Examination of the potential long-lasting protective effect of ICRF-187 against anthracycline-induced chronic cardiomyopathy

Abstract

Dose-related chronic cardiotoxicity represents a major limitation to the optimal use of anthracyclines such as daunorubicin and doxorubicin (8, 11). A number of attempts have been made to reduce the cardiotoxicity without interfering with the antitumor activity. There is evidence that certain substances alter the extent of anthracycline-induced cardiac toxicity. One of these, ICRF-187 [( +)-1,2-bis(3,5-d’ ioxopiperazinyl1 -yl) propane] has been examined in a number of different animal models of anthracycline cardiac toxicity. Pretreatment with this agent has led to a significant attenuation of chronic anthracyclineinduced cardiomyopathy in rabbits (5), dogs (4) and miniature swine (6). The protective activity demonstrated experimentally is relevant to the clinical situation, as shown by the fact that ICRF-187 has recently been found to exert cardioprotection in patients receiving doxorubicin for treatment of metastatic breast cancer (9). Recent observations have suggested that serious anthracycline-induced myocardial alterations might appear in patients a number of years after cessation of anthracycline therapy (10). Previous studies of ICRF-187 cardioprotection in animals were terminated within 3 weeks after the last anthracycline dosing. Therefore, these studies did not ascertain whether the protective effects ofICRF-187 are long-lasting. The present studies, performed in rabbits treated with daunorubicin, were an initial attempt to address this question. In this investigation, the morphology of the myocardium was compared at 3 weeks and at 3 months after final anthracycline dosing.