选择性雌激素受体调节剂

雌激素替代疗法（estrogen replacement therapy,ERT）是治疗绝经后综合征的首选治疗方案,但是长期应用导致子宫内膜增生、乳腺癌等。选择性雌激素受体调节剂主要通过ER亚型、共调节子、靶启动子、雌激素受体相关受体等机制实现其组织选择性,在发挥骨骼、心血管保护作用的同时,减少了对乳腺及生殖系统的副作用。目前,选择性雌激素受体调节剂的种类、作用的组织特异性及其临床应用在医学界引起广泛关注,具有广阔的发展前景。     

女性退行性腰椎滑脱椎体软骨终板内雌激素受体的表达及其意义

探讨雌激素受体(ER)在绝经后女性退变性腰椎滑脱软骨终板内的表达及其意义。方法:用RT-PCR方法检测绝经后女性退变性腰椎滑脱(DS)患者的与女性腰椎管狭窄患者(SS)患者的软骨终板内雌激素受体mRNA的表达;Western blot方法检测绝经后女性退变性腰椎滑脱(DS)患者的与女性腰椎管狭窄患者(SS)患者的软骨终板内雌激素受体蛋白质的表达;用免疫组织化学法(Envision法)检测绝经后女性退变性腰椎滑脱(DS)患者的与女性腰椎管狭窄患者(SS)患者的软骨终板内雌激素受体的分布和表达;分析雌激素、雌激素受体和退变性腰椎滑脱之间的关系。结果:软骨终板中雌激素受体mRNA的表达量在绝经后女性退变性腰椎滑脱患者中较女性腰椎管狭窄患者(SS)明显下调(P＜0．05);绝经后女性退变性腰椎滑脱患者的软骨终板中雌激素受体蛋白质的表达量较女性腰椎管狭窄患者(SS)明显下调(P＜0．05);免疫组织化学结果显示雌激素受体在绝经后女性退变性腰椎滑脱(DS)的软骨终板中仅少量表达,在绝经后女性腰椎管狭窄患者(SS)的软骨终板中表达量较强。结论:绝经后女性退行性腰椎滑脱患者软骨终板中雌激素受体表达量较绝经后女性腰椎管狭窄患者显著下调,可能是引起绝经后女性退行性腰椎不稳高发的原因之一。     

《柳叶刀》：一类药物能有效降低女性患乳腺癌风险

英国一项新研究发现,通常用于治疗某些乳腺癌和卵巢癌的选择性雌激素受体调节剂类药物。也能有效降低女性患乳腺癌的风险。但此类药物有明显副作用,服用者应在医生指导下谨慎选择。英国医学刊物《柳叶刀》4月30日在线刊登的一份报告说,英国伦敦大学玛丽女王学院的研究人员分析了超过8．3万名女性10年来的医疗记录,发现他莫昔芬等4种选择性雌激素受体调节剂药物可有效降低乳腺癌风险。研究显示,持续服用此类药物5年后,乳腺癌患病风险可比常规风险降低约42％,在停药后的前5年内,乳腺癌患病风险仍比常规风险低大约25％。     

雄激素和雌激素受体药物筛选方法的研究进展

雄激素和雌激素受体通过与相应激素特异性结合促进细胞分化和组织生长,发挥重要的生理功能,其功能失调可诱发多种疾病。雄激素和雌激素受体的选择性调节剂是治疗相关疾病的重要药物。基于基因组学、分子生物学、细胞生物学和生物信息学等最新研究成果而发展形成的实验技术或方法被用于新型雄激素和雌激素受体调节剂的筛选,显著加快了新药开发的进程。     

表皮生长因子受体与他莫西芬耐药机制

雌激素受体及其信号通路在乳腺癌的发生发展中发挥着关键作用。到目前为止,抑制或阻断雌激素信号通路的内分泌治疗尤其是他莫西芬,仍是对雌激素受体阳性乳腺癌患者最有效的治疗手段之一。然而,他莫西芬的耐药问题直接影响了乳腺癌患者的治疗及预后。最近多项研究表明雌激素受体与表皮生长因子受体家族尤其是HER2介导的信号传导通路在多个点上相互交叉,彼此影响,与他莫西芬的耐药密切相关     

雌激素受体亚型及其配体调节基因转录机制的研究

本文综述雌激素受体亚型（ERα和ERβ）的结构,功能,组织分布,生理作用及雌激素受体配体调节基因转录的机制,目的是深入系统地了解植物雌激素和选择性雌激素受体调节剂的作用路径及其组织特异性的发生机制,最终为提高雌激素类药物的选择性,优化以临床为基础的药物设计提供一条较为系统的思路。结果表明,ERα和ERβ对不同雌激素类化合物产生不同应答,配体的结构不同,调节基因转录的路径不同和募集的辅调节蛋白的不同是雌激素受体两种亚型组织特异性激活或抑制的主要原因。     

“一类茚并吲哚酮类化合物、其制备方法和用途”获国家发明专利

由上海药物研究所完成的发明＂一类茚并吲哚酮类化合物、其制备方法和用途＂目前获得国家发明专利授权（专利号ZL200410053101.1）。本发明涉及一类全新结构的茚并吲哚酮类化合物、该化合物的制备方法,以及该化合物作为一种新型选择性雌激素受体调节剂在预防和治疗骨质疏松、乳腺癌等疾病药物中的应用。内源性雌激素不但对女性性器官、乳腺及其其他性征的发育和保持有重要的作用,     

围绝经期综合症治疗进展

女性一生中大约有1／3的时间是在绝经后度过的,围绝经期症状使得女性的日常生活及工作受到了很大的影响。传统的治疗方法为激素替代治疗,但因可能会增加乳癌和子宫内膜癌等的发病风险,其应用还存在很大的争议,非激素类药物包括中枢肾上腺素受体激动剂,选择性的5-HT重摄取抑制剂,Y-氨基丁酸类似物,黑升麻类药物等。黑升麻类药物缓解围绝经期症状的疗效是肯定的,黑升麻没有雌激素样作用,可能是通过5-羟色胺受体来发挥作用的。     

围绝经期综合症治疗进展

女性一生中大约有l/3的时间是在绝经后度过的,围绝经期症状使得女性的日常生活及工作受到了很大的影响。传统的治疗方法为激素替代治疗,但因可能会增加乳癌和子宫内膜癌等的发病风险,其应用还存在很大的争议,非激素类药物包括中枢肾上腺素受体激动剂,选择性的5-HT重摄取抑制剂,γ-氨基丁酸类似物,黑升麻类药物等。黑升麻类药物缓解围绝经期症状的疗效是肯定的,黑升麻没有雌激素样作用,可能是通过5-羟色胺受体来发挥作用的。     

α-雌激素受体介导的膜信号转导通路

近年来关于α-雌激素受体(ERα)介导的雌激素膜信号转导成为研究热点。ERα介导的雌激素膜信号转导通路,主要包括一氧化氮信号通路、钙离子信号通路以及蛋白激酶信号通路。这些信号转导过程中有第二信使的动员、ERα与连接蛋白的结合,非受体蛋白激酶的活化、ERα与其他膜蛋白的相互作用等多种细胞事件的参与。阐明ERα在雌激素非基因组信号转导中的作用及机制,对于开发更有效的选择性雌激素受体调节剂、改善肿瘤内分泌治疗效果,具有重要临床意义。     

Selective estrogen receptor modulators (SERMS) and their roles in breast cancer prevention

Tamoxifen has not only proved to be a valuable treatment for estrogen receptor (ER)-positive breast cancer, but is also a pioneering medicine for chemoprevention in high-risk pre- and postmenopausal women. Insights into the pharmacology and toxicology of tamoxifen have led to the recognition of selective ER modulators (SERMs) with estrogen-like actions in maintaining bone density and in lowering circulating cholesterol, but antiestrogenic actions in the breast. Raloxifene, a related SERM, is now available to treat osteoporosis and is also being tested as a preventive for breast cancer and coronary heart disease. Emerging knowledge about the action of SERMs will provide clues for the design of mechanism-based medicines.     

Identification of selective estrogen receptor modulators by their gene expression fingerprints

Clinical studies have shown that estrogen replacement therapy (ERT) reduces the incidence and severity of osteoporosis and cardiovascular disease in postmenopausal women. However, long term estrogen treatment also increases the risk of endometrial and breast cancer. The selective estrogen receptor (ER) modulators (SERMs) tamoxifen and raloxifene, cause antagonistic and agonistic responses when bound to the ER. Their predominantly antagonistic actions in the mammary gland form the rationale for their therapeutic utility in estrogen-responsive breast cancer, while their agonistic estrogen-like effects in bone and the cardiovascular system make them candidates for ERT regimens. Of these two SERMs, raloxifene is preferred because it has markedly less uterine-stimulatory activity than either estrogen or tamoxifen. To identify additional SERMs, a method to classify compounds based on differential gene expression modulation was developed. By analysis of 24 different combinations of genes and cells, a selected set of assays that permitted discrimination between estrogen, tamoxifen, raloxifene, and the pure ER antagonist ICI164384 was generated. This assay panel was employed to measure the activity of 38 compounds, and the gene expression fingerprints (GEFs) obtained for each compound were used to classify all compounds into eight groups. The compound's GEF predicted its uterine-stimulatory activity. One group of compounds was evaluated for activity in attenuating bone loss in ovariectomized rats. Most compounds with similar GEFs had similar in vivo activities, thereby suggesting that GEF-based screens could be useful in predicting a compound's in vivo pharmacological profile.     

Pros and cons of existing treatment modalities in osteoporosis: a comparison between tibolone,SERMs and estrogen (+/-progestogen) treatments

Tibolone, selective estrogen receptor modulators (SERMs) like tamoxifen and raloxifene, and estrogen (±progestogen) treatments prevent bone loss in postmenopausal women. They exert their effects on bone via the estrogen receptor (ER) and the increase in bone mass is due to resorption inhibition. The effect of SERMs on bone mineral density is less than that with the other treatments, but the SERM raloxifene still has a positive effect on vertebral fractures. In contrast to tibolone and estrogens (±progestogen), SERMs do not treat climacteric complaints, whilst estrogen plus progestogen treatments cause a high incidence of bleeding. Estrogen plus progestogen combinations have compromising effects on the breast. Tibolone and SERMs do not stimulate the breast or endometrium. Unlike SERMs, tibolone does not posses antagonistic biological effects via the ER in these tissues. Estrogenic stimulation in these tissues is prevented by local metabolism and inhibition of steroid metabolizing enzymes by tibolone and its metabolites. SERMs and estrogen (±progestogen) treatments increase the risk of venous thromboembolism (VTE), whilst estrogen (±progestogen) combinations have unwanted effects on cardiovascular events. So far, no detrimental effects of tibolone have been observed with respect to VTE or cardiovascular events. The clinical profile of tibolone therefore has advantages over those of other treatment modalities. It is also clear that tibolone is a unique compound with a specific mode of action and that it belongs to a separate class of compounds that can best be described as selective, tissue estrogenic activity regulators (STEARs).     

Effects of SERM (selective estrogen receptor modulator) treatment on growth and proliferation in the rat uterus

Background  

Selective estrogen receptor modulators (SERMs) have been developed in order to create means to control estrogenic effects on different tissues. A major drawback in treatment of estrogen receptor (ER) positive breast cancer with the antagonist tamoxifen (TAM) is its agonistic effect in the endometrium. Raloxifene (RAL) is the next generation of SERMs where the agonistic effect on the endometrium has been reduced.     

Selective estrogen receptor modulators inhibit hepatitis C virus infection at multiple steps of the virus life cycle

We screened for hepatitis C virus (HCV) inhibitors using the JFH-1 viral culture system and found that selective estrogen receptor modulators (SERMs), such as tamoxifen, clomifene, raloxifene, and other estrogen receptor α (ERα) antagonists, inhibited HCV infection. Treatment with SERMs for the first 2 h and treatment 2–24 h after viral inoculation reduced the production of HCV RNA. Treating persistently JFH-1 infected cells with SERMs resulted in a preferential inhibition of extracellular HCV RNA compared to intracellular HCV RNA. When we treated two subgenomic replicon cells, which harbor HCV genome genotype 2a (JFH-1) or genotype 1b, SERMs reduced HCV genome copies and viral protein NS5A. SERMs inhibited the entry of HCV pseudo-particle (HCVpp) genotypes 1a, 1b, 2a, 2b and 4 but did not inhibit vesicular stomatitis virus (VSV) entry. Further experiment using HCVpp indicated that tamoxifen affected both viral binding to cell and post-binding events including endocytosis. Taken together, SERMs seemed to target multiple steps of HCV viral life cycle: attachment, entry, replication, and post replication events. SERMs may be potential candidates for the treatment of HCV infection.     

Comparative effects of raloxifene, tamoxifen and estradiol on human osteoblasts in vitro: Estrogen receptor dependent or independent pathways of raloxifene

SERMs bind to both estrogen receptor (ER)α and β, resulting in tissue dependent estrogen agonist or antagonist responses. Both raloxifene and tamoxifen are most frequently used SERMs and exert estrogen agonistic effects on human bone tissues, but the details of their possible direct effects on human bone cells have remained largely unknown. In our present study, we examined the comparative effects of raloxifene, tamoxifen, and native estrogen, estradiol on human osteoblast cell line, hFOB in vitro. Both the cell numbers and the ratio of the cells in S phase fraction were significantly increased by the treatment of raloxifene or tamoxifen as well as estradiol treatments in hFOB. Gene profile patterns following treatment with raloxifene, tamoxifen, and estradiol demonstrated similar patterns in a microarray/hierarchal clustering analysis. We also examined the expression levels of these genes detected by this analysis using quantitative RT-PCR. MAF gene was induced by raloxifene treatment alone. GAS6 gene was induced by raloxifene and tamoxifen as well as estradiol. An estrogen receptor blocker, ICI 18, 286, inhibited an increase of GAS6 gene expression but not the levels of MAF gene mRNA expression. Results of our present study demonstrated that raloxifene exerted direct protective effects on human osteoblasts in both estrogen receptor dependent and independent manners.     

Identification of 10-dehydrooxyglycyuralin E as a selective human estrogen receptor alpha partial agonist

Selective estrogen receptor modulators (SERMs) act as either agonist or antagonist of estrogen receptor (ER) in a tissue selective manner and have been used in several diseases such as breast cancer, postmenopausal syndrome, osteoporosis, and cardiovascular diseases. However, current SERMs may also increase the risk of serious side effects and trigger drug resistance. Herein, a screening program, that was designed to search for novel SERMs, resulted in the identification of a series of 2-arylbenzofuran-containing compounds that are ligands for ERα, when applying the Gaussia-luciferase reporter assay. One of these compounds, 10-dehydrooxyglycyuralin E (T9) was chemically synthesized. T9 showed anti-estrogenic/proliferative activity in ERα-positive breast cancer cells. Pretreatment of T9 prevented the mRNA expression of GREB1, which is an estrogen response gene. Furthermore, by an in silico docking simulation study we demonstrated that T9 showed interactions directly to ERα. Taken together, these results demonstrated that T9 is a candidate of SERMs and a useful seed compound for the foundation of the selective activity of SERMs.