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Cross-Resistance and Glutathione-S-transferase- Levels among Four Human Melanoma Cell Lines Selected for Alkylating Agent Resistance¹

Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115 [Y. W., B. A. T., S. A. H., T. C. S., K. W. R., A. A.], and the Division of Hematology and Medical Oncology, Oregon Health Sciences University, Portland, Oregon 97201 [W. D. H.]

A panel of four cell sublines, each selected for resistance to a different antineoplastic agent, has been developed from a human malignant melanoma cell line G3361. Following repeated exposure to escalating doses of the drug of interest, cloned sublines were developed that are 9-fold resistant to cisplatin (G3361/CP), 11-fold resistant to 4-hydroxyperoxy-cyclophosphamide (4-HC) (G3361/HC), 4-fold resistant to carmustine (BCNU) (G3361/BCNU), and 4-fold resistant to melphalan (G3361/PAM). The cross-resistance of each resistant cell line was determined for cisplatin, BCNU, 4-HC, melphalan, carboplatin, nitrogen mustard, and Adriamycin. In general, the alkylating agent-resistant cell lines were specifically resistant to the drug used for selection with the exception of the G3361/CP line, which was >10-fold resistant to the cisplatin analogue carboplatin, 4-fold resistant to 4-HC, and slightly (1.5-fold) resistant to melphalan, and the G3361/BCNU line, which was slightly (1.8-fold) resistant to melphalan. Collateral sensitivity of the G3361/CP, G3361/PAM, and G3361/4HC lines to killing by BCNU was also observed.

Glutathione-S-transferase activity was elevated in each of the alkylating agent-resistant cell lines by 3- to 5-fold with chlorodinitrobenzene substrate. On Western blotting, the glutathione-S-transferase- (GST-) isoenzyme protein was elevated in the resistant cells by 3- to 5-fold. A complementary DNA (pTS4-10) coding for GST- has been cloned from a gt11 library, sequenced, and used as a probe to determine the relative levels of GST- mRNA in the alkylating agent-resistant cell lines. GST- mRNA levels were elevated (8- to 15-fold) in the resistant cell lines, indicating that the GST- increases were mediated through an increase in mRNA levels.

GST- elevations are a frequent event in cells selected for alkylating agent resistance, and in some cases, of multiple drug resistance. However, the lack of cross-resistance among cell lines selected for resistance to different alkylating agents, all of which have elevated GST- levels, indicates that increased levels of GST- cannot be the predominate mechanism for resistance to the tested drugs in these cell lines.

¹ This work was supported by grants from the Bristol-Myers Co., Wallingford, CT, and by National Cancer Institute Grant 1PO1-CA38493.

² Present address: University of California at San Diego Medical Center, 225 Dickinson St., #811K, San Diego, CA 92103.

³ To whom requests for reprints should be addressed, at the Division of Hematology and Medical Oncology, Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Rd., Portland, OR 97201.

Received 3/16/89. Revised 8/11/89. Accepted 8/18/89.

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