SELECT Pre-Clinical Trial of Prostate Cancer

前列腺癌的 SELECT 临床前试验

• 批准号: 7544541
• 负责人: Nihal Ahmad
• 金额: $ 25.08万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-07 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7544541
• 关键词: Adenocarcinoma; Advanced Malignant Neoplasm; Age; American; Animal Model; Animals; Antioxidants; Apoptosis; Apoptotic; Area; Binding Proteins; Biological Markers; Breeding; Cancer Biology; Cancer Etiology; Caspase; Cell Aging; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical Chemoprevention; Controlled Clinical Trials; Cyclin-Dependent Kinase Inhibitor; DNA Fragmentation; Data; Development; Diagnosis; Digital Rectal Examination; Disease Management; Double-Blind Method; E-Cadherin; Epidemiology; Funding; Future; Galactosidase; Gamma-glutamyl transferase; Genes; Glucosephosphate Dehydrogenase; Glutathione S-Transferase; Growth Factor; Human; India ink stain; Individual; Institution; Insulin; Insulin-Like Growth Factor I; Integrins; International; Intervention Trial; Knowledge; L-Selenomethionine; Lead; Lipid Peroxidation; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Metastatic Prostate Cancer; Methods; Modeling; Modification; Molecular; Monitor; Mus; NF-kappa B; National Cancer Institute; Neoplasm Metastasis; Oral Administration; Outcome; Oxidases; Oxidative Stress; Pathway interactions; Phase; Placebo Control; Preventive; Prostate; Prostate Cancer Prevention Trial; Protein Family; Protein p53; Proteins; Public Health; Randomized; Research; Research Personnel; Risk; SOD2 gene; Sampling; Selenium; Serum; Southwest Oncology Group; Staging; Study Subject; Suggestion; Superoxide Dismutase; Telomerase; Testing; Therapeutic; Thioredoxin; Time; Tissues; Transgenic Organisms; Tumor Weights; United States; Universities; Vitamin E; Vitamin E Acetate; Weight; Wisconsin; Work; Yeasts; age effect; animal colony; base; catalase; design; enzyme activity; glutathione peroxidase; glutathione synthase; human disease; insulin-like growth factor binding protein-related protein 1; interest; male; men; mouse model; novel; peroxiredoxin 5; pre-clinical; preclinical study; programs; prospective; prostate cancer prevention; prostate carcinogenesis; research study; response; ribosomal protein L19; senescence; serum PSA; treatment effect; tumor growth; tumor progression; tumorigenesis

Prostate Cancer (PCa), next only to lung cancer, is the second leading cause of cancer-related deaths in American males. At present, there are inadequate treatment options for the management of PCa. The public health impact from PCa has spawned tremendous interest in Chemoprevention trials. Preclinical, epidemiological, and phase III randomized, placebo-controlled clinical trials suggest that selenium and vitamin E could be effective in PCa prevention. Based on these studies, 'Selenium and Vitamin E Chemoprevention Trial (SELECT)' has been initiated. It is a randomized, prospective, double-blind study (7- 12 years) designed to determine whether selenium and vitamin E alone and in combination could reduce the risk of PCa among healthy men. This is an outstanding effort of its kind. However, several investigators are critical about the rationale whereas several others have arguments. Two popular questions in this direction are: (1) whether there are sufficient data on these supplements to justify this trial; and (2) whether more biomarkers (which could suggest the possible molecular mechanisms involved) should be included in SELECT trial. The present proposal, on a pre-clinical SELECT Trial in a well-established mouse model of prostate carcinogenesis, should provide answers to these questions. The hypothesis of this proposal is that a combination of vitamin E and selenium will provide synergistic chemopreventive effect against PCa via inhibiting oxidative stress and enhancing apoptotic and/or senescence response. Employing transgenic adenocarcinoma mouse prostate (TRAMP) mice, we propose to conduct a pre-clinical Chemoprevention/ intervention trial that mimics SELECT trial (in human) to determine whether selenium and vitamin E alone and in combination can inhibit PCa development and its metastasis. We will also study the involvement of oxidative stress, apoptosis and cellular senescence during PCa development and its inhibition by vitamin E and/or selenium. Finally, we will study the involvement of NF-kappaB pathway during the modulation in oxidative stress and apoptotic/senescence response of selenium and/or vitamin E treatments in TRAMP model. We believe that a successful completion of our study will provide important information regarding the possible outcome of SELECT trial in humans and may even provide novel information on which suggestions could be made for the modifications for the ongoing or future trials.

前列腺癌（PCA）仅次于肺癌，是与癌症相关死亡的第二大原因 美国男性。目前，PCA管理的治疗选择不足。公众 PCA的健康影响产生了对化学预防试验的极大兴趣。临床前， 流行病学和第三阶段随机，安慰剂对照的临床试验表明硒和 维生素E可以有效预防PCA。基于这些研究，硒和维生素E 化学预防试验（SELECT）已开始。这是一项随机，前瞻性的双盲研究（7- 12年）旨在确定单独和组合硒和维生素E是否可以减少 健康男性的PCA风险。这是同类的杰出努力。但是，有几个调查人员是 对基本原理的批判性，而其他几个也有争论。这两个方向的两个流行问题 是：（1）这些补充剂是否有足够的数据来证明该试验合理； （2）是否更多 生物标志物（可能暗示可能涉及的分子机制）应包括 选择试验。本提案是在一个完善的鼠标模型中进行的临床前选择试验 前列腺致癌作用应为这些问题提供答案。该提议的假设是 维生素E和硒的组合将通过PCA通过 抑制氧化应激并增强凋亡和/或衰老反应。使用转基因 腺癌小鼠前列腺（流浪汉）小鼠，我们建议进行临床前化学预防/ 干预试验模仿精选试验（人类），以确定单独的硒和维生素E是否单独 结合使用可以抑制PCA的发展及其转移。我们还将研究 PCA发育过程中的氧化应激，凋亡和细胞衰老及其对维生素E的抑制作用 和/或硒。最后，我们将研究在调制过程中NF-kappab途径的参与 硒和/或维生素E处理中的氧化应激和凋亡/衰老反应 模型。我们认为，成功完成我们的研究将提供有关 在人类中选定试验的可能结果，甚至可能提供有关哪些建议的新信息 可以为正在进行的或将来的试验进行修改。