Biological activities of a novel selective oestrogen receptor modulator derived from raloxifene (Y134)
Biological activities of a novel selective oestrogen receptor modulator derived from raloxifene (Y134)
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DOI：
10.1038/sj.bjp.0706960
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发表时间：
2007-01-01
影响因子：
7.3
通讯作者：
Wang, M-W
中科院分区：
文献类型：
--
作者：
Ning, M.;Zhou, C.;Wang, M-W
背景与目的：选择性雌激素受体（ER）调节剂（SERM）在乳腺癌和骨质疏松症的治疗中具有重要价值。本研究的目的是表征一类新的SERM合成的核心结构的基础上雷洛昔芬。实验方法：竞争性受体结合和酶为基础的报告基因的方法来研究雷洛昔芬类似物的生物活性，然后在乳腺癌细胞增殖试验中的疗效测定。雌激素受体拮抗剂的影响进行了研究，在雌性大鼠通过测量子宫和乳腺的生长，使用湿重，BrdU掺入和末端芽（TEB）作为indicators.Key结果：五个类似物，属于两个不同的结构系列和显示更高的结合亲和力ER α比ER β进行了功能评价。其中一种类似物Y134在与含有ER α或ER β和雌激素反应元件驱动的荧光素酶的质粒共转染的CV-1细胞中对ER表现出有效的拮抗活性。ER α和ER的IC50估计值分别为0.52 nM和2.94 nM，与雷洛昔芬相当。在Y134浓度低于10 μ M时，观察到的细胞毒性很小。Y134抑制雌激素刺激的ER阳性人乳腺癌MCF-7和T47D细胞的增殖。在相同的剂量下，给予卵巢切除大鼠，Y134是更有效的比雷洛昔芬在逮捕雌激素诱导的副产物TEB和乳腺DNA合成，但它们对子宫的抑制作用是compared.Conclusions和影响：Y134是一种有效的ER拮抗剂，具有更好的乳腺选择性比雷洛昔芬，并显示出潜在的发展作为一种新的SERM用于治疗用途。
Background and purpose: Selective oestrogen receptor (ER) modulators (SERMs) are of great value in the treatment of breast cancer and osteoporosis. The aim of this study was to characterize pharmacologically a new class of SERMs synthesized based on the core structure of raloxifene.Experimental approach: Competitive receptor binding and luciferase-based reporter methods were used to study the bioactivities of raloxifene analogues, followed by efficacy determination in breast cancer cell proliferation assay. ER antagonist effects were investigated in female rats by measuring uterine and mammary gland growth, using wet weight, BrdU incorporation and terminal end bud (TEB) as indicators.Key results: Five analogues, belonging to two different structural series and display higher binding affinities for ER alpha than ER beta were functionally evaluated. One such analogue, Y134, exhibited potent antagonist activity at ERs in CV-1 cells cotransfected with plasmids containing ER alpha or ER beta and oestrogen-response element-driven luciferase. The estimated IC50 value was 0.52 nM for ERa and 2.94 nM for ER, comparable to that of raloxifene. Little cytotoxicity was observed at Y134 concentrations below 10 mu M. Y134 suppressed oestrogen-stimulated proliferation of ER-positive human breast cancer MCF-7 and T47D cells. At an identical dose, administered to ovariectomized rats, Y134 was more effective than raloxifene at arresting oestrogen-induced outgrowth of TEB and mammary gland DNA synthesis, but their inhibitory effects on the uterus were comparable.Conclusions and Implications: Y134 is a potent ER antagonist with better mammary gland selectivity than raloxifene and shows potential for development as a new SERM for therapeutic use.