An introduction to the metabolic determinants of anthracycline cardiotoxicity

Antitumor therapy with doxorubicin and other anthracyclines is limited by the possible development of cardiomyopathy upon chronic administration. Several lines of evidence suggest that a close link exists between cardiotoxicity and the amount of anthracycline that accumulates in the heart and then undergoes one- or two- electron reduction to toxic metabolites or by-products. Alternative metabolic pathways lead to an oxidative degradation of anthracyclines, possibly counteracting anthracycline accumulation and reductive bioactivation; unfortunately, however, the actual role of anthracycline oxidation is only partially characterized. Here, we briefly review the biochemical foundations of reductive versus oxidative anthracycline metabolism. We show that multiple links exist between one pathway of toxic biactivation and another, limiting the search and clinical development of "better anthracyclines" that retain antitumor activity but induce less cardiotoxicity than the available analogues.