Role of iron in anthracycline cardiotoxicity: new tunes for an old song?

The clinical use of anticancer anthracyclines is limited by the development of a distinctive and life-threatening form of cardiomyopathy upon chronic treatment. Commonly accepted mechanistic hypotheses have assigned a pivotal role to iron, which would act as a catalyst for free radical reactions and oxidative stress. Although perhaps involved in acute aspects of anthracycl ine cardiotoxicity, the role of free radical-based mechanisms in long-term effects has been challenged on both experimental and clinical grounds, and alternative hypotheses independent of iron and free radicals have flourishe d, More recently, studies of the role of C-13 hydroxy metabolites of anthra cyclines have provided new perspectives on the role of iron in the cardioto xicity of these drugs, showing that such metabolites can impair intracellul ar iron handling and homeostasis. The present review applies a multisided a pproach to the critical evaluation of various hypotheses proposed over the last decade for the role of iron in anthracycline-induced cardiotoxicity, T he main goal of the authors is to build a unifying pattern that would both account for hitherto unexplained experimental observations and help design novel and more rational strategies toward a much-needed improvement in the therapeutic index of anthracyclines.