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. 1984 Oct;117(1):140–153.

Evaluation of free radical effects and catecholamine alterations in adriamycin cardiotoxicity.

J A Jackson, J P Reeves, K H Muntz, D Kruk, R A Prough, J T Willerson, L M Buja
PMCID: PMC1900556  PMID: 6486242

Abstract

With the goal of evaluating the potential roles of free radicals and catecholamines in the pathogenesis of acute and chronic Adriamycin (ADR) cardiotoxicity, evidence was sought for myocardial free radical toxicity and alterations in myocardial catecholamine levels after acute and chronic administration of ADR to rabbits. In acute studies, male New Zealand white rabbits received intravenous ADR, 1.1 or 5 mg/kg per day for 1 or 3 days or 10 mg/kg for 1 day and were sacrificed 3-72 hours later. Because the glutathione-glutathione peroxidase system is a major pathway for free radical detoxification, glutathione levels and glutathione peroxidase activity were measured. In the acute studies, ADR-treated rabbits exhibited significantly increased levels (up to 50%) of total and reduced glutathione, unchanged levels of oxidized glutathione, and a slight decrease in the percentage of oxidized glutathione. Major effects of dose and sacrifice interval were not observed. However, in animals receiving three injections of 5 mg/kg or one injection of 10 mg/kg ADR, myocytes exhibited fine vacuolization, due to lipid accumulation and dilatation of the sarcoplasmic reticulum, without evidence of coagulation necrosis. In the chronic study, rabbits received 1.1 mg/kg ADR twice weekly for up to 10 weeks. Levels of total and reduced glutathione were increased significantly by 23-36% after 9-12 and 16-20 injections without change in the percentage of oxidized glutathione. The mean percentage of myocytes with vacuolar-myofibrillar degeneration, the characteristic lesion of chronic ADR cardiotoxicity, was 0 after 5-7 injections, 3.3 after 9-12 injection, and 17.2 after 16-20 injections. Glutathione peroxidase activity was not reduced significantly in any group of acute or chronic ADR-treated animals. Tests for lipid peroxidation (malondialdehyde and ethane production) were negative in acute studies. Myocardial catecholamine levels were unchanged in acute and chronic ADR animals. Thus, the cardiac glutathione-glutathione peroxidase system is activated with ADR treatment at the onset of cellular damage, and cellular damage progresses without further alteration of this system, loss of glutathione peroxidase activity, or reduction in myocardial catecholamines in rabbit models of ADR cardiotoxicity. These findings suggest that free radical generation in the heart may contribute to ADR cardiotoxicity, but that other factors probably play a more important role in the pathogenesis of the myocardial damage.

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Selected References

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