Jain P T, Pento J T, Magarian R A
Division of Medicinal Chemistry and Pharmacodynamics, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City 73190.
Anticancer Res. 1992 May-Jun;12(3):585-90.
Compound 5a ([Z]-1, 1-Dichloro-2,3 diphenyl-2-(4-methoxyphenyl)cyclopropane) is a novel cyclopropyl compound which was shown to be a pure antiestrogen. In the present study, the antiproliferative activity of 5a was examined on estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 human breast cancer cells and A-549 human lung cancer cells using the hemocytometric trypan blue exclusion method. Compound 5a inhibited the growth of MCF-7 cells in a dose-related manner over a concentration range of 10(-9) to 10(-5) M, but did not alter the growth of MDA-MB-231 or A-549 cells. Co-administration of estradiol (10(-8) M) reversed the antiproliferative activity of 5a (10(-7) M) on MCF-7 cells. Further, an ER-dependent mechanism of action is supported by the specific ER binding of 5a in MCF-7 cells observed in this study. The influence of 5a on the cell surface morphology of MCF-7 and MDA-MB-231 cells was studied using scanning electron microscopy (SEM). Compound 5a at 10(-6) M reduced the length and density of microvilli (MV) on MCF-7 cells, which was reversed by co-administration of estradiol (10(-8) M). This compound did not alter the cell surface morphology of ER-negative MDA-MB-231 cells. In conclusion, 5a and tamoxifen inhibited the growth of ER-prositive MCF-7 cells in an estradiol-reversible manner, and had no effect on ER-negative MDA-MB-231 cells. The results of this study with human breast cancer cells suggest that 5a may be highly effective in the treatment of estrogen-dependent breast cancer and/or in the prophylactic treatment of women with a high risk of breast cancer development.
化合物5a（[Z]-1,1-二氯-2,3-二苯基-2-(4-甲氧基苯基)环丙烷）是一种新型环丙基化合物，已被证明是一种纯抗雌激素药物。在本研究中，使用血细胞计数板台盼蓝排斥法检测了5a对雌激素受体（ER）阳性的MCF-7和ER阴性的MDA-MB-231人乳腺癌细胞以及A-549人肺癌细胞的抗增殖活性。化合物5a在10(-9)至10(-5)M的浓度范围内以剂量相关的方式抑制MCF-7细胞的生长，但不改变MDA-MB-231或A-549细胞的生长。雌二醇（10(-8)M）的共同给药逆转了5a（10(-7)M）对MCF-7细胞的抗增殖活性。此外，本研究中观察到的5a在MCF-7细胞中的特异性ER结合支持了其依赖ER的作用机制。使用扫描电子显微镜（SEM）研究了5a对MCF-7和MDA-MB-231细胞表面形态的影响。10(-6)M的化合物5a降低了MCF-7细胞上微绒毛（MV）的长度和密度，雌二醇（10(-8)M）的共同给药可逆转这一现象。该化合物未改变ER阴性的MDA-MB-231细胞的表面形态。总之，5a和他莫昔芬以雌二醇可逆的方式抑制ER阳性的MCF-7细胞的生长，对ER阴性的MDA-MB-231细胞无影响。这项对人乳腺癌细胞的研究结果表明，5a在治疗雌激素依赖性乳腺癌和/或预防乳腺癌发生风险高的女性方面可能非常有效。
