Effect of Tamoxifen on the Multidrug-resistant Phenotype in Human Breast Cancer Cells: Isobologram, Drug Accumulation, and Mr 170,000 Glycoprotein (gpl70) Binding Studies

Fabio Leonessa, Mary Jacobson, Bryan Boyle, Jeremy Lippman, Michael McGarvey, Robert Clarke

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65 Scopus citations

Abstract

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 Mr 170,000 glycoprotein (gpl70). CL 10.3 and MCF-7ADR cells are MCF-7 variants which express gpl70. CL 10.3 but not MCF-7ADR cells express functional steroid hormone receptors. Tamoxifen (1-2.5 jum) interacts synergistically with ADR and VBL in CL 10.3 and MCF-7ADR 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 gpl70. The ability of TAM to concurrently increase the cytotoxic effects of ADR and VBL, increase VBL accumulation, and inhibit the binding of azidopine to gpl70 strongly implies that the synergistic effects of TAM are mediated through its effects on gpl70. TAM produces an antagonistic to additive interaction with ADR and VBL in MCF-7 cells, and at high concentrations (5 fm) the synergy apparent in CL 10.3 and MCF-7ADR 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.

Original languageEnglish (US)
Pages (from-to)441-447
Number of pages7
JournalCancer Research
Volume54
Issue number2
StatePublished - Jan 1994
Externally publishedYes

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