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Differential Effects of Anthracycline Drugs on Rat Heart and Liver Microsomal Reduced Nicotinamide Adenine Dinucleotide Phosphate-dependent Lipid Peroxidation

Laboratory of Medicinal Chemistry and Biology, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20205

Rat liver microsomes have previously been utilized as a model biological system to study the activation of Adriamycin to the semiquinone free radical intermediate and the enhancement by Adriamycin of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidation and oxygen consumption. Incubating rat liver microsomes with Adriamycin or other structurally similar benzanthraquinone anticancer drugs resulted in marked stimulation of NADPH-dependent lipid peroxidation. Carminomycin and 4-demethoxydaunorubicin were considerably more potent than Adriamycin, while daunorubicin, deacetyladriamycin, N-dimethyl-adriamycin, aclacinomycin A, adriamycin 14-nicotinate, and steffimycin were approximately equipotent to Adriamycin in this test system. In contrast, lapachol, anthragallol, alkylaminoanthracenedione, mitomycin C, streptonigrin, 5-iminodaunorubicin, and the Adriamycin:DNA complex potently inhibited microsomal lipid peroxidation. Methotrexate, cyclophosphamide, 5-fluorouracil, nogalamycin, or rubidazone had little or no effect. -Tocopherol-deficient rat heart microsomes but not control heart microsomes were susceptible to increased NADPH-dependent lipid peroxidation (up to 10-fold) when incubated with Adriamycin or other anthracycline analogs which stimulated peroxidation in liver microsomes. The rate of NADPH oxidation in the presence of microsomes was enhanced 4-fold by either Adriamycin or daunorubicin; lapachol, anthragallol, aminoanthracenedione, and 5-iminodaunorubicin at concentrations which inhibited lipid peroxidation had no effect on NADPH oxidation. NADPH:cytochrome P-450 reductase activity was unaltered by those drugs which either stimulated or inhibited peroxidation. These results suggest that although several Adriamycin-like anthracycline drugs dramatically stimulated NADPH-dependent, reactive oxygen-mediated lipid peroxidation in rat liver and heart microsomes, other quinone-containing anticancer drugs do not enhance lipid peroxidation. Interestingly, there appears to be a direct correlation between the ability of certain anthracyclines to stimulate heart or liver microsomal lipid peroxidation and the effects of these drugs in other cardiotoxicity model systems.

¹ To whom requests for reprints should be addressed.

Received 10/19/81. Accepted 6/ 7/82.

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