February 19, 1999Open Access
View Full PaperDaunorubicin-Induced Apoptosis in Rat Cardiac Myocytes Is Inhibited by Dexrazoxane
Key Result
Dexrazoxane (10 micromol/L) prevented apoptosis in rat cardiac myocytes induced by daunorubicin (<=1 micromol/L), but not necrosis induced by higher concentrations (>=10 micromol/L).
Structured PICO
Does dexrazoxane prevent daunorubicin-induced apoptosis in rat cardiac myocytes?
P
Population
Primary cultures of neonatal and adult rat ventricular myocytes
I
Intervention
Dexrazoxane (10 micromol/L) or superoxide-dismutase mimetic porphyrin manganese(II/III)tetrakis(1-methyl-4-peridyl)porphyrin (50 micromol/L)
C
Comparator
Daunorubicin alone, or daunorubicin with antioxidants (N-acetylcysteine or the combination of alpha-tocopherol and ascorbic acid)
O
Outcome
Myocyte programmed cell death (apoptosis) within 24 hourssurrogate
Dexrazoxane prevents daunorubicin-induced apoptosis in rat cardiac myocytes, suggesting its clinical utility in limiting anthracycline cardiotoxicity may be mediated by preventing superoxide anion-induced apoptosis.
Abstract
-The clinical efficacy of anthracycline antineoplastic agents is limited by a high incidence of severe and usually irreversible cardiac toxicity, the cause of which remains controversial. In primary cultures of neonatal and adult rat ventricular myocytes, we found that daunorubicin, at concentrations /=10 micromol/L induced necrotic cell death within 24 hours, with no changes characteristic of apoptosis. To determine whether reactive oxygen species play a role in daunorubicin-mediated apoptosis, we monitored the generation of hydrogen peroxide with dichlorofluorescein (DCF). However, daunorubicin (1 micromol/L) did not increase 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 micromol/L), known clinically to limit anthracycline cardiac toxicity, prevented daunorubicin-induced myocyte apoptosis, but not necrosis induced by higher anthracycline concentrations (>/=10 micromol/L). The antiapoptotic action of dexrazoxane was mimicked by the superoxide-dismutase mimetic porphyrin manganese(II/III)tetrakis(1-methyl-4-peridyl)porphyrin (50 micromol/L). The recognition that anthracycline-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 limit the toxicity of these drugs.