Dexrazoxane in the prevention of doxorubicin-induced cardiotoxicity.
OBJECTIVE
To review doxorubicin-induced cardiotoxicity and to evaluate the use of dexrazoxane in its prevention.


METHODS
All animal and human reports involving doxorubicin-induced cardiac adverse effects were searched using MEDLINE combined with a fan search of relevant papers.


METHODS
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.


RESULTS
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.
Seifert
C F
CF
Clinical Pharmacy Services, Rapid City Regional Hospital, SD 57701.
Nesser
M E
ME
Thompson
D F
DF
D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000517:prevention & control*; D004285:Dogs; D004317:Doxorubicin / Q000633:toxicity*; D004357:Drug Synergism; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D051381:Rats; D011929:Razoxane / Q000009:adverse effects / Q000627:therapeutic use*; D013552:Swine; D013556:Swine, Miniature
D011929:Razoxane; D004317:Doxorubicin