January 1, 1995
Ver artículo completoProbucol Protects Against Adriamycin Cardiomyopathy Without Interfering With Its Antitumor Effect
Resultado clave
Probucol completely prevented adriamycin-induced cardiomyopathic changes, normalized left ventricular function, and lowered mortality without interfering with the antitumor properties of adriamycin.
PICO estructurado
Does probucol prevent adriamycin-induced cardiomyopathy without interfering with its antitumor effect in animal models?
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Población
Rats treated with adriamycin and probucol to assess cardiomyopathy, and DBA/2 mice inoculated with lymphoma cells to assess tumor regression.
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Intervención
Probucol (cumulative dose, 120 mg/kg body wt) in 12 equal injections (IP), before and concurrent with adriamycin
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Comparador
Adriamycin alone (cumulative dose, 15 mg/kg body wt in six equal injections IP over 2 weeks)
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Resultado
Cardiomyopathy, congestive heart failure (ascites, congested liver, depressed cardiac function, elevated left ventricular end-diastolic pressure, myocardial cell damage, mortality), and tumor regressionsurrogate
Probucol completely protects against adriamycin-induced cardiomyopathy while preserving its antitumor efficacy in animal models, likely via maintenance of myocardial antioxidant status.
Resumen
BACKGROUND: The usefulness of adriamycin (ADR), a potent antitumor antibiotic, is limited by the development of life-threatening cardiomyopathy and congestive heart failure. Subcellular changes leading to heart failure are suggested to be mediated by a drug-induced increase in free radicals and lipid peroxidation. In an earlier study, concurrent treatment with probucol (PROB), a lipid-lowering drug with strong antioxidant properties, was shown to offer only partial protection against ADR 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 properties 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 treatment, cardiomyopathy and congestive heart failure were characterized by ascites, congested liver, depressed cardiac function, elevated left ventricular end-diastolic pressure, and myocardial cell damage. Myocardial glutathione peroxidase (GSHPx) activity was decreased and lipid peroxidation was increased. Administration of PROB (cumulative dose, 120 mg/kg body wt) in 12 equal injections (IP), before and concurrent with ADR, completely prevented these cardiomyopathic changes, normalized left ventricular function, lowered mortality, and eliminated ascites. Treatment with PROB was also accompanied by an increase in myocardial GSHPx and superoxide dismutase activities with a concomitant decrease in lipid peroxidation. Tumor regression in syngeneic DBA/2 mice inoculated with L5178Y-F9 lymphoma cells in the ADR+PROB group was significant and comparable to the ADR group. CONCLUSIONS: These data show for the first time that PROB can provide complete protection against ADR cardiomyopathy without interfering with antitumor properties of the drug. This protective effect of PROB may be related to the maintenance of the antioxidant status of the heart.