DOXORUBICIN CARDIOTOXICITY - ANALYSIS OF PREVAILING HYPOTHESES

被引:605
作者
OLSON, RD
MUSHLIN, PS
机构
[1] UNIV WASHINGTON,DEPT MED,SEATTLE,WA 98195
[2] HARVARD UNIV,BRIGHAM & WOMENS HOSP,SCH MED,DEPT ANESTHESIA,BOSTON,MA 02115
关键词
Anthracyclines; Cardiotoxicity; Daunorubicin; Doxorubicin; Free radicals; Metabolites Calcium;
D O I
10.1096/fasebj.4.13.2210154
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Anthracyclines, such as doxorubicin and daunorubicin, are highly effective anticancer agents that produce a well-described but incompletely understood cardiac toxicity. According to a popular hypothesis, anthracyclines injure the heart by generating oxygen-centered free radicals. This free radical hypothesis, however, appears to be inconsistent with many observations, such as the frequent failure of anthracyclines at cardiotoxic doses to produce evidence of increased free radical generation. Other explanations of cardiotoxicity involve platelet-activating factor, prostaglandins, histamine, calcium, and C-13 hydroxy anthracycline metabolites. These C-13 hydroxy metabolites, on the basis of in vitro data, are considerably more potent than parent compounds as myocardial depressants and as inhibitors of ATPases of sarcoplasmic reticulum, mitochondria, and sarcolemma. Further studies will be required to determine whether metabolites or the other putative injurious agents discussed contribute substantially to the cardiomyopathy of anthracycline therapy. The hypotheses presented in this paper should provide a useful framework for subsequent investigations into the mechanisms of anthracycline cardiotoxicity.
引用
收藏
页码:3076 / 3086
页数:11
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