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

Br J Pharmacol. 2007 Jul;151(6):771-8. doi: 10.1038/sj.bjp.0707294. Epub 2007 May 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / adverse effects*
  • Cardiomyopathies / chemically induced
  • Cardiomyopathies / physiopathology
  • Cardiomyopathies / prevention & control
  • Cardiovascular Agents / pharmacology
  • Cardiovascular Agents / therapeutic use*
  • DNA, Mitochondrial / drug effects
  • Doxorubicin / adverse effects*
  • Electron Transport Complex IV / drug effects
  • Electron Transport Complex IV / metabolism
  • Energy Metabolism / drug effects
  • Gene Expression
  • Male
  • Malondialdehyde / metabolism
  • Mitochondria, Heart / drug effects*
  • Mitochondria, Heart / genetics
  • Oxidative Phosphorylation / drug effects
  • Rats
  • Rats, Wistar
  • Razoxane / pharmacology
  • Razoxane / therapeutic use*
  • Reactive Oxygen Species / metabolism
  • Superoxides / metabolism


  • Antibiotics, Antineoplastic
  • Cardiovascular Agents
  • DNA, Mitochondrial
  • Reactive Oxygen Species
  • Superoxides
  • Malondialdehyde
  • Razoxane
  • Doxorubicin
  • Electron Transport Complex IV