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.


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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