Protection against doxorubicin-induced cardiotoxicity in weanling rats by dexrazoxane |
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Authors: | Paola Della Torre G Mazué Arturo Podestà Donatella Moneta Umberto Sammartini A R Imondi |
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Institution: | (1) Worldwide Toxicology, Pharmacia & Upjohn, 20014 Nerviano (MI), Italy, IT;(2) Pharmaceutical Product Development Division, Battelle Memorial Institute, 505 King Avenue, Columbus, Ohio 43201-2693, USA Tel.: +1-614-424-7131; Fax: +1-614-424-3716, US |
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Abstract: | Purpose: Dexrazoxane (DZR) protects against anthracycline-induced cardiotoxicity in several laboratory animal species and in patients
with breast cancer. Encouraging results have also been obtained in a limited number of pediatric oncology patients. We conducted
studies to determine the safety and cardioprotective activity of DZR in the doxorubicin (DOX)-treated weanling rat simulating
the rapidly growing immature child. Methods: Male weanling rats and young adult rats, 20␣days old and 7 weeks old, respectively, were given 1 mg/kg DOX i.v., either
alone or with 20 mg/kg DZR, once weekly for 7 weeks. Rats were sacrificed at weeks 8, 12 or 26 following blood collection
for hematology and serum chemistry. Hearts were weighed and examined histologically. Results: DOX, either alone or with DZR, inhibited growth, and body weight remained below that of controls throughout the 26 weeks
of study. There were no biologically significant hematologic changes in either the DOX- or DZR + DOX-treated young rats. DOX
caused a slight increase in liver and kidney weights relative to body weight and a slight increase in serum cholesterol and
triglycerides in the young rats. These effects were ameliorated or delayed by DZR. DOX, either alone or with DZR, caused a
marked atrophy of the testes in the young rats which had recovered by week 26. In the mature rats, DOX caused a significant
decrease in the WBC 1 week after the last treatment, and the WBC was significantly lower in the rats given DZR + DOX compared
to those given DOX alone. There were marked increases in liver and kidney weight, serum cholesterol and triglycerides in the
mature rats given DOX alone but not in those given DZR + DOX. There was also a marked testicular atrophy in the mature rats
given either DOX or DZR + DOX but, unlike that observed in the young rats, this had not returned to normal by week 26. DOX-induced
cardiotoxicity was less severe in the younger rats than in the mature rats but in both age groups, the lesion progressed rapidly
until week 12, 5 weeks after the last dose, and remained relatively stable or progressed slightly thereafter. DZR provided
significant cardioprotection in both age groups at all time points examined. Moreover, in both age groups, the severity of
the cardiomyopathy in the DZR-treated rats was somewhat less at week 26 than it was at week 12. Conclusions: The results indicate that the pharmacologic effects of DZR, including its ability to protect against cardiotoxicity, are
similar in immature and adult male animals treated with DOX.
Received: 3 March 1998 / Accepted: 13 May 1998 |
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Keywords: | Dexrazoxane Doxorubicin Cardiotoxicity |
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