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Characterization of a Cisplatin-resistant Human Ovarian Carcinoma Cell Line Expressing Cross-Resistance to 5-Fluorouracil but Collateral Sensitivity to Methotrexate

Laboratory of Cellular Chemotherapy, Imperial Cancer Research Fund, Lincoln's Inn Fields, London WC2A 3PX, United Kingdom [B. T. H., S. A. S., L. K. H., W. C. M. D., R. D. H. W.]; TNO Medical Biological Laboratory, P. O. Box 45, 139, 2280 AA Rijswijk, the Netherlands [A. M. J. F-S.]; and Biochemical Pharmacology, Department of Medical Oncology, City of Hope National Medical Center, Duarte, California 91010 [T. T., K. J. S.]

In vitro exposure of the TR170 ovarian carcinoma cell line to six intermittent 24-h treatments with a 90% inhibitory concentration of cisplatin (CDDP) (0.15 µg/ml; 0.5 µM) resulted in a 2-fold stably resistant subline designated TR170/CP+ (B. T. Hill et al., Int. J. Cancer, 39: 219–225, 1987). Resistance to CDDP in these CP+ cells has now been associated with reduced uptake of ^195mCDDP (2-fold; P < 0.01) and decreased removal of specific Pt-DNA adducts, quantitated immunochemically, indicative of an apparent increased tolerance of CDDP-induced DNA damage. Specifically these resistant cells appeared deficient in removal of the major cis-Pt-(NH₃)₂d(pGpG) adduct and the difunctional cis-Pt(NH₃)₂d(GMP)₂ lesion, showed less efficiency in removing cis-Pt(NH₃)₂d(pApG) adducts, but proved as proficient as the parental cell line in removing DNA-DNA interstrand cross-links. Activities of DNA polymerase- and -ß were comparable in both lines, and no significant alterations in glutathione metabolism were identified. Response to acute X-irradiation was not modified in these TR170/CP+ cells, but they showed marked (10-fold) cross-resistance to 5-fluorouracil and, unusually, proved collaterally sensitive (12-fold) to methotrexate. Resistance to 5-fluorouracil was associated with significantly increased thymidylate synthase activity (P < 0.01), but this was not reflected in altered gene expression, while increased sensitivity to methotrexate was accompanied by increased drug uptake but by unaltered activity and expression of dihydrofolate reductase. These results indicate that exposure to CDDP can result in numerous alterations, both intracellularly and at the cellular membrane, reflected in significant changes in the tumor cells' responses to the cytotoxic effects of a range of antitumor drugs. The clinical relevance of these observations remains to be established.

¹ To whom requests for reprints should be addressed, at the Imperial Cancer Research Fund Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.

² K. J. S. is supported by NIH Grant CA50618.

Received 12/16/91. Accepted 3/18/92.

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