(Circulation. 1995;91:10-15.)
© 1995 American Heart Association, Inc.
Articles |
Probucol Protects Against Adriamycin Cardiomyopathy Without Interfering With Its Antitumor Effect
From the Division of Cardiovascular Sciences (N.S.-I., M.H., P.K.S.), Department of Physiology, and St Boniface General Hospital Research Center; and the Department of Immunology (D.A.C.), Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
Correspondence to Dr P.K. Singal, St Boniface General Hospital Research Center, Rm R3022, 351 Tache Ave, Winnipeg, Manitoba, Canada R2H 2A6.
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 of 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.
Key Words: antioxidants • heart failure
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|
|
|
|
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|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
 An Antidote to Adriamycin Cardiotoxicity? Journal Watch Cardiology, March 1, 1995; 1995(301): 15 - 15. [Full Text]
|
|
|
|
 |
|
 AN ANTIDOTE TO ADRIAMYCIN CARDIOTOXICITY? Journal Watch (General), January 20, 1995; 1995(120): 7 - 7. [Full Text]
|
|