Combination hormonal, chemotherapy and radiotherapy in vitro. Implications for therapy in vivo

Hormonal therapy in breast cancer is widely employed, but its mechanism of action is poorly understood. We therefore studied the effect of 17β-estradiol (E2) and tamoxifen on an estrogen receptor-positive human breast cancer cell line (MCF-7). Neither E2 nor tamoxifen was significantly cytotoxic, even at pharmacologic doses. Physiologic doses of E2 enhanced proliferation, shortened overall cell cycle time and increased the proportion of cells in DNA synthesis. Pharmacologic concentrations of E2 decreased proliferation as well as the proportion of S-phase cells. When S-phase agents were used (ARA-C and MTX), physiologic concentrations of E2 enhanced killing whereas pharmacologic doses did not. Radiation survival curve parameters were unaffected by either concentration of the hormone. Sublethal (two-dose) damage repair was unaffected as well. The combination of S-phase agents with pharmacologic doses of hormones may lower the therapeutic ratio, whereas more physiologic concentrations may enhance the therapeutic efficacy of these agents