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Potentiation of Doxorubicin Cytotoxicity by Buthionine Sulfoximine in Multidrug-resistant Human Breast Tumor Cells

Clinical Pharmacology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892

Resistance to antineoplastic drugs is a major problem in the clinical management of cancer. Previous studies have demonstrated that the cytotoxicity of certain anticancer drugs is increased by lowering the glutathione (GSH) levels with buthionine sulfoximine (BSO), a specific inhibitor of -glutamylcysteine synthetase. In this study we report that the resistance to doxorubicin, an anthracycline antibiotic and the most active agent in the treatment of breast cancer, can be partially reversed by exposing MCF-7 doxorubicin-resistant breast tumor cells (MCF-7/ADR^R) to minimally cytotoxic doses of BSO. We found that the BSO treatment (50 µM, 48 h) of MCF-7/ADR^R cells resulted in 80 to 90% depletion in total GSH concentrations. The toxicity of doxorubicin, as determined by growth inhibition and clonogenic assays, was significantly potentiated in the BSO-treated GSH-depleted cells relative to control breast tumor cells, and a dose-modifying factor of 5 to 7 was observed. Since the cytotoxicity of doxorubicin has been associated with its ability to undergo enzymatic activation and to form hydroxyl (^·OH) radicals in this cell line, we also quantitated the ^·OH formation in the BSO-treated and untreated MCF-7/ADR^R cells using electron spin resonance spin-trapping techniques. These results show that doxorubicin stimulated at least 2-fold more ^·OH formation in the tumor cells after GSH levels were decreased by 90%. These results indicate that GSH plays an important role in modulating doxorubicin-induced ^·OH formation via the scavenging of hydrogen peroxide by glutathione peroxidase and thus partially protects MCF-7/ADR^R cells from the cytotoxic effect of doxorubicin.

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

Received 5/ 5/88. Revised 8/16/88. Revised 10/21/88. Accepted 10/27/88.

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