ALKYL PCDFS--INHIBITION OF MAMMARY CANCER

烷基PCDFS--抑制乳腺癌

• 批准号: 2843979
• 负责人: Stephen H. Safe
• 金额: $ 10.57万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-14 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2843979
• 关键词: antineoplastics; aromatic hydrocarbon receptor; athymic mouse; breast neoplasms; chemical related neoplasm /cancer; cholesterol; combination cancer therapy; disease /disorder model; dosage; drug interactions; drug screening /evaluation; estrogen inhibitor; estrogen receptors; histopathology; hormone related neoplasm /cancer; laboratory rat; neoplasm /cancer pharmacology; neoplastic cell; neoplastic growth; polychlorodibenzofuran; tamoxifen; tissue /cell culture; uterus neoplasms

Mammary and endometrial cancer are among the leading causes of premature death in North American women. Approximately one in nine women in this country will develop breast cancer during their lifetime and the incidence of mammary cancer has been increasing. Over 150,000 new cases of endometrial cancer are diagnosed worldwide each year. Epidemiology studies have clearly demonstrated that both mammary and endometrial cancer share a common set of risk factors including: early age at menarche, late age at menopause, obesity, parity and increased exposure to unopposed estrogen. A high percentage of early stage mammary tumors are estrogen receptor positive (ER+), and many of these patients respond to antiestrogen or endocrine therapy with drugs such as tamoxifen which has now been successfully used for treatment of several million women with breast cancer. Unfortunately, resistance to tamoxifen can develop in some patients and there is now increasing concern that long term use of this drug increases the risk for endometrial cancer. Therefore, it is imperative to develop new drugs which can be used alone or in combination therapy (e.g. with tamoxifen) for treatment of hormone-dependent tumors. Our studies have identified alternate-substituted alkyl PCDFs as a new mechanism-based class of antiestrogens which block estrogen-induced mammary and endometrial cell/tumor growth via crosstalk between the ER and Ah receptor signaling pathways. Based on results of previous studies, the antitumorigenic activities of selected alkyl PCDFs will be thoroughly investigated in the DMBA-induced rat mammary tumor model (Aim 1) and athymic nude mice bearing breast cancer cell xenografts (Aim 2). Aim 3 will focus on their inhibition of endometrial cancer growth in rodent models and Aim 4 will determine the important interaction of tamoxifen and alkyl PCDFs in both mammary and endometrial cancer models. These studies will also determine tissue-specific inhibition of tamoxifen-induced estrogenic responses in the uterus, bone and on serum cholesterol levels by alkyl PCDFs. Preliminary studies indicate that alkyl PCDFs block the effects of tamoxifen only in the uterus. Thus the proposed studies will define a new mechanism-based class of antiestrogens that can be used alone or in combination with tamoxifen for treatment of breast and endometrial cancer.

乳腺癌和子宫内膜癌是北美女性过早死亡的主要原因之一。在这个国家，大约每九名妇女中就有一人会在一生中患上乳腺癌，乳腺癌的发病率一直在上升。全世界每年新诊断的子宫内膜癌病例超过15万例。流行病学研究清楚地表明，乳腺癌和子宫内膜癌都有一组共同的危险因素，包括：月经初潮早、绝经晚、肥胖、产次和暴露于未经对抗的雌激素。早期乳腺肿瘤中雌激素受体阳性(ER+)的比例很高，这些患者中的许多人对抗雌激素或内分泌治疗有反应，如他莫昔芬，该药物现已成功地用于治疗数百万女性乳腺癌。不幸的是，一些患者会对他莫昔芬产生耐药性，现在越来越多的人担心长期使用这种药物会增加患子宫内膜癌的风险。因此，开发可单独使用或与他莫昔芬联合治疗激素依赖型肿瘤的新药势在必行。我们的研究发现，交替取代的烷基PCDFs是一类新的基于机制的抗雌激素，它通过ER和AH受体信号通路之间的串扰来阻断雌激素诱导的乳腺和子宫内膜细胞/肿瘤的生长。在前人研究的基础上，我们将在DMBA诱导的大鼠乳腺肿瘤模型(AIM 1)和荷瘤裸鼠模型(AIM 2)中深入研究所选择的烷基PCDF的抗肿瘤活性。目标3将重点放在它们对啮齿动物模型中子宫内膜癌生长的抑制作用，而目标4将确定他莫昔芬和烷基多氯联苯并呋喃在乳腺癌和子宫内膜癌模型中的重要相互作用。这些研究还将确定组织特异性地抑制他莫昔芬在子宫、骨骼中诱导的雌激素反应，以及烷基多氯二苯并呋喃对血清胆固醇水平的抑制。初步研究表明，烷基多氯二苯并呋喃仅在子宫内阻断他莫昔芬的作用。因此，拟议的研究将确定一类新的基于机制的抗雌激素，可以单独使用或与他莫昔芬联合用于治疗乳腺癌和子宫内膜癌。