SELECT Pre-Clinical Trial of Prostate Cancer

选择性前列腺癌临床前试验

基本信息

批准号：
7176801
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
项目类别：
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/7176801
关键词：
Adenocarcinoma Advanced Malignant Neoplasm Age American Animal Model Animals Antioxidants Apoptosis Apoptotic Area Binding Proteins Biological Markers Breeding CDKN1A gene Cancer Biology Cancer Etiology Caspase Cell Aging Cessation of life Chemoprevention Chemopreventive Agent Controlled Clinical Trials Cyclin-Dependent Kinase Inhibitor DNA Fragmentation Data Development Diagnosis Digital Rectal Examination Disease Management Double-Blind Method E-Cadherin 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 NAD(P)H oxidase NF-kappa B National Cancer Institute Neoplasm Metastasis Oral Administration Outcome Oxidative Stress Pathway interactions Phase Placebo Control Preventive Prostate Prostate Cancer Prevention Trial Protein Family Protein p53 Proteins Public Health Purpose Randomized Research Research Personnel Risk SOD2 gene Sampling Selenium Selenium/vitamin E 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 Week Weight Wisconsin Work Yeasts age effect animal colony base carcinogenesis 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 oncoprotein p21 p27 Cell Cycle Protein p27 Enzyme Inhibitor peroxiredoxin 5 pre-clinical preclinical study programs prospective prostate cancer prevention research study response ribosomal protein L19 senescence serum PSA treatment effect tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：前列腺癌（PCa）仅次于肺癌，是美国男性癌症相关死亡的第二大原因。目前，治疗 PCa 的治疗方案不足。 PCa 对公共健康的影响引起了人们对化学预防试验的极大兴趣。临床前、流行病学和 III 期随机、安慰剂对照临床试验表明，硒和维生素 E 可有效预防 PCa。基于这些研究，“硒和维生素 E 化学预防试验 (SELECT)”已经启动。这是一项随机、前瞻性、双盲研究（7-12 年），旨在确定硒和维生素 E 单独或联合使用是否可以降低健康男性患前列腺癌的风险。这是同类中一项杰出的努力。然而，一些研究人员对其基本原理持批评态度，而其他一些研究人员则提出了论点。这个方向的两个常见问题是：（1）这些补充剂是否有足够的数据来证明这项试验的合理性； (2) SELECT 试验中是否应纳入更多生物标志物（可以提示可能涉及的分子机制）。目前的提案是在成熟的前列腺癌小鼠模型中进行临床前 SELECT 试验，应该为这些问题提供答案。该提案的假设是，维生素 E 和硒的组合将通过抑制氧化应激和增强细胞凋亡和/或衰老反应，对 PCa 提供协同化学预防作用。我们建议采用转基因前列腺腺癌小鼠 (TRAMP) 小鼠进行一项临床前化学预防/干预试验，模拟 SELECT 试验（在人类中），以确定硒和维生素 E 单独或联合使用是否可以抑制 PCa 的发展及其转移。我们还将研究 PCa 发育过程中氧化应激、细胞凋亡和细胞衰老的参与以及维生素 E 和/或硒的抑制作用。最后，我们将研究 TRAMP 模型中硒和/或维生素 E 治疗的氧化应激和细胞凋亡/衰老反应调节过程中 NF-kappaB 通路的参与。我们相信，我们研究的成功完成将为人类 SELECT 试验的可能结果提供重要信息，甚至可能提供新的信息，为正在进行或未来的试验的修改提出建议。