Modulatory effects of tamoxifen and recombinant human alpha-interferon on doxorubicin resistance.

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 alpha-interferon (IFN-alpha) 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 microM in ChR C5 cells and 0.4 microM in AuX B1 cells. In ChR C5 cells, IFN-alpha (500 units/ml) for 24 h had no affect on DOX cytotoxicity, but tamoxifen (1.0 microM) for 24 h enhanced DOX cytotoxicity with the 50% inhibitory concentration decreased by 2-fold to 4.2 microM. A combination of IFN-alpha (500 units/ml) for the initial 24 h followed by TAM (1.0 microM) 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 microM. The combination IFN-alpha 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-alpha 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-alpha and TAM may partially reverse DOX resistance and may potentially be useful in enhancing the clinical effectiveness of DOX.