PROBUCOL PROTECTS AGAINST ADRIAMYCIN CARDIOMYOPATHY WITHOUT INTERFERING WITH ITS ANTITUMOR EFFECT

Background The usefulness of adriamycin (ADR), a potent antitumor anti biotic, is limited by the development of life-threatening cardiomyopat hy and congestive heart failure. Subcellular changes leading to heart failure are suggested to be mediated by a drug-induced increase in fre e radicals and lipid peroxidation. In an earlier study, concurrent tre atment with probucol (PROB), a lipid-lowering drug with strong antioxi dant properties, was shown to offer only partial protection against AD R cardiomyopathy. The present study had two aims: to determine whether this protective effect can be improved further by extended treatment with PROB, and to determine whether PROB affects the antitumor propert ies of ADR. Methods and Results ADR (cumulative dose, 15 mg/kg body wt ) was administered in rats in six equal injections (IP) over a period of 2 weeks. Three weeks after the end of treatment, cardiomyopathy and congestive heart failure were characterized by ascites, congested liv er, depressed cardiac function, elevated left ventricular end-diastoli c pressure, and myocardial cell damage. Myocardial glutathione peroxid ase (GSHPx) activity was decreased and lipid peroxidation was increase d. Administration of PROB (cumulative dose, 120 mg/kg body wt) in 12 e qual injections (IP), before and concurrent with ADR, completely preve nted these cardiomyopathic changes, normalized left ventricular functi on, lowered mortality, and eliminated ascites. Treatment with PROB was also accompanied by an increase in myocardial GSHPx and superoxide di smutase activities with a concomitant decrease in lipid peroxidation. Tumor regression in syngeneic DBA/2 mice inoculated with L5178Y-F9 lym phoma cells in the ADR+PROB group was significant and comparable to th e ADR group. Conclusions These data show for the first time that PROB can provide complete protection against ADR cardiomyopathy without int erfering with antitumor properties of the drug. This protective effect of PROB may be related to the maintenance of the antioxidant status o f the heart.