio-myopathy as well as its a nt it um or a ct io n w e re e ar li erthought to involve a common pathway. However,

more recently it has become possib le to distinguishthe mechanism s underlying these dual effects of ad-riamycin, as discussed here.Cardiomyopathic changesS eve ral c han ges tha t m ight pl ay a ro le i n th e p ath o-g en es is o f a dr ia my ci n- in du ce d c ar di om yo pa th y h av ebeen described. The listincludes inhibition of nu-cleic acid and protein synthesis (19, 27, 28), re leaseof vasoactive am ine (29); alterations in adrenergicf un ct io n ( 23 ); a bn or ma li ti es i n m it oc ho nd ri a ( 30 );lysosomal changes (26); modifications of sarcolem -mal Ca2 transport (31); attenuations in adenylatecyclase , NaK tATPase, and Ca2-ATPase activities(32); imbalance in myocardial electroly tes (33); for-mation of free radicals (34-36); lip id peroxidation(26, 34, 37) and depletion of non-protein tissue suif-h ydr yl gr oup s (38 -40 ). Ho wev er, mos t of t he studiessupport the view that an increase in oxidative stressevidenced by an increase in free radicals and lip idperoxidation aswellas a decrease in antioxidantsandsuifflydrylgroups plays an important role in thepathogenesis of adriamycin cardiomyopathy (13, 34).

Increased oxidative stress by adriamycin can be ex-plained by its chemical structure, which is very proneto the generation of free radicals. Adriamycin is atetracyclic aglycone to which an amino sugar is at-tached via a glycosidic bond. The quinone ring,w hi ch i sa p ar t o f t he t et ra cy cl in em oi et y, u nd er go esredox cycling between quinone and semiquinone.During this process, e lectrons generated are cap-t ure d by o xi diz ing age nts i ncl udi ng oxy gen , wh icht he n i ni ti at es c ha in r ea ct io n l ea di ng t o t he g en er -ation of free radicalspecies,followed by cardiomyo-cyte injuryand cardiomyopathy (34). D irect supportf or t hi s co nc ep t o f o xi da ti ve s tr es swas provided byt he d ete cti on by el ect ron sp in r eso nan ce spe ctr os-c opy o f adn am ycin-gen erated oxy gen s pec ies ( 41-43). Cytochrome P450 reductase and xanthineo xid ase ha ve a lso be en fou nd to catalyze the reduc-tion of the anthraquinone to a sem iquinone free rad-ical (44, 45). Indirect support was offered by studiesthat found an increase in tissue malondialdehyde,w hi ch i sa p ro du ct o f l ip idp er ox id at io n ( 31 , 3 7) . Ad -riamycin has also been shown to depress different an-tioxidants, thus contributing to increased oxidativestress (15,38). Several review articles (13,34,46) pro-vide the reader w ith more details of adriamycin-in-duced free radical production and lip id peroxidationa s w el l a s d es cr ip ti on s o f a dr ia my ci n- ca us ed s ub ce l-lular changes leading to heart failure.Antitumor actionBecause adriamycin has been shown to produce freeradicals, it was suggested earlier that free radical in-jury might be a mechanism of adriamycin antitumor


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action (47, 48). The formation of free radicals i nbreast cancer c el lsa s w el l a s i n s om e o th er c el lt yp esexposed to high concentrations of adriamycin was es-tablished (48-51). Another important point sup-porting the concept of free radical-m ediatedantitumor action is that adriamycin easily binds w ithiron, forming an adriamycin-iron complex. Adria-mycin bound to iron can also complex with DNA.These complexes can stimulate the production ofpa rti all yr edu ced for ms of ox yge n (5 2-5 4). Th eseradicals are formed in the neighborhood of DNAstrands (52, 53), and free radical-induced DNA dam -age as well as strand breaks are extensively describedin literature (55).

A careful review of the available literature revealsthat relatively high in vitro concentrations of adria-my cin we re us ed t o d emo nst rat e th e f ree ra dic al- me-diated DNA damage in tumor cells (56). Doses usedin in vivo conditions are much lower, suggesting thata free radical mechanism might not be the primaryc au se o f t he a nt it um or a ct iv it yo f a dr ia my ci n. T hi sp oi nt i ss up po rt ed b y a m ul ti tu de o f s tu di es in w hi chthe addition of differentantioxidantssuch asvitaminC (57, 58), superoxide dismutase (58), N-acetylcy-steine (37, 59), glutathione (60), catalase(58), andpro buc ol (1 5) did no t co mpr omi se adr iam yci n cyto-toxicity in a variety of tumor cells.

However, o ther mechanism s explain inhibition ofDNA replication by adriamycin , and thus its cytotox-icity and antitumor action, w ithout the involvementof free radicals.A directintercalationof adriamycinbetween DNA base p ai rs ( 61 ) i nt er fe re sw it h D NAreplication; th is is a cooperative interaction betweenadriamycin and DNA (62). Adriamycin-mediated in-hibition of DNA topoisomerase 11(63) has also beenshown to inhibit DNA replication. Adriamycin-to-p ois ome ras e Il -DN A com ple x pre ven ts r epa iri ng o fthe broken DNA strands (64). A t lower adriamycinconcentrations sim ilar to that observed in clin ical sit-uations, L1210 cells had only DNA topoisomerase II-me dia ted , pro tei n-a sso cia ted st ran d br eak s ( 65) ,whereas w ith increased adriamycin concentrations,c el lsd ie d m ai nl y d ue t o d ir ec ts tr an d b re ak s, n ot th ep ro te in -a ss oc ia te do ne s ( 50 ). T hu s, a dr ia my ci n c anexert an antitumor effect w ithout involving free rad-ical production. Antitumor action at low concentra-tions of adriamycin independent of free radicalmediation has been reconciled with the free radical-mediated cardiotoxic effect of the drug seen athigher cumulative doses in a schem e shown in Fig . 1.ApoptosisProgrammed cell death, or apoptosis, is a phenom -enon that has attracted much attention in recentyears. Adriamycin-induced apoptosis was observed intumor cells (66, 67). A lopecia, or loss of hair due toch emo the rap y, w as s ugg est ed t o b e th e res ult of a d-

Figure 1. D istinction between the cardioto xic and antitu mormechanisms of a ct io n o f a dr iam yc in . It is p roposed that prob-ucolin terup tshefreeradical- media tedathw aya nd p re ve ntscard iotoxic effects of adriam ycin .

riamycin-induced apoptosis of hair follicleells(68).Renal and intestinalepithelialcellsfrom adriamycin-treated spontaneously hypertensive rats showedapoptosis whereas none was observed in cardiomyo-cytes (69).Additional studiesdealing with the possi-ble role of apoptosis in adriamycin cardiotoxicity aren eed ed b efo re rul ing ou t its r ol e i n t he l os so f myo-cardialfunction.

ANTIOXIDANTS AND ADRIAMYCIN INCOMBINATION THERAPY

One of the firstantioxidants testedagainstadriamy-cm cardiomyopathy was v it am in E , w it h v er y encour-aging findings (37). A bolus in jection of vitam in E,24 h before adriamycin injection , prevented the de-velopment of typicalultrastructuralardiomyopathicchanges i n m ic e (37). However, in subsequent years,several conflicting reports appeared with respect tothe efficacy of antioxidants in m itigating the processof cardiomyopathy. These differences may have beendue to the experimental model as well as type an ddose of the antioxidant used.

Further research showed that v it am in E w as c ar di o-protectiveonly against acute cardiotoxicityof adria-mycin, whereas it offered no protection against thedevelopment of chronic cardiomyopathy (70). Ac omb ine d v ita min E/ sel eni um su ppl eme nta tio n als ofailed to reduce adriamycin-induced mortality in


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mice (71) or protect against adriamycin-induced car-diomyopathy in dogs (72). In the follow ing years,m an y d if fe re nt a nt io xi da nt s w e re t es te d wi th l im it edsuccess:ascorbic acid (57), reduced glutath ione (60),se len org ani c com pou nd P Z51 (73), oleanolic and ur-solic acids (74), and ambroxol (75). It appears that ac ar ef ul c ha ra ct er iz at io no f t he a ni ma l m od el a nd a noptim ization of the dose of the drug are of para-mount importance in order to find consistency in theprotective effects of a given antioxidant. Optim iza-tion of the dose of an antioxidant used is convinc-ingly highlighted in a recent study using transgenicm ice in which a 100-fold increase in catalase wasfound to be protective; a 200-fold increase in thesame antioxidant enzyme offered no protection,whereas a 500-fold increase was found to promoteadriamycin toxicity (76).

The most attention has been aroused by the iron-chelating agent ICRF-187 (77, 78). P retreatm ent w ithth is compound significantly reduced the appearanceof adriamycin-induced cardiomyopathy in a dogmodel (79), supporting the pathogenic role of oxi-dative stress. This combination therapy was also in-troduced into clinical practice (80). However,problem s with this combination therapy soon be-came obvious because of the potentiation of adria-mycin haemotoxicity by ICRF-187 (80).P rob ucol: an effective antioxidantProbucol was used in the 1970s and 1980s as a lip id-lowering drug. Its use declined, however, because ofan unfavorable effect on the plasma lip id profiledemonstra ted by a decrease in high-density lipopro-te in (HDL) levels. A t about the same tim e that prob-ucol was determined to be unsuitable forhyperlip idem ic pathologies, its strong antioxidantproperties came to light (81, 82). The chemical struc-ture of probucol resembles vitam in E in that it hastwo phenolic groups; vitam in E has only one and isconsidered to be an important biological antioxi-dant. Our laboratory has tested the beneficial effectsof probucol against adriamycin-induced cardiomy-opathy (14, 15, 83) in an established and reliable an-imal model (24). Combination therapy w ith probucolin one study showed a partial protection (14). How-ever, in a subsequent study, when an optim al dose ofprobucol was used, complete prevention of the de-velopment of adnamycin-induced cardiomyopathywas seen (15). Decrease in endogenous antioxidants,increase i n l ip idp er ox id at io n, h em od yn am ic a nd u l-trastructural changes, and ascites as well as others ign s of he art fai lur ed ue t o ad ria myc in tr eat men twere normalized with probucol adm inistration (15).

P ro bu co l d id n ot a ff ec ta nt it um or p ro pe rt ie s of a d-riamycin, as tested in the tumor-bearing m ice (15).Another important finding was t ha t p ro bu co l a lo neas well as in combination with adriamycin caused an

increase in endogenous antioxidant enzyme activ itiesin the heart (13), m aking it an ideal agent for en-hancing antioxidant defense in the lipid (i.e., in themembranes) as well as water (i.e., in the cytosol) com-partm ents. That adriamycin increased plasma as wellas cardiac lip ids and probucol modulated thesechanges (83) could also indicate a role in keepingthe progression of cardiomyopathy under check.Hence, the success of probucol-adriamycin combi-nation therapy in an animal model justifies urgentclini caltrial sto esta blishits effectin cancer patients.Concerns that discouraged the use of probucol as alip id-lowering agent (its H DL -l ow er in g p ro pe rt y)should not matter in its safe use in cancer patients.Decrease in HDL could be an issue only in thechronic use of probucol, whereas in the proposedprotocol the usage would be for a lim ited tim e. Fur-thermore, the benefit of preventing cardiomyopathyand congestive heart failure definitely outweighs theconsequences of a temporary decrease in plasmaHDL levels of cancer patients. Thus, probucol m aybe unique in being an antioxidant, promotingendogenous antioxidants, lowering plasma lipids,and having no effect on the antitumor efficacy ofadriamycin, making it an ideal drug for adjuncttherapy.

Research cited in this paper was supported by grants fromthe M anitoba Heart and Stroke Foundation. P .K .S . w as sup-ported by the M edical R esearch Council of Canada and N.I.by the Manitoba Health Research Council.

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