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Modulation of Cisplatin Resistance in Human Malignant Melanoma Cells¹

Department of Medicine and the Cancer Center, University of California, San Diego, La Jolla, California 92093 [E. F. M., K. D. A., J. A. J., R. C., S. B. H.]; and Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire 03755 [A. F.]

² To whom requests for reprints should be addressed, at UCSD Cancer Center 8421, 225 Dickinson Street, San Diego, CA 92103.

Previous studies have shown that the combination of dacarbazine, carmustine, cisplatin (DDP), and tamoxifen (TAM) produced a 53% overall response rate in patients with disseminated melanoma. Deletion of TAM from the regimen resulted in a fall in the response rate to 10%, and reincorporation of TAM returned the response rate to 52%, suggesting an important role for TAM. Using the human melanoma cell line T-289, we examined the nature of the interaction between TAM and each member of this combination in clonogenic assays in soft agar. The combination of TAM with DDP was highly synergistic as demonstrated by median effect analysis, whereas TAM was antagonistic with carmustine and an activated form of dacarbazine. The mean combination index at 50% kill was 0.26 ± 0.02 (mean ± SD) for TAM and DDP. This marked synergism was observed at concentrations of TAM that are clinically achievable. TAM had no effect on the uptake of the DDP analogue [³H]dichloro(ethylenediamine)platinum(II). There was no effect on the formation or repair of DDP intrastrand DNA adducts. Similarly, there was no effect demonstrated on the intracellular concentrations of glutathione or metallothioneins. We conclude that the interaction between TAM and DDP is truly synergistic in this cell line and is accomplished through none of the four mechanisms commonly associated with DDP resistance.

¹ Supported by Grant CA-52151 from the NIH and Grant 100-R041 from Bristol-Myers Squibb and grants from the Swiss National Foundation and the Swiss Cancer League. This work was conducted in part by the Clayton Foundation for Research-California Division. R. C. and S. B. H. are Clayton Foundation Investigators. R. C. is a recipient of a Young Investigator Award and a Clinical Research Career Development Award from the American Society of Clinical Oncology.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 4/22/92. Accepted 10/ 7/92.

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