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Sensitization of Human Melanoma Cells to the Cytotoxic Effect of Melphalan by the Glutathione Transferase Inhibitor Ethacrynic Acid¹

Department of General Oncology, Radiumhemmet, Karolinska Hospital, S-104 01 Stockholm [J. H., U. J., U. R.], and Department of Biochemistry, University of Uppsala, Biomedical Center, P.O. Box 576, S-751 23 Uppsala [K. B., V. M. C., B. M.], Sweden

Glutathione transferases are enzymes implied in the resistance of tumor cells to bifunctional alkylating cytostatic drugs. We have investigated the effect of the glutathione transferase inhibitor by ethacrynic acid on the cytotoxicity of melphalan to a human melanoma cell line (RPMI 8322) with a high level of glutathione transferase activity. Using 1-chloro-2,4-dinitrobenzene as substrate, ethacrynic acid was shown to inhibit the activity of purified human glutathione transferases, with 50% inhibition values of 1, 10, and 15 µM for transferase µ (class mu), transferase (class alpha) and transferase (class pi), respectively, all of which occur in RPMI 8322 cells. Ethacrynic acid at a concentration of 20 µM, which by itself was noncytotoxic, increased the cytotoxicity of melphalan to RPMI 8322 human melanoma cells approximately 2-fold. The induction of DNA interstrand cross-links by 40 µM melphalan was increased 1.4-fold by 30 µM ethacrynic acid. These results indicate that a potentiation of the cytotoxic effect of bifunctional alkylating agents can be achieved by inhibition of glutathione transferases and that the enhanced cytotoxicity may be caused at least in part by increased formation of drug-DNA adducts.

¹ This investigation was supported by grants from the Swedish Cancer Society and the Gustav V Jubilee Fund (to J. H., B. M., and U. R.), and the Swedish Natural Science Research Council (to B. M.).

² To whom requests for reprints should be addressed.

Received 7/25/90. Accepted 10/ 3/90.

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