SENSITIZATION TO DOXORUBICIN RESISTANCE IN BREAST CANCEL CELL-LINES BY TAMOXIFEN AND MEGESTROL-ACETATE

Acquired drug resistance is a major factor in the failure of doxorubic in-based chemotherapy in breast cancer. We determined the ability of m egestrol acetate and/or tamoxifen to reverse doxorubicin drug resistan ce in a doxorubicin-resistant breast cancer line (the human MCF-7/ADR) . The cytotoxicity of doxorubicin, megestrol acetate, and/or tamoxifen was determined in the sensitive and resistant cell lines utilizing th e sulphorhodamine B assay. Tamoxifen alone produced an IC50 (concentra tion resulting in 50% inhibition of control growth) of 10.6 mu M, wher eas megestrol acetate alone resulted in an IC50 of 48.7 mu M in the MC F-7/ADR cell line. The IC50 of doxorubicin in MCF-7/ADR was 1.9 mu M. Neither megestrol acetate alone nor tamoxifen alone at 1 or 5 mu M alt ered the IC50 of doxorubicin. However, the combination of tamoxifen (1 or 5 mu M) and megestrol acetate (1 or 5 mu M) synergistically sensit ized MCF-7/ADR cells. Additionally, megestrol acetate and tamoxifen in hibited iodoarylazidoprazosin binding to P-glycoprotein, and, in their presence, there was an increased doxorubicin accumulation in the MCF- 7/ADR cells. Furthermore, the combination of tamoxifen and megestrol a cetate had much less effect on the cytotoxicity of doxorubicin in MCF- 7 wild-type cells. Clinically achievable concentrations of tamoxifen a nd megestrol acetate can largely sensitize MCF-7/ADR to doxorubicin. T he combination of these three drugs in a clinical trial may be informa tive.