New Developments in Anthracycline-Induced Cardiotoxicity
Authors: Mordente, A.; Meucci, E.; Silvestrini, A.; Martorana, G. E.; Giardina, B.
Source: Current Medicinal Chemistry, Volume 16, Number 13, May 2009 , pp. 1656-1672(17)
Publisher: Bentham Science Publishers
Abstract:Anthracyclines are among the most effective anticancer drugs ever developed. Unfortunately, their clinical use is severely limited by the development of a progressive dose-dependent cardiomyopathy that irreversibly evolves toward congestive heart failure, usually refractory to conventional therapy. The pathophysiology of anthracycline-induced cardiomyopathy remains controversial and incompletely understood. The current thinking is that anthracyclines are toxic per se but gain further cardiotoxicity after one-electron reduction with ROS overproduction or two-electron reduction with conversion to C-13 alcohol metabolites. ROS overproduction can probably be held responsible for anthracycline acute cardiotoxicity, but not for all the aspects of progressive cardiomyopathy. Intramyocardial formation of secondary alcohol metabolites might play a key role in promoting the progression of cardiotoxicity toward end-stage cardiomyopathy and congestive heart failure.
In this review we also discuss recent developments in: a) the molecular mechanisms underlying anthracycline-induced cardiotoxicity; b) the role of cytosolic NADPH-dependent reductases in anthracycline metabolism; c) the influence of genetic polymorphisms on cardiotoxicity outcome; d) the perspectives on the most promising strategies for limiting or preventing anthracycline-induced cardiotoxicity, focusing on controversial aspects and on recent data regarding analogues of the natural compounds, tumor-targeted formulations and cardioprotective agents.
Document Type: Research Article
Affiliations: Institute of Biochemistry and Clinical Biochemistry, Catholic University School of Medicine, Largo F. Vito 1, 00168 Roma, Italy.
Publication date: May 1, 2009
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