Preclinical animal models of cardiac protection from anthracycline-induced cardiotoxicity.

The chronic cardiotoxic effects of anthracyclines were initially detected in clinical trials with daunorubicin and doxorubicin. The clinical importance of anthracycline-induced chronic cardiotoxicity has led to the development of several animal models of this syndrome. Animal species examined in detail as models of this cardiac toxicity include the rabbit, the normotensive and spontaneously hypertensive rat, the mouse, the pig, and the dog. The advantages and disadvantages of these animal models differ according to species: small animals can be used for comparative investigations of anthracycline analogues and/or protectors, which may be available only in limited amounts, while large animals can be used for studies in which evaluation of cardiac function are to be made. Among the various animals examined, the spontaneously hypertensive rat and the beagle dog are considered the most suitable small and large animal models, respectively, because of the reproducibility of the lesions induced by anthracyclines in the two species. A variety of pharmacologic agents has been tested for cardioprotective activity. The most successful of these agents are those that function as antioxidants, because they either scavenge reactive oxygen species or prevent their formation. The most clinically useful of these agents is ICRF-187 (dexrazoxane), which has been found to be cardioprotective in all animal models.