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DNA Interstrand Cross-Link and Free Radical Formation in a Human Multidrug-resistant Cell Line from Mitomycin C and Its Analogues

Clinical Pharmacology Branch [L. D., S. R., H. M. E., B. K. S.] and Laboratory of Molecular Pharmacology [J. M. C.], National Cancer Institute, NIH, Bethesda, Maryland 20892

A subline of the human breast tumor cell line (MCF-7), selected for resistance to Adriamycin and having the multidrug resistance phenotype, also developed significant cross-resistance to mitomycin C and its two analogues, BMY 25282 and BMY 25067. Because mitomycin C and the analogues contain both quinone and aziridine moieties, the mechanism of tumor cell kill is thought to involve alkylation and cross-linking of DNA molecules, hence they are not expected to show cross-resistance to cells selected for resistance to a DNA intercalator. Studies to understand this novel observation show that the resistant MCF-7 cells form significantly less hydroxyl radical and DNA cross-linking in the presence of mitomycin C and BMY 25282 than the sensitive cells. Although BMY 25067 formed less free radicals in the resistant cells, similar to the other two drugs, the formation of DNA cross-links was identical in both cell lines, indicating a somewhat different mechanism of tumor cell kill by this analogue. DNA cross-link formation increased slightly with time in the sensitive cells while there was a small decrease in the resistant cells. This difference in the formation of toxic intermediates appeared to result from enhanced detoxification of reactive species (hydrogen peroxide and alkylating intermediates) as a result of significantly higher glutathione peroxidase (14-fold) and glutathione S-transferase (44-fold) activities in the resistant cell line. These events, i.e., free radical formation and DNA alkylation, showed a good correlation with the cytotoxicity in drug-sensitive cells, indicating that both mechanisms contribute to cell killing of human breast tumor cells.

¹ To whom requests for reprints should be addressed, at Bldg. 10, 6N-119, National Cancer Institute, NIH, Bethesda, MD 20892.

Received 10/20/88. Revised 2/16/89. Revised 7/ 6/89. Accepted 10/31/89.

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