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Differential Oxygen Radical Susceptibility of Adriamycin-sensitive and -resistant MCF-7 Human Breast Tumor Cells

Biochemical Pharmacology Section, Clinical Pharmacology Branch, Clinical Oncology Program, Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20892

Recent evidence supports the concept that Adriamycin cytotoxicity may be mediated by drug semiquinone free radical and oxyradical generation. We tested this hypothesis further by exposing drug-sensitive (WT) and 500-fold Adriamycin-resistant MCF-7 human breast tumor cells (ADR^R) to exogenous superoxide- and hydrogen peroxide-generating systems and subsequently monitored cell proliferation as a measure of cytotoxicity. The ADR^R tumor cells tolerated a 4-fold greater exposure than sensitive cells to superoxide generated by the xanthine/xanthine oxidase system. Likewise, exposure to hydrogen peroxide produced by the action of glucose oxidase on glucose revealed a 4-fold diminished susceptibility of the drug-resistant cells to this reduced form of oxygen. Similar results were obtained by the direct application of hydrogen peroxide to cells. For both cell lines, cytotoxicity was dependent upon the magnitude and the duration of reactive oxygen exposure. When WT and ADR^R cells were cultured under hyperoxia (95% O₂:5% CO₂), in order to stimulate the intracellular production of oxyradicals, proliferation was inhibited to a greater extent in the drug-sensitive cell line. Additionally, hyperoxia potentiated the cytotoxicity of Adriamycin to both sensitive and drug-resistant cells, but the effect depended upon the concentration of the drug. Under hyperoxic conditions, Adriamycin caused oxygen radical-dependent cytotoxicity to the WT tumor cells at clinically relevant drug concentrations as low as 2 to 3 nM. With ADR^R tumor cells, hyperoxia increased the cytotoxicity of Adriamycin at concentrations above 5 M. Paradoxically, both the WT and the ADR^R tumor cells were equally susceptible to the cytotoxic effects of irradiation. It is known that the Adriamycin-resistant MCF-7 cells greatly overexpress glutathione peroxidase and glutathione transferase activities; however, other biochemical defenses against reactive drug intermediates and oxygen radicals have been reported to be similar in the two cell lines. We have reexamined those observations in this report. The resistance of ADR^R breast tumor cells to Adriamycin appears to be associated with a developed tolerance to superoxide, most likely because of a twofold increase in superoxide dismutase activity, and a decreased susceptibility to hydrogen peroxide, most likely because of 12-fold augmented selenium-dependent glutathione peroxidase activity. Acting in concert, these two enzymes would decrease the formation of hydroxyl radical from reduced molecular oxygen intermediates. Taken together, these observations support a role for oxygen radicals in the cytotoxic mechanism of Adriamycin at pharmacological levels of 10 nM and below, and suggest further that the development of resistance to this drug by the MCF-7 WT tumor cells may have a component linked to oxygen free radicals.

¹ To whom requests for reprints should be addressed, at the National Cancer Institute, NIH, Building 10, Room 6N119, Bethesda, MD 20892.

Received 4/21/88. Revised 8/18/88. Accepted 10/ 5/88.

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