The
triphenylethylene antiestrogen tamoxifen (TAM) is believed to exert its antitumor effect via the
estrogen receptor (ER). To test this hypothesis and to differentiate between ER-mediated and general cytotoxic effects of TAM, the growth-inhibitory effects of TAM and its in vivo metabolite
4-hydroxytamoxifen (
OH-TAM) have been studied in five continuous human
cancer cell lines, MCF7 and T47D (mammary
carcinoma, ER positive), BT20 and MDA-MB-231 (mammary
carcinoma, ER negative), and ME8 (
melanoma, ER negative). All five cell lines are completely killed by concentrations of TAM and
OH-TAM above 10(-6) M, regardless of ER status. TAM and
OH-TAM have little effect on the ER-negative lines at concentrations below 10(-6) M, whereas the ER-positive lines are highly sensitive to TAM
at 10(-7) M and to
OH-TAM
at 10(-9) M. Inhibition of growth parallels the relative affinity of these drugs for the ER. We conclude that, above 10(-6) M, the growth-inhibitory effects of TAM and
OH-TAM in tissue culture are the results of a mechanism other than that via the ER system and that only at lower concentrations are the true ER-mediated effects seen. Plasma concentrations of TAM and
OH-TAM in
breast cancer patients treated with TAM are in the same range as the concentrations in vivo at which growth inhibition is seen, leading to the conclusion that both compounds contribute to the overall effect of TAM in vivo.