New Developments in Anthracycline-Induced Cardiotoxicity

Author(s): A. Mordente , E. Meucci , A. Silvestrini , G. E. Martorana , B. Giardina .

Journal Name: Current Medicinal Chemistry

Volume 16 , Issue 13 , 2009

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.

Keywords: Anthracycline, secondary alcohol metabolites, cardiotoxicity, aldo-keto reductases, carbonyl reductases, genetic polymorphisms

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Article Details

VOLUME: 16
ISSUE: 13
Year: 2009
Page: [1656 - 1672]
Pages: 17
DOI: 10.2174/092986709788186228
Price: $58

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