Lykkesfeldt A E, Larsen S S, Briand P
Department of Tumor Endocrinology, Danish Cancer Society, Copenhagen.
Int J Cancer. 1995 May 16;61(4):529-34. doi: 10.1002/ijc.2910610417.
The pure steroidal anti-estrogens ICI 164,384 and ICI 182,780 are very potent growth inhibitors of the estrogen receptor-positive human breast cancer cell line MCF-7. However, long-term treatment of MCF-7 cells with 10(-7) M concentrations of these compounds results in selection of proliferating colonies of resistant cells. Our report describes 4 ICI 164,384- and 3 ICI 182,780-resistant MCF-7 sublines established after long-term treatment. Resistant sublines are estrogen receptor-positive, and all sublines have lost expression and estrogen inducibility of the progesterone receptor protein. Based on IC50 concentrations, all tested resistant sublines had a reduced sensitivity to pure anti-estrogens on the order of 100- to 1000-fold compared with parent MCF-7 cells. All resistant cell lines have survived propagation for more than 15 subcultivations in the presence of 10(-7) M pure anti-estrogen. The MCF-7/182R-6 subline has been tested for stability of resistance and appeared to be stably resistant after 13 weeks of propagation without the selective pressure of ICI 182,780. Cell lines resistant to the ICI 182,780 compound are cross-resistant to the ICI 164,384 compound and vice versa. However, the sublines resistant to pure antiestrogens are sensitive to tamoxifen. Our results show that although the pure steroidal anti-estrogens are very potent growth inhibitors, they do not circumvent development of resistance.
纯甾体类抗雌激素药物ICI 164,384和ICI 182,780是雌激素受体阳性的人乳腺癌细胞系MCF - 7非常有效的生长抑制剂。然而，用10(-7) M浓度的这些化合物对MCF - 7细胞进行长期处理会导致耐药细胞增殖集落的选择。我们的报告描述了长期处理后建立的4个对ICI 164,384耐药和3个对ICI 182,780耐药的MCF - 7亚系。耐药亚系为雌激素受体阳性，所有亚系均丧失了孕激素受体蛋白的表达及雌激素诱导性。根据半数抑制浓度(IC50)，与亲代MCF - 7细胞相比，所有测试的耐药亚系对纯抗雌激素的敏感性降低了100至1000倍。所有耐药细胞系在10(-7) M纯抗雌激素存在下已传代培养超过15次仍存活。MCF - 7/182R - 6亚系已测试耐药稳定性，在没有ICI 182,780选择压力的情况下传代培养13周后似乎仍稳定耐药。对ICI 182,780化合物耐药的细胞系对ICI 164,384化合物交叉耐药，反之亦然。然而，对纯抗雌激素耐药的亚系对他莫昔芬敏感。我们的结果表明，尽管纯甾体类抗雌激素是非常有效的生长抑制剂，但它们并不能避免耐药性的产生。
