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Abstract

Stimulation of mouse heart and liver microsomal lipid peroxidation by anthracycline anticancer drugs: characterization and effects of reactive oxygen scavengers.

E G Mimnaugh, T E Gram and M A Trush
Journal of Pharmacology and Experimental Therapeutics September 1983, 226 (3) 806-816;
E G Mimnaugh
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T E Gram
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M A Trush
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Abstract

The interaction of adriamycin or several other quinone-containing anthracycline anticancer drugs with mouse heart or liver microsomes resulted in greatly enhanced NADPH oxidation and 5- to 10-fold stimulation of NADPH-dependent, reactive oxygen-mediated microsomal lipid peroxidation. Adriamycin, daunorubicin, desacetyladriamycin and aclacinomycin A all stimulated lipid peroxidation maximally when included at concentrations of 100 to 200 microM, whereas carminomycin and 4-demethoxydaunorubicin produced equivalent enhancement of peroxidation at lower concentrations of 30 to 50 microM. Mitomycin C markedly increased heart microsomal lipid peroxidation, but, interestingly, had little effect when liver microsomes were used. In contrast, 5-imino-daunorubicin and alkylaminoanthracenedione inhibited both heart and liver microsomal lipid peroxidation. NADPH supported anthracycline-stimulated lipid peroxidation, however, an NADPH-generating system provided greater activity. NADH was only about 50% as effective as NADPH and served as cofactor with liver microsomes but not with heart microsomes. Scavengers of reactive oxygen such as superoxide dismutase, reduced glutathione and 1,3-dimethylurea diminished the anthracycline-stimulated heart and liver microsomal lipid peroxidation, indicating that superoxide radical and hydroxyl radical participated in the peroxidation reactions. Ethylenediaminetetraacetic acid was also inhibitory, which suggests trace amounts of iron were also required. Adriamycin, 4-demethoxydaunorubicin, carminomycin, aclacinomycin A and mitomycin C strikingly enhanced peroxidation of unsaturated lipids in mouse lung and kidney microsomes, indicating that anthracycline-mediated enhanced reactive oxyradical generation may have toxic consequences in those organs as well as in the heart. These observations support the proposal that anthracycline-accentuated membrane lipid peroxidation may be relevant to the pathogenesis of anthracycline cardiotoxicity.

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Journal of Pharmacology and Experimental Therapeutics
Vol. 226, Issue 3
1 Sep 1983
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Abstract

Stimulation of mouse heart and liver microsomal lipid peroxidation by anthracycline anticancer drugs: characterization and effects of reactive oxygen scavengers.

E G Mimnaugh, T E Gram and M A Trush
Journal of Pharmacology and Experimental Therapeutics September 1, 1983, 226 (3) 806-816;

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Abstract

Stimulation of mouse heart and liver microsomal lipid peroxidation by anthracycline anticancer drugs: characterization and effects of reactive oxygen scavengers.

E G Mimnaugh, T E Gram and M A Trush
Journal of Pharmacology and Experimental Therapeutics September 1, 1983, 226 (3) 806-816;
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