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.