alexa Dexrazoxane in the prevention of doxorubicin-induced cardiotoxicity.


Biochemistry & Physiology: Open Access

Author(s): Seifert CF, Nesser ME, Thompson DF

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Abstract OBJECTIVE: To review doxorubicin-induced cardiotoxicity and to evaluate the use of dexrazoxane in its prevention. DATA SOURCES: All animal and human reports involving doxorubicin-induced cardiac adverse effects were searched using MEDLINE combined with a fan search of relevant papers. DATA EXTRACTION: Animal, in vitro cellular, and human data are thoroughly reviewed with particular emphasis on doxorubicin-induced cardiotoxicity, including clinical manifestations, risk factors, and mechanisms of toxicity. The role of dexrazoxane in the prevention of doxorubicin-induced cardiotoxicity is reviewed, including mechanism of effect, animal data, and human trials. DATA SYNTHESIS: Anthracyclines are associated with a cumulative, dose-dependent, irreversible cardiomyopathy that can lead to congestive heart failure and death. The incidence of cardiotoxicity rises sharply at a total lifetime dose of more than 550 mg/m2. Through its semiquinone metabolite, doxorubicin appears to generate superoxide anion and superhydroxide free radicals with iron as a cofactor. Because of poor myocardial concentrations of superoxide dismutase, catalase, and glutathione peroxidase, these free radicals cause extensive lipid peroxidation and mitochondrial destruction. CONCLUSIONS: Dexrazoxane is hydrolyzed to its active form intracellularly and binds iron to prevent the formation of superhydroxide radicals, thus preventing mitochondrial destruction. The effect of dexrazoxane on the prevention of doxorubicin-induced cardiotoxicity is impressive in both animal and human studies. Further research is needed to clearly demonstrate the effect dexrazoxane has on the antitumor effects of combination chemotherapy while defining optimal dosing strategies to minimize myelosuppression and maximize cardioprotection.
This article was published in Ann Pharmacother and referenced in Biochemistry & Physiology: Open Access

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