DEXRAZOXANE IN THE PREVENTION OF DOXORUBICIN-INDUCED CARDIOTOXICITY

OBJECTIVE: To review doxorubicin-induced cardiotoxicity and to evaluat e the use of dexrazoxane in its prevention. DATA SOURCES: All animal a nd human reports involving doxorubicin-induced cardiac adverse effects were searched using MEDLINE combined with a fan search of relevant pa pers. DATA EXTRACTION: Animal, in vitro cellular, and human data are t horoughly reviewed with particular emphasis on doxorubicin-induced car diotoxicity, including clinical manifestations, risk factors, and mech anisms of toxicity. The role of dexrazoxane in the prevention of doxor ubicin-induced cardiotoxicity is reviewed, including mechanism of effe ct, animal data, and human trials. DATA SYNTHESIS: Anthracyclines are associated with a cumulative, dose-dependent, irreversible cardiomyopa thy 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/m(2). Through its semiquinone metabolite, doxorubicin appears to generate superoxide anion and superhydroxide free radicals with iro n as a cofactor. Because of poor myocardial concentrations of superoxi de dismutase, catalase, and glutathione peroxidase, these free radical s cause extensive lipid peroxidation and mitochondrial destruction. CO NCLUSIONS: Dexrazoxane is hydrolyzed to its active form intracellularl y and binds iron to prevent the formation of superhydroxide radicals, thus preventing mitochondrial destruction. The effect of dexrazoxane o n the prevention of doxorubicin-induced cardiotoxicity is impressive i n both animal and human studies. Further research is needed to clearly demonstrate the effect dexrazoxane has on the antitumor effects of co mbination chemotherapy while defining optimal dosing strategies to min imize myelosuppression and maximize cardioprotection.