Lippman M, Bolan G, Huff K
Cancer Treat Rep. 1976 Oct;60(10):1421-9.
A variety of antiestrogens can be shown to antagonize estrogen action in animal model systems. Several of these compounds are useful in the management of metastatic human breast cancer. To further elucidate their mechanism of action, we studied several of these compounds using human breast cancer cell lines maintained in long-term tissue culture as a model system. Antiestrogens including tamoxifen (NSC-180973; ICI-46474), nafoxidine. CI-628, and clomiphene citrate inhibit macromolecular synthesis below control levels in two human breast cell lines. This effect is limited to cell lines which contain estrogen receptors. Simultaneous addition of as little as 1000-fold less estradiol prevents antiestrogen effects. Sequential addition of estrogen for up to 48 hours to cells incubated in antiestrogen reverses inhibition. If cells are continued in antiestrogen alone for more than about 3 days, inhibitory effects become irreversible. The cells detach from the surface of the culture vessel and are no longer viable. Tamoxifen competes with 3H-estradiol for specific receptor sites but with about a 100-fold lower apparent affinity. Direct binding of 3H-tamoxifen and 3H-estradiol to duplicate cytoplasmic extracts reveals equivalent numbers of binding sites but a 20-fold lower affinity for the antiestrogen. There is reasonable agreement between concentrations of tamoxifen which bind to receptor and concentrations which inhibit cells.
多种抗雌激素药物已被证明在动物模型系统中可拮抗雌激素作用。其中几种化合物可用于治疗转移性人类乳腺癌。为了进一步阐明其作用机制，我们使用长期组织培养的人乳腺癌细胞系作为模型系统，对其中几种化合物进行了研究。包括他莫昔芬（NSC - 180973；ICI - 46474）、萘福昔定、CI - 628和枸橼酸氯米芬在内的抗雌激素药物，在两种人乳腺癌细胞系中可将大分子合成抑制至对照水平以下。这种效应仅限于含有雌激素受体的细胞系。同时添加低至对照量千分之一的雌二醇即可阻止抗雌激素的作用。在抗雌激素环境中培养的细胞，连续添加雌激素长达48小时可逆转抑制作用。如果细胞单独在抗雌激素环境中培养超过约3天，抑制作用将变得不可逆。细胞会从培养容器表面脱离，不再存活。他莫昔芬与³H - 雌二醇竞争特异性受体位点，但其表观亲和力约低100倍。³H - 他莫昔芬和³H - 雌二醇与重复的细胞质提取物的直接结合显示，结合位点数量相当，但抗雌激素的亲和力低20倍。与受体结合的他莫昔芬浓度和抑制细胞的浓度之间存在合理的一致性。
