FREE RADICAL-DEPENDENT DNA LESIONS ARE INVOLVED IN THE DELAYED CARDIOTOXICITY INDUCED BY ADRIAMYCIN IN THE RAT

The role of free radicals in the genesis of adriamycin (ADR)-induced d elayed cardiotoxicity and the cardioprotective effects of the spin tra p N-tert-butyl-alpha-phenylnitrone (PBN) were investigated in an in vi vo rat model. As ADR and free radicals are no longer present in the my ocardium by the time the delayed effects of the drug become apparent, ADR has been proposed to act by causing early radical-dependent DNA le sions, resulting in impaired synthesis of critical target proteins. DN A lesions were detected 10 days after ADR treatment (3X3 mg/kg i.v.) a nd were still present at the time of onset of the delayed cardiomyopat hy. PBN, administered by a slow-release osmotic pump to maintain const ant plasma levels throughout the time of persistence of ADR in the myo cardium (approximately 2 weeks), prevented the development of DNA lesi ons, as well as the late contractile and electrical impairment induced by the anthracycline, thus supporting the hypothesis that free radica ls play a causal role in both phenomena.