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Expression of the c-Ha-ras Oncogene in Mouse NIH 3T3 Cells Induces Resistance to Cisplatin¹

Department of Medicine and the Cancer Center, University of California, San Diego, La Jolla, California 92093 [S. I., D. K. H., F. B. T., S. C. M., P. A. A., S. B. H.]; Department of Pharmacology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15261 [A. B., J. S. L.]; and Department of Pharmacology, Dartmouth Medicine School, Hanover, New Hampshire 03756 [A. E.]

The effect of expression of the c-Ha-ras oncogene on cisplatin (DDP) sensitivity was examined in murine NIH 3T3 cells transfected with the dexamethasone (DEX)-inducible mouse mammary tumor virus promoter linked to an activated c-Ha-ras gene [LTR H-ras(A) cells]. Treatment of these cells with 5 µM DEX for 24 h induced c-Ha-ras expression and produced an 8.2 ± 1.3-fold (SD) increase in DDP resistance as quantitated by clonogenic assay. Induction of the c-Ha-ras oncogene reduced DDP accumulation by 40% and intrastrand adduct formation by 17%. In nontransfected wild-type NIH 3T3 cells, DEX did not induce DDP resistance nor did it decrease DDP accumulation. Induction of c-Ha-ras expression did not alter cellular glutathione content or the activity of glutathione-S-transferase in the LTR H-ras(A) cells. DEX increased cellular metallothionein content by 1.6-fold in NIH 3T3 cells and 3.3-fold in LTR H-ras(A) cells. We conclude that DEX-induced overexpression of a mutant c-Ha-ras gene confers DDP resistance and that this resistance is associated with an impairment of cellular drug accumulation and an increase in metallothionein content.

¹ This work was supported by Grants CA35309 from the NIH; Grants CH-377, 486, and 368 from the American Cancer Society; grants from Bristol Myers Co.; and a grant from the Jikei University School of Medicine, Tokyo, Japan. This work was conducted in part by the Clayton Foundation for Research, California Division. P. A. A. and S. B. H. are Clayton Foundation Investigators.

² To whom requests for reprints should be addressed, at the Department of Medicine 0812, University of California, San Diego, La Jolla, CA 92093.

Received 7/16/90. Accepted 8/13/91.

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