Chemoprevention of Tamoxifen-induced Endometrial cancer by black cohosh and red c

黑升麻和红c对他莫昔芬诱发的子宫内膜癌的化学预防

基本信息

批准号：
7738811
负责人：
Birgit Maria Dietz
金额：
$ 19.82万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-17 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7738811
关键词：
4-Hydroxy-Tamoxifen Adult Adverse effects Agonist Animals Anti-Inflammatory Agents Anti-inflammatory Antioxidants Attenuated Black Cohosh Extract Blood Blood specimen Botanicals Breast Breast Cancer Cell Breast Cancer Prevention Cancer Model Cancer Survivor Cancer cell line Cancerous Cell Extracts Cell Proliferation Cells Chemoprevention Chemopreventive Agent Cimicifuga racemosa Clinical Collaborations Color Cytochrome P450 DNA Data Development Drug Metabolic Detoxication Endometrial Carcinoma Endometrial Neoplasms Endometrium Enzymes Estrogen Antagonists Estrogen Receptor Modulators Estrogen Receptors Estrogens FOS Protein Female Figs - dietary Funding Gene Proteins Genes Glutathione S-Transferase Goals Growth High Risk Woman Hot flushes Human Implant In Vitro Incidence Inhibition of Cell Proliferation Insulin-Like Growth Factor I Knowledge Lesion Literature Liver Malignant Neoplasms Mammary Gland Parenchyma Measures Mediating Menopausal Symptom Metabolism Modeling Mutation Nude Mice Oxidative Stress Pathway interactions Patients Population Premalignant Premalignant Cell Prodrugs Property Proteins Proto-Oncogene Proteins c-fos Quinone Reductases Rattus Relative (related person)Reporting Risk Safety Sampling Selective Estrogen Receptor Modulators TFF1 gene Tamoxifen Toxic effect Trifolium pratense Tumor Promotion Tumor Volume Uterus Woman base c-myc Genes cancer cell cancer risk complement C2a deprivation dietary supplements hydroxytamoxifen improved in vitro Assay in vivo lifetime risk malignant breast neoplasm prevent public health relevance research study response sulfotransferase tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Chemoprevention of Tamoxifen-induced Endometrial cancer by black cohosh and red clover Breast cancer is the most common cancer in women. The selective estrogen receptor modulator tamoxifen, which antagonizes estrogen in breast tissue, is efficacious in the treatment and prevention of breast cancer. In tamoxifen treated patients, botanical dietary supplements such as red clover and black cohosh extracts are frequently used for the alleviation of tamoxifen related menopausal symptoms. Very few studies about the modifying effects of these botanicals on tamoxifen's safety and efficacy have been reported. Tamoxifen's major side effect is an enhanced endometrial cancer risk. Tamoxifen's ER1 mediated uterotrophic activity and its reactive metabolites are believed to be responsible for this effect. Black cohosh and red clover contain anti-oxidative, anti-proliferative, anti-inflammatory, and detoxification enzyme inducing compounds, which could inhibit the initiation or retard the promotion and progression of cancerous cells. The central hypothesis of this project is that black cohosh and red clover reduce the carcinogenic effects of tamoxifen on the endometrium by inhibition of cell proliferation (Aim I) and through enhancing detoxification pathways (Aim 2). To support this hypothesis we propose the following specific aims: 1. What is the effect of red clover or black cohosh on tamoxifen-stimulated endometrial cancer? Recent data suggest that black cohosh and red clover can attenuate tamoxifen-stimulated endometrial cancer growth by inhibiting cell proliferation. We will measure the influence of these botanicals on tamoxifen stimulated endometrial tumor growth in ovariectomized athymic nude mice, an established endometrial cancer model for studying estrogenic influences. The mechanism of interaction will be examined by analyzing the expression of pro-proliferative genes and proteins important for tamoxifen mediated tumor promotion in vivo and in vitro. To further identify active compounds, we will examine the anti-proliferative effect of isolated compounds in endometrial cancer cells and in an immature rat model. 2. What is the effect of black cohosh or red clover on detoxification pathways of reactive tamoxifen metabolites? Our data indicate that both botanical upregulate the cellular antioxidative response machinery, thus reducing the carcinogenic effect of tamoxifen's reactive metabolites. We will study the ability of these botanicals to induce the detoxification enzymes, quinone reductase and glutathione-S-transferase, in the uterus and liver of adult rats. We will also analyze whether black cohosh and red clover prevent tamoxifen induced oxidative stress in these animals. Additionally, we will examine the effect of the botanicals on tamoxifen's metabolism to active or reactive metabolites in the blood. To elucidate the compounds responsible for the various effects, isolated constituents will be assayed in vitro. The completion of these specific aims will provide an overall picture of the effect of these botanicals and purified compounds on the efficacy of tamoxifen and on tamoxifen induced endometrial cancer, which is of importance considering the increasing number of breast cancer survivors and women at high risk undergoing tamoxifen treatment. PUBLIC HEALTH RELEVANCE: The selective estrogen receptor modulator, tamoxifen, is very effective in treatment and prevention of breast cancer; however, it causes menopausal symptoms and has carcinogenic effects on the endometrium. We hypothesize that red clover and black cohosh, both frequently used for the alleviation of menopausal symptoms, will reduce tamoxifen-induced endometrial cancer due to their cancer chemopreventive properties.

描述（由申请人提供）：黑莫昔芬诱导的子宫内膜癌的化学预防，黑co和红三叶草乳腺癌是女性最常见的癌症。抗乳腺组织中雌激素的选择性雌激素受体调节蛋白莫昔芬在治疗和预防乳腺癌方面有效。在他莫昔芬治疗的患者中，植物饮食补充剂（例如红三叶草和黑色同chosh提取物）经常用于缓解他莫昔芬相关的绝经症状。关于这些植物因子对他莫昔芬的安全性和功效的修改作用的研究很少。他莫昔芬的主要副作用是增强的子宫内膜癌风险。他莫昔芬的ER1介导的子营养活性及其反应性代谢产物被认为是造成这种作用的原因。黑色同胞和红三叶草含有抗氧化，抗增殖，抗炎和排毒酶诱导化合物，可以抑制或阻碍癌细胞的促进和进展。该项目的中心假设是，黑色同胞和红三叶草通过抑制细胞增殖（AIM I）和增强解毒途径（AIM 2）来减少他莫昔芬对子宫内膜的致癌作用。为了支持这一假设，我们提出了以下特定目的：1。红三叶草或黑色同胞对他莫昔芬刺激的子宫内膜癌的影响是什么？最近的数据表明，黑色同胞和红三叶草可以通过抑制细胞增殖来减弱他莫昔芬刺激的子宫内膜癌的生长。我们将测量这些植物体对他莫昔芬刺激的子宫内膜肿瘤生长的影响，这是一种已建立的子宫内膜癌模型，用于研究雌激素的影响。通过分析对他莫昔芬介导的体内和体外促进肿瘤促进的促增强基因和蛋白质的表达，将检查相互作用的机制。为了进一步鉴定活性化合物，我们将检查子宫内膜癌细胞中分离化合物的抗增殖作用和未成熟大鼠模型。 2。黑山co或红三叶草对反应性他莫昔芬代谢物的排毒途径有什么影响？我们的数据表明，两者都会上调细胞抗氧化反应机制，从而降低了他莫昔芬反应性代谢产物的致癌作用。我们将研究这些植物体在成年大鼠的子宫和肝脏中诱导排毒酶，喹酮还原酶和谷胱甘肽-S-转移酶的能力。我们还将分析黑色同壳和红三叶草是否可以防止他莫昔芬诱导这些动物的氧化应激。此外，我们将研究植物体对他莫昔芬代谢对血液中活性或反应性代谢产物的影响。为了阐明负责各种作用的化合物，将在体外测定分离的成分。这些特定目标的完成将为这些植物药的影响以及纯化的化合物对他莫昔芬和他莫昔芬诱导的子宫内膜癌的疗效的影响提供总体图，考虑到高风险接受他莫昔芬治疗的高风险，这一点很重要。公共卫生相关性：选择性雌激素受体调节剂他莫昔芬在治疗和预防乳腺癌方面非常有效。但是，它会引起绝经症状，并对子宫内膜具有致癌作用。我们假设红三叶草和黑色cohosh经常用于缓解绝经症状，将由于其癌症化学预防特性而降低他莫昔芬诱导的子宫内膜癌。