Daunorubicin-induced apoptosis in rat cardiac myocytes is inhibited by dexrazoxane

The clinical efficacy of anthracycline antineoplastic agents is limited by a high incidence of severe and usually irreversible cardiac toxicity, the c ause of which remains controversial. In primary cultures of neonatal and ad ult rat ventricular myocytes, we found that daunorubicin, at concentrations less than or equal to 1 mu mol/L, induced myocyte programmed cell death wi thin 24 hours, as defined by several complementary techniques. In contrast, daunorubicin concentrations greater than or equal to 10 mu mol/L induced n ecrotic cell death within 24 hours, with no changes characteristic of apopt osis. To determine whether reactive oxygen species play a role in daunorubi cin-mediated apoptosis, we monitored the generation of hydrogen peroxide wi th dichlorofluorescein (DCF). However, daunorubicin (1 mu mol/L) did not in crease DCF fluorescence, nor were the antioxidants N-acetylcysteine or the combination of alpha-tocopherol and ascorbic acid able to prevent apoptosis . In contrast, dexrazoxane (10 mu mol/L), known clinically to limit anthrac ycline cardiac toxicity, prevented daunorubicin-induced myocyte apoptosis, but not necrosis induced by higher anthracycline concentrations (greater th an or equal to 10 mu mol/L). The antiapoptotic action of dexrazoxane was mi micked by the superoxide-dismutase mimetic porphyrin manganese(II/III)tetra kis( 1-methyl-4-peridyl)porphyrin (50 mu mol/L). The recognition that anthr acycline-induced cardiac myocyte apoptosis, perhaps mediated by superoxide anion generation, occurs at concentrations well below those that result in myocyte necrosis, may aid in the design of new therapeutic strategies to li mit the toxicity of these drugs.