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

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