Key result
Dexrazoxane prevents late doxorubicin-induced cardiomyopathy by preserving mitochondrial function.
Why the study?
Does dexrazoxane prevent doxorubicin-induced mitochondrial lesions and chronic cardiomyopathy in a rat model?
Does dexrazoxane prevent doxorubicin-induced mitochondrial lesions and chronic cardiomyopathy in a rat model?
Dexrazoxane prevents late-onset doxorubicin cardiomyopathy in a preclinical model by protecting cardiac mitochondria from ROS-induced genetic and functional damage.
Should not yet alter doxorubicin regimens; leaves open translation of mitochondrial protection to human late-onset cardiomyopathy.
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.
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Lebrecht et al. (2007) studied Doxorubicin-induced chronic cardiomyopathy (n=34). Dexrazoxane vs. Doxorubicin 0.8 mg/kg IV weekly for 7 weeks alone was evaluated on Cardiomyopathy score (p=<0.001). Dexrazoxane co-administration prevented doxorubicin-induced late-onset cardiomyopathy and preserved cardiac mitochondria from genetic and functional damage.
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