Inhibition of Doxorubicin Chronic Toxicity in Catalase-Overexpressing Transgenic Mouse Hearts

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• 作者：Y. James Kang ; Xiuhua Sun ; Yan Chen ; and Zhanxiang Zhou
• 刊名：Chemical Research in Toxicology
• 出版年：2002
• 出版时间：January 2002
• 年：2002
• 卷：15
• 期：1
• 页码：1 - 6
• 全文大小：335K
• 年卷期：v.15,no.1(January 2002)
• ISSN：1520-5010

文摘

Catalase is an important antioxidant enzyme, which has been shown to provide cardiacprotection from acute toxicity induced by doxorubicin, a most effective anticancer agent. Becausecumulative dose-dependent chronic cardiomyopathy due to a long-term administration ofdoxorubicin is a significant clinical problem, the present study was undertaken to test thehypothesis that catalase also provides protection against doxorubicin chronic cardiotoxicity.Transgenic mice containing cardiac catalase activities of 15-, 60-, or 100-fold higher than normaland nontransgenic controls were treated with doxorubicin in a cumulative dose of 45 mg/kg infive equal iv injections (9 mg/kg every other week) over a period of 10 weeks. On the secondday after the last injection, the mice were sacrificed for analysis of cardiotoxicity. As comparedto nontransgenic controls, doxorubicin-reduced body weight gain was significantly inhibitedin the transgenic mice. There were 15% mortality in nontransgenic mice, but no mortalitywas observed in transgenic mice during the course of treatment. Light microscopic examinationrevealed that doxorubicin-induced myocardial morphological changes were markedly suppressedin the transgenic mice in an activity-dependent fashion. Under electron microscopy, extensivesarcoplasmic vacuolization and severe disruption of mitochondrial fine structure were observedin nontransgenic cardiomyocytes, but all markedly suppressed in the transgenic mice. Theresults indicate that catalase elevation in the heart prevents doxorubicin chronic cardiomyopathy.