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Effect of Buthionine Sulfoximine on Toxicity of Verapamil and Doxorubicin to Multidrug Resistant Cells and to Mice¹

Departments of Internal Medicine and Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510

Resistance of tumor cells to chemotherapeutic drugs may be due to several mechanisms within a single cell line. Resistance to doxorubicin in the human multidrug resistant breast cancer cell line, MCF-7 Adr^R, has been attributed to increased glutathione (GSH) S-transferase and GSH peroxidase activity, as well as to increased expression of the mdr1 gene product, P-glycoprotein. We studied the potentiation of doxorubicin activity in these cells by buthionine sulfoximine (BSO), a specific inhibitor of -glutamylcysteine synthetase, and by verapamil and trans-flupenthixol, agents which interact with P-glycoprotein. Treatment with BSO enhanced the effect of doxorubicin by 1.5-fold, while verapamil or trans-flupenthixol caused a greater reversal of drug resistance. The combination of BSO with trans-flupenthixol produced no further potentiation of doxorubicin activity. However, the combination of BSO with verapamil and doxorubicin caused up to a 10-fold increment in antiproliferative effect. To explore the mechanism by which BSO interacted with this drug combination, we determined whether or not BSO might potentiate the effects of verapamil. These studies demonstrated that the effects of BSO were predominantly due to an increase in verapamil toxicity rather than to doxorubicin toxicity. In addition, when mice received concentrations of BSO in their drinking water sufficient to deplete GSH and were treated with verapamil, the calcium channel blocker was lethal to 9 of 12 mice receiving BSO compared to 1 of 10 control animals receiving verapamil alone. These studies demonstrate that BSO does not markedly increase the pharmacological effect of doxorubicin against MCF-7 Adr^R cells and suggest that alterations in GSH and related enzymes are not a major factor in drug resistance in this cell line. Furthermore, BSO can increase the toxicity of verapamil, a finding which may have important implications for clinical trials.

¹ This work was supported by National Cancer Institute Grant CA43888 and CA08341 and by Grant CH-49507 from the American Cancer Society.

² Present address, Department of Medicine, S-102C, Stanford University Medical Center, Stanford, CA 94305.

³ Burroughs-Wellcome Scholar in Clinical Pharmacology. To whom requests for reprints should be addressed, at Section of Medical Oncology, P.O. Box 3333, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510.

Received 6/29/90. Accepted 10/ 2/90.

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