reduction of chronic doxorubicin cardiotoxicity in dogs by ... · doxorubicin cardiotoxicity. the...

[CANCER RESEARCH 41. 3436-3440, September 1981]

Reduction of Chronic Doxorubicin Cardiotoxicity in Dogs by Pretreatmentwith (Â±)-1,2-Bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF-187)

Eugene H. Herman1 and Victor J. Ferrans

Division of Drug Biology, Food and Drug Administration, Washington, D. C. 20204 [E. H. H.], and the Pathology Branch, National Heart, Lung, and Blood InstituteNIH, Bethesda, Maryland 20205 [V. J. F.]

ABSTRACT

Adult beagle dogs were given doxorubicin (1.0 mg/kg bodyweight i.v.) either alone or 30 min after ICRF-187 (NSC169780) (12.5 mg/kg body weight i.p.) at weekly intervals.Control dogs received 0.9% NaCI solution i.v. 30 min afterICRF-187 Â¡.p.(12.5 mg/kg body weight). One week after the

15th injection (300 mg/sq m total dose), the animals weresacrificed. The frequency and extent of cellular lesions weregraded on a scale of 0 to 4 +. Such lesions, consisting mainlyof vacuolization and myofibrillar loss, were noted in the heartsof all six dogs given doxorubicin alone. The lesions were severe(4 + ) in five of these animals and moderate (2 + ) in one. Incontrast, no abnormalities were noted in the hearts of four ofthe six dogs pretreated with ICRF-187 before doxorubicin

administration; the remaining two animals in this group hadminimal alterations (1 +). At the dosage regimen used in thepresent experiments, doxorubicin did not induce lesions inlungs, liver, kidney, diaphragm, small intestine, or skeletalmuscles. Comparable decreases in white blood cell count, redblood cell count, hemoglobin, and serum iron concentrationwere found in animals receiving doxorubicin with or withoutICRF-187. Concurrent administration of ICRF-187 offers a

promising means of reducing the chronic cardiotoxicity induced by doxorubicin.

INTRODUCTION

A major limitation to the effective use of daunorubicin ordoxorubicin is dose-related cardiomyopathy (5, 19, 20). Con

siderable efforts are under way to find a means of reducing therisk of cardiomyopathy while at the same time maintaining thetherapeutic efficacy of these agents. Recent attempts to solvethe problem have involved the use of modified drug scheduling(8, 32, 34), the development of less cardiotoxic analogs (6,11,28), and the administration of agents which would protect themyocardium from daunorubicin or doxorubicin toxicity (14-17,24, 25, 29-31). There is some indication that certain com

pounds can modify daunorubicin or doxorubicin toxicity. Inearlier studies, pretreatment with ICRF-1592 caused a signifi

cant reduction in high-dose daunorubicin toxicity (17). ICRF-

159 also possesses antineoplastic activity (9, 13) and enhances the experimental antitumor activity of daunorubicin(35). ICRF-187, the more water-soluble isomer of ICRF-159,

also reduces the acute toxicity of high doses of daunorubicin(14). Recently, pretreatment with ICRF-187 was found to re-

' To whom requests for reprints should be addressed.2 The abbreviations used are: ICRF-159, (Â±)-1,2-bis(3,5-dioxopiperazinyl-1-

yOpropane; LDH, lactic dehydrogenase; SGOT, serum glutamate-oxalate trans-aminase; CPK. creatine phosphokinase.

Received December 15. 1980; accepted June 3, 1981.

duce cardiac toxicity in rabbits treated chronically at 3-weekintervals with daunorubicin (16). Since doxorubicin is at present much more widely used clinically than is daunorubicin, thepresent studies were undertaken to determine whether pretreatment with ICRF-187 would also protect against chronic

doxorubicin cardiotoxicity. The beagle dogs were selected asthe animal model to study because these animals are largelyfree of the respiratory infections and renal toxicity that arefrequently encountered in chronic studies with rabbits (29, 34).In addition, we have found that the cardiac lesions are moreconsistent in the dog than in the rabbit.

MATERIALS AND METHODS

Fifteen beagle dogs (1 to 1.5 years old) of either sex, weighingbetween 8.2 and 11.5 kg, were divided into 2 groups of 6 animals and1 group of 3 animals. The dogs in Groups 1 (4 male, 2 female) and 2(2 male, 4 female) received weekly i.v. injections of doxorubicin (1.0mg/kg body weight) for a total of 15 weeks. In Group 2, the dogs werepretreated 30 min before doxorubicin administration with ICRF-187

(12.5 mg/kg body weight i.p.). Group 3, composed of 3 dogs (2female, 1 male), received ICRF-187 (12.5 mg/kg i.p.), followed in 30min by an i.v. injection of 0.9% NaCI solution. ICRF-187 and lyophilized

doxorubicin were dissolved in 0.9% NaCI solution just before use andinjected in doses of 10 and 5 mg/ml, respectively. Animals werereturned to their pens, observed daily, and weighed weekly. Bloodsamples for biochemical and hematological analysis were obtainedfrom the jugular vein just before giving the drug and at 3-week intervals

thereafter. The last sample was obtained just before the animals weresacrificed, 1 week after the 15th drug injection. A complete bloodcount and serum determinations of urea nitrogen, creatinine, glucose,total protein, albumin, globulin, total bilirubin, direct bilirubin, totallipids, triglycÃ©rides, uric acid, cholesterol, sodium, potassium, phosphorus, calcium, chloride, serum glutamate-pyruvate transaminase

LDH, alkaline phosphatase, SGOT, and CPK of each sample wereperformed by Met-Path Laboratories, Rockville, Md. A 2-tailed, paired-sample f test statistical analysis was used to determine treatment-

related differences in biochemical and hematological results.One week after the 15th injection (total dose of doxorubicin, 15.0

mg/kg), the animals were killed, and the entire heart and samples ofliver, kidney, small intestine, skeletal muscle, and diaphragm wereexcised from each animal and fixed in 10% neutral formalin. Fourblocks of tissue from each heart, including sections from the leftventricular free wall, anterior and posterior papillary muscles, andventricular septum, were embedded in paraffin and in glycol methac-rylate plastic resin. Sections of plastic-embedded tissues were stainedwith hematoxylin-eosin or with toluidine blue. All other tissues wereembedded in paraffin and stained with hematoxylin-eosin.

The frequency and severity of doxorubicin-induced cardiac lesions

were assessed by light microscopic examination of sections stainedwith toluidine blue. These changes were graded on a scale of 0 to 4+on the basis of the number of muscle cells showing myofibrillar lossand cytoplasmic vacuolization: 0 = no damage; 1 + = involvement ofonly an occasional cell; 4+ = severe involvement of 50% or more

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Doxorubicin Cardiotoxicity

cells, and 2+ and 3+ = intermediate degrees of involvement. Thereported cardiomyopathy score for each animal represents the meanvalue rounded to the nearest whole number for all 4 sections examined.Sections were evaluated without prior knowledge of the pretreatmentgiven to the animals. A x2test was utilized to determine the significance

of differences in the severity of cardiomyopathy scores betweengroups.

RESULTS

General Toxicity and Weight Change. None of the dogsreceiving doxorubicin, the combination of doxorubicin andICRF-187, or ICRF-187 alone died during the 15-week experimental period. Except for alopecia, the 1-mg/kg dose of

doxorubicin had little overt effect on the dogs. By the fifthweek, alopecia was noted around the limbs. As the dosingcontinued, the alopecia spread to the head, trunk, and tail.Similar effects were noted in the dogs given the combination ofICRF-187 and doxorubicin. Animals receiving ICRF-187 alone

did not show this effect.A temporary reduction in food consumption was noted during

the first 24 hr after doxorubicin administration, regardless ofpretreatment with ICRF-187. During the course of the studies,the dogs receiving only ICRF-187 increased in body weight

from 10.5 Â±0.6 (S.E.) to 10.8 Â±0.4 kg; animals receivingdoxorubicin alone lost an average of 1.2 kg (from 9.7 Â±0.8 to8.5 Â±0.6 kg), and those receiving ICRF-187 and doxorubicin

lost an average of 0.4 kg (from 9.7 Â±0.4 to 9.3 Â±0.5 kg). Thedifference in amount of weight change was statistically significant (p < 0.05) only in the group receiving doxorubicin alone.

Gross Anatomic Changes. There were few gross anatomicchanges suggestive of cardiomyopathy in any of the animals.Edema and cardiac enlargement were not apparent. One dox-orubicin-treated dog showed mild right ventricular dilation and

pulmonary congestion.Myocardial Alterations. The cardiac lesions observed in the

present experiments were comparable to those observed previously in doxorubicin-treated humans (3, 5), dogs (12), rabbits

(18, 27), and rats (23, 26). The lesions showed 2 characteristics: cytoplasmic vacuolization and myofibrillar loss. Both ofthese changes involved progressively larger numbers of cellsas the lesions increased in severity. The vacuolization involvedthe formation of multiple clear membrane-limited vacuoles that

filled the cytoplasm of the affected cells and often caused themto appear larger than normal. The myofibrillar loss resulted ina pale but nonvacuolated appearance of the cytoplasm. Bothtypes of change often coexisted in the same cells. Animalsgiven doxorubicin alone showed the most severe cardiac alter

ations; typical examples are shown in Fig. 1. Five of 6 animalsfrom this group had a lesion score of 4+ (Table 1). In contrast,lesions were absent in 4 of the 6 animals given doxorubicin incombination with ICRF-187; a lesion score of 1+ was observedin the other 2 animals in this group. The difference in cardiomyopathy severity scores in the group given doxorubicin aloneand the group given doxorubicin together with ICRF-187 was

highly significant (p < 0.001) (Table 1). An example of themost severe lesions in the animals receiving doxorubicin andICRF-187 is shown in Fig. 2. No cardiac lesions were presentin animals receiving ICRF-187 alone (Fig. 3).

Pathology of Noncardiac Tissues. At the dosage schedulesused, there were no histological lesions in kidney, lung, smallintestine, diaphragm, or skeletal muscle that were attributableto doxorubicin or to ICRF-187. A few scattered inflammatory

cells were noted in the livers of 3 animals given doxorubicinand of 1 animal given ICRF-187.

Clinical Chemistry and Hematological Determinations. Atthe end of the experiment, the serum concentrations of glucose, creatinine, urea nitrogen, bilirubin, total lipids, total protein, triglycÃ©rides, uric acid, cholesterol, sodium, potassium,SGOT, LDH, CPK, and alkaline phosphatase in all groups wereessentially unchanged from the control values obtained at thebeginning of the experiment. The average serum iron concentrations were significantly reduced from base-line control levels

in the groups given doxorubicin alone (198 Â±24 to 124 Â±12/ig/100 ml; p < 0.02) and doxorubicin with ICRF-187 (231 Â±

14 to 113 Â± 10 jug/100 rnl; P < 0.005). The degree ofreduction was comparable in both groups. The serum ironconcentration was unchanged in those animals receiving ICRF-

187 alone (239 Â±14 to 240 Â±33jug/100ml).Compared to control values, the RBC, WBC, and hemoglobin

Table 1Effect of ICRF- ) 8 7 pretreatment on incidence and severity of doxorubicin-

induced chronic cardiomyopathy in dogsAnimals were given ICRF-187 (12.5 mg/kg) or 0.9% NaCI solution i.p. 1 hr

before doxorubicin (1 mg/kg) or NaCI solution i.v. at 15 weekly intervals. Animalswere sacrificed 1 week after the last drug administration.

No. of dogs attaining following cardiomyopathyscore

TreatmentgroupICRF-1

87 controlDoxorubicinICRF-1 87-doxorubicin03

0410

0220

1030 0040

50i183/30/6

6/6b

Where ratios are given, the numerator denotes the number of animals witha cardiomyopathy score of 1 or less, and the denominator denotes the numberof animals examined.

6 Score significantly greater than that of the doxorubicin group by x2 analysis

test(p< 0.001).

Table 2

Mean WBC and RBC, hemoglobin concentration, and hematocrit values before and 1 week after the 15th dosing period

WBC(x103)Treatment

groupICRF-187

DoxorubicinICRF-1 87-doxoru

bicinControl11.8

Â±1.1a12.2 Â±0.9o10.6 Â±l.l"16

wk9.6

Â±1.07.05 Â±0.9C7.6 Â±0.8aRBC

(x10')Control6.63

Â±0.46.89 Â±0.166.88 Â±0.2916

wk6.87

Â±0.375.4 Â±0.1C5.8 Â±0.2eHemoglobin

(g/100ml)Control16.6

Â±1.017.0 Â±0.417.0 Â±0.716

wk17.5

Â±1.013.4 Â±0.4C14.2 Â±0.5eHematocrit

(%)Control48.7

Â±7.849.5 Â±0.949.1 Â±2.016wk51

Â±2.741.0 Â±1.0Â°43.4 Â±1.4d

" Mean Â±S.E. (n = 3).6 Mean Â±S.E. (n - 6).0 Significantly different from control (p < 0.001).d Significantly different from control (p < 0.02)." Significantly different from control (p < 0.01).

SEPTEMBER 1981 3437



E. H. Herman and V. J. Ferrans

concentration were significantly reduced in the groups treatedwith doxorubicin (p < 0.001) and with the combination ofICRF-187 and doxorubicin ( p < 0.02) (Table 2). The hematocrit

also was reduced in both groups, but only in the doxorubicingroup was this decrease significant (p < 0.01). The valuesobtained in the animals treated with ICRF-187 alone remained

essentially unchanged during the course of the experiments.

DISCUSSION

Three methods of reducing anthracycline cardiotoxicity arecurrently under investigation. Dose schedule modification hasbeen attempted with varying degrees of success. The incidenceof cardiac failure was reduced when smaller doses of doxorubicin were given at weekly intervals or over prolonged infusionperiods (8, 21, 32, 34). These schedules result in lower peaklevels of doxorubicin in plasma compared to the every-3-week

schedule (7). The lower levels of doxorubicin to which the heartis exposed appear to be a key feature in reducing the incidenceof congestive heart failure. The clinical effectiveness of smallweekly doses of doxorubicin is still being evaluated. Detailedanatomic evaluation of the cardiac lesions developing in humans after exposure to more frequent, lower doses of doxorubicin has not been reported.

Small weekly doses of doxorubicin produced extensive myo-

cardial alterations in rabbits (34). Similar observations weremade in the present experiments, in which 5 of 6 dogs given15 weekly doses of doxorubicin (1 mg/kg; 300 mg/sq m, totaldose) had evidence of severe cardiomyopathy. The main features of this cardiomyopathy, intracellular vacuolization andmyofibrillar loss, were similar to those caused by doxorubicinin humans and in a variety of animal species (3, 5, 12, 18, 23,26, 27) when doxorubicin was given less frequently but athigher doses (12). These lesions were also similar to thosefound in beagle dogs. In previous studies of doxorubicin-

treated dogs, the most severe damage was reported in the leftventricle and ventricular septum (30). In the present study,these areas were found to have consistently high cardiomyopathy scores. The lesions were scattered diffusely throughoutthe various layers of the myocardium and were not localized inthe vicinity of the coronary vessels as has been reportedpreviously in the rabbit and rat (18, 26, 36). In spite of theseverity of these lesions, all animals in the present studysurvived the entire experimental period; however, in anotherstudy the majority of dogs given the same weekly dose (1 mg/kg) died from cardiotoxicity when the duration of the experiment was extended to 20 weeks (30). Clearly, the cardiotoxiceffects of doxorubicin can occur in spite of different treatmentschedules.

A second approach to overcoming current limitations on theuse of doxorubicin has been to develop less cardiotoxic anthracycline analogs. No analog yet tested with antitumor activity in experimental systems has been totally devoid of cardiactoxicity in the rat or rabbit models (11 ). Analogs of doxorubicinwhich have been used clinically include rubidazone, carmino-mycin, AD 32, aclacinomycin A, quelamycin, 4-epiadriamycin,

and detorubicin (6, 28). These compounds have been examined to various extents, but none has demonstrated a clearadvantage over doxorubicin with regard to both antineoplasticactivity and cardiac toxicity (6, 28).

It has been suggested that the cardiotoxicity of doxorubicin

is mediated through the production of Superoxides or by activation of the anthracyclines to a free radical state (1). Thisfinding led to the observation that lipid peroxidation and acutemyocardial damage induced by anthracyclines in mice, rats,and rabbits could be prevented by pretreatment with the freeradical scavenger vitamin E (22, 23, 33). In chronic studies,comparable protection by vitamin E has not been observed (4,15, 19).

In the present study, pretreatment with ICRF-187 caused a

significant reduction in doxorubicin cardiotoxicity. One important effect was that the hearts of 4 of the 6 dogs pretreatedwith ICRF-187 remained essentially normal despite the 15

weekly injections of doxorubicin. This finding is all the morestriking since the same dose of doxorubicin caused severelesions in 5 of the 6 dogs which were not pretreated with ICRF-187. A second aspect of this protection was noted in thefrequency and extent of the alterations in the remaining 2animals pretreated with ICRF-187. Vacuolization and myofi

brillar loss in these 2 animals occurred only to a minor extent;in fact, these changes were significantly less extensive thanthe mildest lesions seen in any of the animals not pretreatedwith ICRF-187.

A reduction in doxorubicin-induced myocardial cellular injury

would be expected to be accompanied by other signs ofprotection, such as an increase in the tolerated cumulativedose and a decrease in the incidence of cardiac-related deaths.

All animals survived under the conditions of the present experiment, and it is possible that these other effects would havebecome apparent with a longer experimental period.

The most obvious general toxic effect caused by doxorubicinin the dog was alopecia. Pretreatment with ICRF-187 did not

prevent this toxicity. In rats and rabbits, doxorubicin has beenreported to cause toxicity in organs such as the kidney (23,31, 36). With the exception of bone marrow suppression,doxorubicin elicited no alterations in any of the extracardiactissues examined. This observation is supported by the factthat the majority of the results of blood chemical determinationsremained essentially unchanged throughout the duration of theexperiment. Three plasma enzymes (CPK, LDH, and SGOT)which have been used as indicators of cardiac damage werenot altered in the animals showing severe cardiomyopathy.These findings are similar to observations made in other animals receiving doxorubicin (18, 26) and suggest that serumlevels of the 3 enzymes are not reliable indicators of slowlyprogressive cardiac damage such as that elicited by the anthracyclines.

As mentioned above, potentially lethal extracardiac toxicity,such as the bone marrow suppression and the gastrointestinaldamage found in some other studies (12), was not a problemat the dose and duration of treatment used in the presentexperiments. In the hamster, acute single high doses of dau-

norubicin significantly lowered the WBC, and this effect wasgreater in those animals pretreated with ICRF-187 (14). The

additive effect on bone marrow suppression seen when highdoses are used apparently does not occur when the 2 agentsare given chronically at lower doses. Significant depression ofWBC, RBC, and hemoglobin occurred in the dogs with chronicdoxorubicin administration. A similar effect was noted in animals given the combination of ICRF-187 and doxorubicin;

however, in these animals, the magnitude of these changeswas no greater than that observed in dogs receiving doxorub-




Doxorubicin Cardiotoxicity

Â¡einalone. The average serum iron concentrations were reduced to a similar degree in the groups treated with doxorubicinalone and with doxorubicin and ICRF-187. The mechanism of

this reduction is not clear.The mechanism by which ICRF-187 alters the chronic car-

diotoxicity caused by doxorubicin has not been clarified. Theracemic compound ICRF-159 exerts antineoplastic effects by

normalizing the vasculature of developing tumors (22). Bothexperimental and clinical evidence indicates that ICRF-159enhances the effect of ionizing radiation (2). The reduction indoxorubicin cardiotoxicity would seem to be independent ofthese 2 actions. An additional mechanism of action is suggested by the structure of ICRF-187. Since this compound isa nonpolar derivative of EDTA, it could enter myocardial cellsand exert protective effects by functioning as a chelating agentand altering critical concentrations of divalent cations. Thehearts of rabbits treated with doxorubicin have elevated levelsof calcium (27), but it is uncertain whether this increase is acause or a result of the toxicity of doxorubicin. At present,there is little information regarding pharmacokinetic propertiesof ICRF-187, and thus the extent to which either of the com

pounds alters the intracellular concentration of calcium in myocardium has not been determined. Likewise, it is not knownwhether ICRF-187 alters intracellular concentrations of other

cations such as copper and iron. There is evidence that coppercan react directly with the unhydrolyzed ICRF-159 molecule(10). The same sort of reaction between ICRF-187 and iron

could have important implications, particularly if the cardiotoxicaction of doxorubicin is mediated through production of highlyreactive oxygen-containing radicals. Iron and doxorubicin have

recently been shown to form a complex that catalyzes the invitro formation of such radicals (13). An ICRF-187-induced

decrease in iron concentration could conceivably lead to areduction in the formation of hydroxyl radicals in vivo. Thesequestions are currently under investigation.

The reduction in doxorubicin toxicity by ICRF-187 is not

uniform for all tissues. Studies in hamsters showed that pretreatment with ICRF-187 did not ameliorate the bone marrowdepression but did reduce the mortality produced by dauno-rubicin (14). In the present experiments, doxorubicin-induced

bone marrow depression and alopecia were not influenced bypretreatment with ICRF-187. Furthermore, the data availableindicate that pretreatment with ICRF-187 does not interfere

with the antitumor activity of daunorucinin or doxorubicin (35).These factors, together with the potential for significant ICRF-

187 cardioprotection, would seem to provide the basis formore effective use of doxorubicin. In addition, elucidation ofthe nature of the protective effect of ICRF-187 could provide a

critical insight into the pathogenesis of daunorubicin or doxorubicin cardiotoxicity.

ACKNOWLEDGMENTS

The authors acknowledge the valuable technical assistance provided byDonald Gates.

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31. Van Vleet. J. F., Greenwood, L., Ferrans, V. J., and Rebar. A. H. Effect ofselenium-vitamin E on Adriamycin-induced cardiomyopathy in rabbits. Am.J. Vet. Res.. 39. 997-1010. 1978.

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Fig. 1. Histological section of heart of dog treated with 1-mg/kg dose ofdoxorubicin weekly for 15 weeks and sacrificed 1 week after last dose. Widespread vacuolization and loss of myofibrils are evident. This area corresponds toa cardiomyopathy score of 3-t-. One-/im-thick plastic section. Toluidine blue, x

300.Fig. 2. Histological section of heart of dog pretreated with 12.5-mg/kg dose

of ICRF-187 before each of 15 weekly injections of doxorubicin (1 mg/kg) andsacrificed 1 week after last dose. Only minimal changes are present in the field,in the form of one single vacuolated cell. This area corresponds to a cardiomyopathy score of 1 +. One-jim-thick plastic section. Toluidine blue, x 300.

Fig. 3. Normal histology is shown in this section of heart from dog sacrificed1 week after last of 15 weekly injections of ICRF-187 (12.5 mg/kg). This areacorresponds to a cardiomyopathy score of 0. One-fim-thick plastic section.Toluidine blue, x 300.




1981;41:3436-3440. Cancer Res Eugene H. Herman and Victor J. Ferrans (ICRF-187)Pretreatment with (±)-1,2-Bis(3,5-dioxopiperazinyl-1-yl)propane Reduction of Chronic Doxorubicin Cardiotoxicity in Dogs by

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