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Modulatory Effects of Tamoxifen and Recombinant Human -Interferon on Doxorubicin Resistance¹

Division of Surgical Oncology, Eastern Virginia Medical School, Norfolk, Virginia 23507

Doxorubicin (DOX) resistance is frequently due to the multidrug resistance gene product P-glycoprotein. This study examined the effects of two biochemical modulators, recombinant human -interferon (IFN-) and tamoxifen (TAM), on the DOX sensitivity, DOX retention, and P-glycoprotein expression of the multidrug-resistant Chinese hamster ovary cell line ChR C5 and the parent AuX B1 cell line. In the absence of either modulator, the 50% inhibitory concentration for DOX after 1-h incubation as determined using a microculture tetrazolium assay was 8.3 µM in ChR C5 cells and 0.4 µM in AuX B1 cells. In ChR C5 cells, IFN- (500 units/ml) for 24 h had no affect on DOX cytotoxicity, but tamoxifen (1.0 µM) for 24 h enhanced DOX cytotoxicity with the 50% inhibitory concentration decreased by 2-fold to 4.2 µM. A combination of IFN- (500 units/ml) for the initial 24 h followed by TAM (1.0 µM) for another 24 h was even more effective in ChR C5 cells with the DOX 50% inhibitory concentration decreased by 4-fold to 2.1 µM. The combination IFN- and TAM dramatically increased DOX accumulation in the resistant ChR C5 cells without significantly affecting P-glycoprotein expression as measured using flow cytometric analysis. IFN- and/or TAM had no effect on DOX cytotoxicity or accumulation in parent DOX-sensitive AuX B1 cells. Both cell lines were estrogen and progesterone receptor negative. These data indicate that synergism between IFN- and TAM may partially reverse DOX resistance and may potentially be useful in enhancing the clinical effectiveness of DOX.

¹ Supported in part by the Sentara Endowment Fund and American Cancer Society (CDA 92-283). These results have been presented in abstract and preliminary form at the 26th Annual Meeting of the Association for Academic Surgery, Montreal, Quebec, Canada, November 19, 1992.

² To whom requests for reprints should be addressed, at Eastern Virginia Medical School, 825 Fairfax Avenue, Norfolk, VA 23507-1912.

Received 12/22/92. Accepted 4/20/93.