Mechanism(s)of antitumor action of tamoxifen and soy

他莫昔芬和大豆的抗肿瘤作用机制

• 批准号: 6658979
• 负责人: ANDREAS I. CONSTANTINOU
• 金额: $ 45.95万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-28 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6658979
• 关键词: AP1 protein; athymic mouse; breast neoplasms; cancer prevention; chemoprevention; estrogen receptors; estrogens; genetic regulatory element; hormone related neoplasm /cancer; neoplasm /cancer genetics; nutrition aspect of cancer; nutrition related tag; phytoestrogens; soybeans; tamoxifen

DESCRIPTION (provided by applicant): Tamoxifen, an estrogen receptor alpha (ERa) antagonist, is an effective chemopreventive agent against breast cancer. The soy phytoestrogens genistein and daidzein selectively bind to ERbeta. Theoretically, these soy phytoestrogens (also known as soy isoflavones) may enhance or negate tamoxifen's chemopreventive effects. Women at high risk for developing breast cancer, or breast cancer patients with ER-positive tumors, are now treated with tamoxifen to prevent primary breast tumors or the development of recurrences, respectively. However, it is presently uncertain if these women are benefited or harmed by consuming soy products, or by taking phytoestrogens as supplements. Our recent preliminary studies in the dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis rat model suggest that soy compound(s), possibly phytoestrogens, enhance tamoxifen's chemopreventive action. We hypothesize that soy phytoestrogens (or other soy compounds) enhance tamoxifen's antitumor action. The proposed mechanism of action is that tamoxifen, acting mainly as an ER-alpha antagonist, and soy phytoestrogens acting mainly as ER-beta-selective agents, exert antiproliferative and/or antioxidant effects against mammary carcinogenesis. We propose to elucidate the mechanism(s) whereby tamoxifen and phytoestrogens exert their antitumor effects by examining both ER-dependent and ER-independent signaling pathways. The specific aims are: (1) Determine if the antitumor effects of 4-hydroxytamoxifen (4-OHT) and soy phytoestrogens are mediated through the estrogen response element (ERE), the activator protein-1 (AP-1) pathway, or the G-C rich simianvirus-40-protein-1 (SP-1) pathway. (2) Determine if the antioxidant response element (ARE) mediates the individual and combined effects of 4-OHT and soy phytoestrogens. (3) Evaluate how the combination of tamoxifen and soy phytoestrogens affects tumor recurrence in the DMBA/rat mammary carcinogenesis model, and the development of tamoxifen-stimulated mammary tumors in athymic mice. Increasing numbers of women are taking tamoxifen together with soy or soy isoflavones, yet little is known about the effects of this combination. This study will systematically explore their interactions to determine their safety and efficacy.

描述（由申请人提供）：他莫昔芬，一种雌激素受体α (ERa)拮抗剂是一种有效的乳腺癌化学预防剂。 大豆植物雌激素染料木黄酮和大豆苷元选择性结合ER β。 理论上，这些大豆植物雌激素（也称为大豆雌激素）可能 增强或消除他莫昔芬的化学预防作用。高危妇女 发生乳腺癌或ER阳性肿瘤的乳腺癌患者， 现在使用他莫昔芬治疗以预防原发性乳腺肿瘤或 复发的发展。然而，目前尚不确定， 这些妇女因食用豆制品或服用 植物雌激素作为补充剂。我们最近对 二甲基苯并蒽诱发大鼠乳腺癌模型 提示大豆化合物，可能是植物雌激素，增强他莫昔芬 化学预防作用我们假设大豆植物雌激素（或其他大豆 化合物）增强他莫昔芬的抗肿瘤作用。拟议的机制 作用是他莫昔芬，主要作为ER-α拮抗剂，和大豆 植物雌激素主要作为ER-β-选择剂发挥作用， 对乳腺癌发生的抗增殖和/或抗氧化作用。我们 建议阐明他莫昔芬和植物雌激素 通过检测ER依赖性和ER非依赖性来发挥其抗肿瘤作用 信号通路具体目的是：（1）确定是否存在抗肿瘤 4-羟基他莫昔芬（4-OHT）和大豆植物雌激素的作用是通过 通过雌激素反应元件（ERE），激活蛋白-1（AP-1） 途径或富含G-C的猿猴病毒-40-蛋白-1（SP-1）途径。(2)确定 如果抗氧化反应元件（ARE）介导个体和组合 4-OHT和大豆植物雌激素的影响。(3)评估如何结合 他莫昔芬和大豆植物雌激素影响DMBA/大鼠的肿瘤复发 乳腺癌发生模型，以及他莫昔芬刺激的 无胸腺小鼠的乳腺肿瘤。越来越多的妇女正在采取 他莫昔芬与大豆或大豆异黄酮一起，但很少有人知道， 这种组合的影响。本研究将系统地探讨其 以确定其安全性和有效性。

项目成果

Targeting colon cancer cells with genistein-17.1A immunoconjugate.

使用金雀异黄素-17.1A 免疫缀合物靶向结肠癌细胞。

• 发表时间: 2003
• 期刊: International journal of oncology.
• 作者: Gentile,MichelleS;Vasu,Chenthamarakshan;Green,Albert;Murillo,Genoveva;DasGupta,TapasK;Constantinou,AndreasI;Prabhakar,BellurS;Salti,GeorgeI
• 通讯作者: Salti,GeorgeI