Model systems for cardiotoxic effects of anthracyclines.

The use of anthracycline antibiotics in cancer chemotherapy is limited by their cardiotoxic qualities. For the evaluation of new derivatives animal model systems are required. Cardiomyopathy can be induced in rabbits and monkeys, but these models are too expensive for screening purposes. In rats, anthracycline antibiotics cause morphologic lesions of the heart muscle, but these are more difficult to demonstrate than in larger animals. However, significant changes of the heart function (electrocardiogram (ECG), cardiac output), the function of heart mitochondria (inhibition of electron transfer, uncoupling of oxidative phosphorylation and inhibition of Ca translocation) occur in a dose-related manner. Intraventricular conduction defect demonstrated in the ECG is one of the earliest and most consistent expressions of the cardiotoxic properties of anthracyclines. It was therefore used as primary screening parameter. The results of the screening of over 50 new anthracyclines has shown that the cardiotoxic properties vary considerably and that they are not closely related to the chemotherapeutic and the hematotoxic properties. Interesting structure-activity relationships were observed in a series of rubidazone derivatives substituted at the benzhydrazone part of the molecule.