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Synergy between Tamoxifen and Cisplatin in Human Melanoma Cells Is Dependent on the Presence of Antiestrogen-binding Sites¹

Division of Hematology/Oncology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29403 [J. A. J., E. F. M.], and Department of Medicine, Theodore Gildred Cancer Facility, University of California, San Dolla, California 92093 [K. D. A., R. D. C., S. B. H.]

We have demonstrated previously that cisplatin (DDP) and tamoxifen (TAM) act synergistically to kill human melanoma T-289 cells, and that the observed synergy is lost in the 3-fold TAM-resistant subline, 289/TAM₆. We have identified the intracellular antiestrogen-binding sites (AEBSs), defined by their ability to bind antiestrogens while having no affinity for estrogen, as a possible mediator of this synergy. We report here that [³H]TAM binds to AEBSs, as defined by the ability of N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine-HCl, an AEBS-specific ligand, to compete with [³H]TAM binding. Furthermore, we have characterized the number of binding sites and their affinity for [³H]TAM by Scatchard analysis in whole-cell lysates, microsomal fractions, and nuclear fractions of both cell lines by competing [³H]TAM binding with increasing concentrations of unlabeled TAM. These data demonstrate that the loss of a high-affinity AEBS from the nuclear fraction of the 289/TAM₆ cell line correlates with the loss of synergy between DDP and TAM in these cells. This implicates AEBSs as a critical component of the mechanism that mediates the synergistic interaction of DDP and TAM in human melanoma cells.

¹ Supported by Grant CA-51251 from the National Institutes of Health, Grants from the Swiss National Science Foundation and the Swiss Cancer League. This work was conducted in part by the Clayton Foundation for Research-California Division. S. B. H. and R. D. C. are Clayton Foundation investigators. R. D. C. is a recipient of a Young Investigator Award and a Clinical Research Career Development Award from the American Society of Clinical Oncology.

² To whom requests for reprints should be addressed, at Division of Hematology/Oncology, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425.

Received 12/ 5/96. Accepted 5/ 3/97.

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