Role of Secondary Alcohol Metabolites in Anthracycline Cardiotoxicity: from Hypotheses to New Drugs

Abstract

The clinical use of doxorubicin and other anticancer anthracyclines is limited by the possible development of a life-threatening form of cardiomyopathy. Here, we briefly review biochemical and pharmacological studies that identify secondary alcohol metabolites as important mediators of cardiotoxicity induced by anthracyclines. The pharmacokinetics and pharmacodynamics of secondary alcohol metabolites suggest that they might cause cardiotoxicity while not mediating or actually diminishing the antitumour potency of anthracyclines. This concept implies that novel anthracyclines forming fewer amounts of their secondary alcohol metabolites might prove to spare the vulnerable cardiomyocytes while also retaining good activity in cancer cells, thus offering advantages over currently available anthracyclines in terms of therapeutic index. MEN 10755 (sabarubicin) is a newly designed disaccharide anthracycline that fits well in this context: it forms less alcohol metabolite than doxorubicin, and consistently induces less cardiac toxicity in laboratory animals in the face of an equal or even improved spectrum of activity in human tumour xenografts. On the basis of these preclinical findings, MEN 10755 has entered clinical trials, which will define its activity and safety and will serve an opportunity to probe the "secondary alcohol metabolite hypothesis" of cardiotoxicity. Keywords: anthracyclines, cardiotoxicity, secondary alcohol metabolites, iron, men, drug discovery