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Dexrazoxane prevents doxorubicin-induced long-term cardiotoxicity and protects myocardial mitochondria from genetic and functional lesions in rats.
Br J Pharmacol 2007; 151(6):771-8BJ

Abstract

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.

Authors+Show Affiliations

Department of Rheumatology and Clinical Immunology, Medizinische Universitätsklinik, Freiburg, Germany.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17519947

Citation

Lebrecht, D, et al. "Dexrazoxane Prevents Doxorubicin-induced Long-term Cardiotoxicity and Protects Myocardial Mitochondria From Genetic and Functional Lesions in Rats." British Journal of Pharmacology, vol. 151, no. 6, 2007, pp. 771-8.
Lebrecht D, Geist A, Ketelsen UP, et al. Dexrazoxane prevents doxorubicin-induced long-term cardiotoxicity and protects myocardial mitochondria from genetic and functional lesions in rats. Br J Pharmacol. 2007;151(6):771-8.
Lebrecht, D., Geist, A., Ketelsen, U. P., Haberstroh, J., Setzer, B., & Walker, U. A. (2007). Dexrazoxane prevents doxorubicin-induced long-term cardiotoxicity and protects myocardial mitochondria from genetic and functional lesions in rats. British Journal of Pharmacology, 151(6), pp. 771-8.
Lebrecht D, et al. Dexrazoxane Prevents Doxorubicin-induced Long-term Cardiotoxicity and Protects Myocardial Mitochondria From Genetic and Functional Lesions in Rats. Br J Pharmacol. 2007;151(6):771-8. PubMed PMID: 17519947.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dexrazoxane prevents doxorubicin-induced long-term cardiotoxicity and protects myocardial mitochondria from genetic and functional lesions in rats. AU - Lebrecht,D, AU - Geist,A, AU - Ketelsen,U-P, AU - Haberstroh,J, AU - Setzer,B, AU - Walker,U A, Y1 - 2007/05/21/ PY - 2007/5/24/pubmed PY - 2007/11/6/medline PY - 2007/5/24/entrez SP - 771 EP - 8 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 151 IS - 6 N2 - 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. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/17519947/Dexrazoxane_prevents_doxorubicin_induced_long_term_cardiotoxicity_and_protects_myocardial_mitochondria_from_genetic_and_functional_lesions_in_rats_ L2 - https://doi.org/10.1038/sj.bjp.0707294 DB - PRIME DP - Unbound Medicine ER -