title: Dexrazoxane prevents doxorubicin-induced long-term cardiotoxicity and protects myocardial mitochondria from genetic and functional lesions in rats.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  Dexrazoxane prevented doxorubicin induced late-onset cardiomyopathy and also protected the cardiac mitochondria from acquired ultrastructural, genetic and functional damage.
authors.affiliation: Department of Rheumatology and Clinical Immunology, Medizinische Universitätsklinik, Freiburg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Lebrecht
authors.forename: A
authors.initials: A
authors.lastname: Geist
authors.forename: U-P
authors.initials: UP
authors.lastname: Ketelsen
authors.forename: J
authors.initials: J
authors.lastname: Haberstroh
authors.forename: B
authors.initials: B
authors.lastname: Setzer
authors.forename: U A
authors.initials: UA
authors.lastname: Walker
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D009202:Cardiomyopathies / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D002317:Cardiovascular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004272:DNA, Mitochondrial / Q000187:drug effects; D004317:Doxorubicin / Q000009:adverse effects*; D003576:Electron Transport Complex IV / Q000187:drug effects / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D015870:Gene Expression; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000235:genetics; D010085:Oxidative Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011929:Razoxane / Q000494:pharmacology / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D002317:Cardiovascular Agents; D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D013481:Superoxides; D008315:Malondialdehyde; D011929:Razoxane; D004317:Doxorubicin; D003576:Electron Transport Complex IV