Clinical Trial of Selenium and Prostate Biomarkers

描述（由申请人提供）：尽管针对前列腺癌（PC）取得了进展，但该疾病的治疗仍然需要大量的经济和生活质量成本。而且，由于治疗并不总是有效的，PC每年仍然杀死大约30，000名美国男性。预防，包括化学预防，仍然是一个潜在的有吸引力的方法。在众多的化学预防剂中，硒似乎很有前途;它的化学预防效用被PI领导了几年的营养预防癌症（NPC）试验强烈建议。在NPC试验中，分配到补充200 mcg硒/天的男性经历了比分配到安慰剂的男性低50%的PC死亡率;这些结果有助于导致硒用于患有高级别前列腺上皮内瘤变（HGPIN）的男性的试验和硒和维生素E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，降低雄激素受体（AR）和AR靶基因的表达，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配至每日剂量为400 mcg的硒代蛋氨酸的预处理补充剂或安慰剂来进行测试。补充8-9周后，在治疗时，将从前列腺的外周区获得活检核心样品并冷冻，然后显微解剖，通过qRT-PCR分析良性组织的AR表达作为主要终点，PSA、KLK 2、DHCR 24、CDC 6和HNFSa作为次要终点。此外，我们将探讨硒代谢中的关键酶巯基甲基转移酶的活性与硒蛋氨酸补充反应相关的假设。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（如HGPIN和SELECT）的结果。

DESCRIPTION (provided by applicant): 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.