Dexrazoxane prevents doxorubicin‐induced long‐term cardiotoxicity and protects myocardial mitochondria from genetic and functional lesions in rats

Background and purpose: Doxorubicin causes a chronic cardiomyopathy in which reactive oxygen species (ROS) accumulate over time and are associated with genetic and functional lesions of mitochondria. Dexrazoxane is a cardioprotective iron chelator that interferes with ROS production. We aim to analyze the effects of dexrazoxane on mitochondria in the prevention of doxorubicin‐induced chronic myocardial lesions. Experimental approach: Wistar rats (11 weeks of age) were injected with intravenous doxorubicin (0.8 mg kg ‐1 weekly for 7 weeks) with or without simultaneous dexrazoxane (8 mg kg ‐1 ). Animals were killed at 48 weeks. Cardiomyopathy was scored clinically and histologically and cardiac mitochondria were analyzed. Key results: Compared to control rats receiving saline, rats treated with doxorubicin alone developed a clinical, macroscopic, histological and ultrastructural cardiomyopathy with low cytochrome c‐oxidase (COX) activity (26% of controls). The expression of the mtDNA‐encoded COX II subunit was reduced (64% of controls). Myocardia exhibited a high production of ROS (malondialdehyde 338% and superoxide 787% of controls). Mitochondria were depleted of mitochondrial DNA (mtDNA copy number 46% of controls) and contained elevated levels of mtDNA deletions. Dexrazoxane co‐administration prevented all these effects of doxorubicin on mitochondria, except that hearts co‐exposed to doxorubicin and dexrazoxane had a slightly lower mtDNA content (81% of controls) and mtDNA deletions at low frequency. Conclusions and Implications: Dexrazoxane prevented doxorubicin induced late‐onset cardiomyopathy and also protected the cardiac mitochondria from acquired ultrastructural, genetic and functional damage. British Journal of Pharmacology (2007) 151 , 771–778; doi: 10.1038/sj.bjp.0707294