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 α-interferon (IFN-α) 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-α (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-α (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-α 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-α 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-α and TAM may partially reverse DOX resistance and may potentially be useful in enhancing the clinical effectiveness of DOX.

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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.

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