Clinical Trial of Selenium and Prostate Biomarkers

硒和前列腺生物标志物的临床试验

• 批准号: 7339042
• 负责人: James Marshall
• 金额: $ 41.08万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-10 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7339042
• 关键词: American; Androgen Receptor; Androgens; Benign; Biological Markers; Cancer Patient; Cancer Prevention Trial; Cell Cycle; Chemoprevention; Chemopreventive Agent; Clinical Trials; Core Biopsy; Daily; Desmosterol; Disease; Dose; Down-Regulation; End Point; Enzymes; Freezing; Gene Targeting; Genes; Human; Human Glandular Kallikrein 2; Laboratories; Lead; Living Costs; Malignant neoplasm of prostate; Metabolism; Nutritional; Oxidoreductase; Patient Schedules; Peripheral; Phenotype; Placebos; Population; Prevention; Prostate; Prostate-Specific Antigen; Prostatectomy; Prostatic; Prostatic Intraepithelial Neoplasias; Quality of life; Randomized; Receptor Signaling; Sampling; Selenium; Selenium/vitamin E; Selenomethionine; Signal Transduction; Supplementation; Testing; Tissues; Week; cancer therapy; day; experience; hepatocyte nuclear factor 6; human data; in vivo; killings; men; mortality; response; thiol S-methyltransferase; transcription factor

In spite of progress against prostate cancer (PC), treatment of the disease still exacts significant financial and quality-of-life costs. And, as treatment is not always effective, PC still kills some 30,000 American men each year. Prevention, including chemoprevention, remains a potentially attractive approach. Among the numerous chemopreventive agents, selenium appears promising; its chemopreventive utility was strongly suggested by the Nutritional Prevention of Cancer (NPC) trial, led for several years by the PI. In the NPC trial, men assigned to supplementation by 200 meg selenium/day experienced 50% lower PC mortality than men assigned to placebo; these results helped to lead to the trials of selenium for men with high grade prostatic intraepithelial neoplasia (HGPIN) and to the Selenium and Vitamin E Chemoprevention Trial (SELECT). The mechanisms underlying the chemopreventive action of selenium in PC are poorly understood. Results from our laboratory indicate that selenium alters androgen signaling, with decreased expression of the androgen receptor (AR), and AR target genes such as prostate-specific antigen (PSA), kallikrein 2 (KLK2), 24-dehydrocholesterol reductase (DHCR24), cell division cycle 6 (CDC6), and hepatocyte nuclear factor 3a (HNF3a). These findings need to be tested in human populations; we propose to do this by randomizing prostate cancer patients scheduled for brachythrapy and prostatectomy to pretreatment supplementation by daily dose of 400 meg selenomethionine, or to placebo. After 8-9 weeks of supplementation, at treatment, biopsy core samples will be obtained from the peripheral zone of the prostate and frozen, then microdissected, with benign tissue analyzed by qRT-PCR for expression of AR as the primary endpoint, and for PSA, KLK2, DHCR24, CDC6 and HNFSa as secondary endpoints. In addition, we will explore the hypothesis that the activity of thiol methyltransferase, a key enzyme in selenium metabolism, correlates with the response to selenomethionine supplementation. This study will provide key in vivo, human data on the mechanisms of selenium's action in the prostate, and greatly help interpret the results of the important chemoprevention trials such as HGPIN and SELECT.

尽管对前列腺癌（PC）的进展，疾病的治疗仍然需要显着 财务和生活质量成本。而且，由于治疗并不总是有效的，PC仍然杀死了大约30，000人 美国人每年预防，包括化学预防，仍然是一个潜在的有吸引力的 approach. 在众多的化学预防剂中，硒似乎很有前途，其化学预防效用 癌症的营养预防（NPC）试验强烈建议，该试验由 Pi.在NPC试验中，每天补充200 mcg硒的男性经历了50%的 PC死亡率低于分配到安慰剂组的男性;这些结果有助于导致硒试验 对于患有高度前列腺上皮内瘤变（HGPIN）的男性， 化学预防试验（SELECT）。 硒在PC中的化学预防作用的机制知之甚少。 我们实验室的结果表明，硒改变雄激素信号传导， 雄激素受体（AR）和AR靶基因，如前列腺特异性抗原（PSA），激肽释放酶 2（KLK 2）、24-脱氢胆固醇还原酶（DHCR 24）、细胞分裂周期6（CDC 6）和肝细胞 核因子3a（HNF 3a）。这些发现需要在人群中进行测试;我们建议这样做。 这是通过将计划进行近距离放射治疗和前列腺切除术的前列腺癌患者随机分组， 治疗前补充400 mcg日剂量的硒代甲硫氨酸或安慰剂。8-9岁之后 在治疗时，将从外周区获得活检核心样本 将前列腺组织冷冻，然后进行显微解剖，通过qRT-PCR分析良性组织， AR表达作为主要终点，PSA、KLK 2、DHCR 24、CDC 6和HNFSa作为主要终点。 次要终点。此外，我们还将探讨巯基活性 甲基转移酶是硒代谢中的关键酶，与对硒的反应相关。 硒代蛋氨酸补充剂。 这项研究将提供关于硒在前列腺中作用机制的关键体内人体数据， 并极大地帮助解释重要的化学预防试验的结果，如HGPIN和 选择.