Interactions between SERMs, soy and black cohosh

SERM、大豆和黑升麻之间的相互作用

• 批准号: 7098688
• 负责人: HEATHER S SHAW
• 金额: $ 12.57万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7098688
• 关键词: adult human (21+); athymic mouse; biological signal transduction; breast neoplasms; cell line; cell proliferation; clinical research; estrogen receptors; female; genetic transcription; genistein; high performance liquid chromatography; human subject; pharmacokinetics; phytoestrogens; raloxifene; tamoxifen; tissue /cell culture; young adult human (21-34)

DESCRIPTION (provided by applicant): Tamoxifen is the most commonly used selective estrogen receptor modulator (SERM) in the treatment and prevention of breast cancer. Raloxifene, a newer SERM, is currently widely used for treatment of osteoporosis and is in trials for breast cancer prevention. A new health awareness is growing among women, resulting in the use of natural supplements such as soy and black cohosh for the treatment and prevention of menopausal symptoms. Each of these substances has also been shown to contain phytoestrogens, plant derived substances, which interact functionally with ER. Therefore, there is a potential for competition between soy or black cohosh and SERMs, which may result in decreased efficacy of the prescribed medication. It is essential to know whether this interaction exists and what ramifications it may have in order to properly counsel patients about the combined use of SERMs and phytoestrogen containing natural supplements. We hypothesize that the natural products soy and black cohosh and/or their metabolites will alter the effects of tamoxifen and raloxifene on 1) ER-dependent transcription and cellular proliferation in vitro and 2) anti-tumor efficacy in a human breast cancer xenograft model in nude mice. The ultimate objective of this study is to determine the safety of combined use of SERMs and natural product dietary supplements. To begin to address this long-term goal, we plan to: 1) Determine effects of addition of genistein, daidzein, equol, and 27-deoxyactein to tamoxifen, its metabolites, and raloxifene on ER-signaling of MCF-7 human breast cancer cells and proliferation of MCF-7 and MDA-MB-231 ceils in vitro. 2) Determine effects of addition of soy and black cohosh to tamoxifen and raloxifene on ER-signaling of MCF-7 cells and proliferation of MCF-7 and MDA-MB-231 cells in vitro in a simulated system of human colonic fermentation and hepatic metabolism. 3) Determine pharmacokinetics of black cohosh in female volunteers. 4) Determine pharmacokinetics of black cohosh and soy in immunocompetent mice. 5) Determine interactions between ingested standardized soy or black cohosh and tamoxifen on MCF-7 breast cancer growth in an in vivo nude mouse model. The sponsors of the proposed study and the laboratories in which the candidate is working have extensive experience in isolation and characterization of natural products and in cancer research, which is essential to accomplishing the scientific goals outlined here as well as facilitating the development of the candidate into a productive independent investigator.

描述（由申请人提供）：他莫昔芬是治疗和预防乳腺癌的最常用的选择性雌激素受体调节剂（SERM）。雷昔芬是一种新的Serm，目前广泛用于治疗骨质疏松症，并正在试验预防乳腺癌。女性的健康意识正在增长，导致使用大豆和黑色同岛等自然补充剂来治疗和预防更年期症状。这些物质中的每一种也已被证明包含植物雌激素，植物衍生物质，它们与ER的功能在功能上相互作用。因此，大豆或黑色同胞和SERM之间的竞争可能会导致处方药的疗效降低。必须知道这种相互作用是否存在以及为了适当地咨询患者的综合使用Serm和含有天然补充剂的植物雌激素，它可能会有什么影响。 我们假设天然产物大豆和黑山co和/或它们的代谢产物将改变他莫昔芬和雷昔芬对1）体外依赖性转录和细胞增殖的作用，以及2）抗肿瘤疗效对人类乳腺癌在裸鼠模型中的抗肿瘤功效。这项研究的最终目的是确定Serms和Natural产品饮食补充剂的合并使用的安全性。为了开始解决这一长期目标，我们计划：1）确定对他莫昔芬（其代谢产物的代谢产物）以及roxifene的添加染料木黄酮，大兹蛋白，雌激素和27-脱氧酸的影响对MCF-7人类乳腺癌细胞的ER信号以及MCF-7和MDA-MB-231 CEIL的ER信号。 2）确定对他莫昔芬和roxifene中添加大豆和黑昔芬对MCF-7细胞的ER信号以及MCF-7和MDA-MB-231细胞的增殖的影响，在模拟的人类结肠发酵和肝脏代谢的模拟系统中。 3）确定女性志愿者中黑科什的药代动力学。 4）确定免疫能力小鼠中黑色同胞和大豆的药代动力学。 5）确定在体内裸小鼠模型中，在MCF-7乳腺癌生长上摄入的标准大豆或黑莫昔芬与他莫昔芬之间的相互作用。 拟议的研究的赞助商和候选人正在工作的实验室具有丰富的天然产品和癌症研究表征的丰富经验，这对于完成此处概述的科学目标以及促进候选人将候选人发展成生产性独立研究者至关重要。