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Effect of Tamoxifen on the Multidrug-resistant Phenotype in Human Breast Cancer Cells: Isobologram, Drug Accumulation, and M_r 170,000 Glycoprotein (gp170) Binding Studies¹

Vincent T. Lombardi Cancer Research Center [F. L., M. J., B. B., J. L., M. M., R. C.], and Department of Physiology and Biophysics [R. C.], Georgetown University Medical School, Washington, DC 20007

² To whom requests for reprints should be addressed, at Room S128A, Vincent T. Lombardi Cancer Research Center, Georgetown University Medical School, 3800 Reservoir Road NW, Washington, DC 20007.

We have performed isobologram analyses of the ability of tamoxifen (TAM) to alter the response to Adriamycin (ADR) and vinblastine (VBL) in human breast cancer cells. MCF-7 cells express functional receptors for estrogen and progesterone but do not express detectable levels of M_r 170,000 glycoprotein (gp170). CL 10.3 and MCF-7^ADR cells are MCF-7 variants which express gp170. CL 10.3 but not MCF-7^ADR cells express functional steroid hormone receptors. Tamoxifen (1–2.5 µM) interacts synergistically with ADR and VBL in CL 10.3 and MCF-7^ADR cells. TAM increases the cytotoxicity of VBL and ADR and the intracellular levels of [³H]VBL by approximately 2–3-fold. TAM also prevents the binding of [³H]azidopine to gp170. The ability of TAM to concurrently increase the cytotoxic effects of ADR and VBL, increase VBL accumulation, and inhibit the binding of azidopine to gp170 strongly implies that the synergistic effects of TAM are mediated through its effects on gp170. TAM produces an antagonistic to additive interaction with ADR and VBL in MCF-7 cells, and at high concentrations (5 µM) the synergy apparent in CL 10.3 and MCF-7^ADR cells is lost. While TAM clearly has a significant potential for use as a chemosensitizing agent, the design of clinical trials may require careful consideration.

¹ This work was supported by USPHS Grants NCI U01-CA51908 and P30-CA51008 from the National Cancer Institute (R. C).

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 4/19/93. Accepted 11/12/93.

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