Hu X F, Veroni M, De Luise M, Wakeling A, Sutherland R, Watts C K, Zalcberg J R
Department of Medicine, Heidelberg Repatriation Hospital, Vic., Australia.
Int J Cancer. 1993 Nov 11;55(5):873-6. doi: 10.1002/ijc.2910550529.
Both primary and acquired resistance to the growth-inhibitory effects of anti-estrogens (e.g., tamoxifen) limits the clinical usefulness of these drugs in the treatment of breast cancer. The new, steroidal anti-estrogen ICI 182,780 was tested for its ability to inhibit the proliferation of a tamoxifen-resistant variant of the parental MCF-7 human breast-cancer cell line. Two cell lines cloned from the MCF-7 line were used for these experiments: a tamoxifen-sensitive line, MCF 5-21, and a tamoxifen-resistant line, MCF 5-23. Compared with tamoxifen, ICI 182,780 appeared to be 150 and 1540 times more effective in inhibiting cell growth in the 5-21 and 5-23 sub-lines respectively. ICI 182,780 completely circumvented tamoxifen resistance at a concentration of (5 to 10) x 10(-9) M in this model. Based on IC50 concentrations, the 5-23 line was 22-fold more resistant to tamoxifen than the 5-21 line, but only 2-fold more resistant to ICI 182,780, reducing relative resistance by 10-fold in the resistant line. There were no differences in ER parameters between the 2 lines. ER numbers/cell were: 40500 and 34800 and the KD 0.48 and 0.15 x 10(-9) M in the 5-21 and 5-23 cells respectively. In the 5-23 cells, the concentrations of ICI 182,780 and tamoxifen resulting in a 50% inhibition of 3H-estradiol binding were 2.3 x 10(-8) M and 1 x 10(-6) M, respectively (cf. estradiol 0.89 x 10(-9) M). Thus, one potential mechanism for the increased effectiveness of ICI 182,780 may relate to the increased affinity of this drug for the estrogen receptor as compared with tamoxifen.
对抗雌激素（如他莫昔芬）生长抑制作用的原发性和获得性耐药均限制了这些药物在乳腺癌治疗中的临床应用。新型甾体抗雌激素ICI 182,780被测试其抑制亲本MCF - 7人乳腺癌细胞系的他莫昔芬耐药变体增殖的能力。从MCF - 7系克隆的两个细胞系用于这些实验：一个他莫昔芬敏感系，MCF 5 - 21，和一个他莫昔芬耐药系，MCF 5 - 23。与他莫昔芬相比，ICI 182,780在抑制5 - 21和5 - 23亚系细胞生长方面分别似乎有效150倍和1540倍。在该模型中，ICI 182,780在浓度为(5至10)×10(-9) M时完全克服了他莫昔芬耐药性。基于IC50浓度，5 - 23系对他莫昔芬的耐药性比5 - 21系高22倍，但对ICI 182,780仅高2倍，使耐药系中的相对耐药性降低了10倍。两系之间的雌激素受体（ER）参数无差异。5 - 21和5 - 23细胞中每个细胞的ER数量分别为40500和34800，解离常数（KD）分别为0.48和0.15×10(-9) M。在5 - 23细胞中，导致3H - 雌二醇结合50%抑制的ICI 182,780和他莫昔芬浓度分别为2.3×10(-8) M和1×10(-6) M（对比雌二醇为0.89×10(-9) M）。因此，ICI 182,780有效性增加的一个潜在机制可能与该药物相对于他莫昔芬对雌激素受体的亲和力增加有关。
