Tang B L, Teo C C, Sim K Y, Ng M L, Kon O L
Department of Biochemistry, National University of Singapore.
Biochim Biophys Acta. 1989 Nov 20;1014(2):162-72. doi: 10.1016/0167-4889(89)90029-3.
The antiproliferative effect of 10(-6) M antiestrogens in an estrogen receptor-negative lymphoid cell line (K36) was enhanced in lipoprotein-poor growth medium. The enhancement was not due to increased bioavailability because cellular uptake of [3H]tamoxifen was not increased and the lipoprotein fraction of serum had negligible [3H]tamoxifen-binding capacity. Cholesterol and lipoproteins, but not mevalonate, reversed the cytostatic effect of antiestrogens. Reversal by cholesterol was dose-related (10(-7) M to 10(-5) M), while that by lipoproteins could also be demonstrated in medium undepleted of lipoproteins. The cytostatic efficacy of a series of ten compounds correlated well with their relative binding affinities for solubilized antiestrogen-binding sites from K36 cells when log IC50 values (concentration required to reduce [3H]thymidine incorporation by 50%) were plotted against log RBA50 values (concentration required to reduce [3H]tamoxifen binding by 50%) (correlation coefficient 0.94). Transmission electron microscopy of antiestrogen-treated cells showed evidence of disordered cytokinesis which was partially reversed by cholesterol. These observations implicate the antiestrogen-binding protein in the antiproliferative effect of antiestrogens in nonestrogen target cells.
在脂蛋白贫乏的生长培养基中，10⁻⁶ M抗雌激素对雌激素受体阴性淋巴细胞系（K36）的抗增殖作用增强。这种增强并非由于生物利用度增加，因为[³H]他莫昔芬的细胞摄取未增加，且血清中的脂蛋白部分对[³H]他莫昔芬的结合能力可忽略不计。胆固醇和脂蛋白可逆转抗雌激素的细胞生长抑制作用，而甲羟戊酸则不能。胆固醇的逆转作用呈剂量相关（10⁻⁷ M至10⁻⁵ M），脂蛋白的逆转作用在未耗尽脂蛋白的培养基中也可得到证实。当将对数IC50值（使[³H]胸腺嘧啶掺入减少50%所需的浓度）与对数RBA50值（使[³H]他莫昔芬结合减少50%所需的浓度）作图时，一系列十种化合物的细胞生长抑制效力与其对K36细胞中可溶性抗雌激素结合位点的相对结合亲和力密切相关（相关系数为0.94）。抗雌激素处理细胞的透射电子显微镜检查显示有细胞分裂紊乱的迹象，胆固醇可部分逆转这种紊乱。这些观察结果表明抗雌激素结合蛋白在非雌激素靶细胞中抗雌激素的抗增殖作用中起作用。
