Selenium Colorectal Cancer Chemoprevention Trials

描述（由申请人提供）：结直肠腺瘤（CRAs）是大多数结直肠癌（CRC）病例的良性前体，是癌症死亡的主要原因；晚期cra最有可能发展为CRC。虽然大多数cra可以在结肠镜检查时切除，但在3-5年后再次进行结肠镜检查的患者中，有20-50%出现异时性cra，即新的cra。此外，一部分crc不能通过结肠镜筛查来预防，因此需要其他预防策略，如化学预防。作为一种补充剂，硒（Se），一种微量膳食矿物质，被纳入特殊的硒蛋白中，作为非黑色素瘤皮肤癌化学预防试验的次要终点，先前被证明可以预防结直肠癌和普遍的CRAs。通过随机对照试验（RCTs）比较干预组和安慰剂组之间的同步CRA率，以及FDA认可的CRA替代物对CRC的影响，可以评估CRC的化学预防药物。目前还没有报道将硒补充剂用于结直肠癌化学预防或任何其他肿瘤前疾病作为主要终点的随机对照试验。这项申请是为期3年的资助，以完成硒试验（SeT）；一项随机对照试验，每天硒200克作为硒化酵母，其中随机化已完成。主要的研究假设是，使用酵母硒治疗3至5年将降低异时性cra的发生率，且没有相关的严重毒性。在2014年初完成所有1800名SeT参与者的研究，并进行数据分析和报告。最近发表的研究表明，过量硒暴露可能会增加2型糖尿病（T2D）的风险。虽然人类硒相关T2D的机制尚不清楚，但动物研究表明，谷胱甘肽过氧化物酶1 （GPX1）的慢性激活可能导致高胰岛素血症、高血糖、胰岛素抵抗和肥胖。GPX1是一种有效的抗氧化硒蛋白。因此，硒补充剂是否会导致T2D的问题具有重要的公共卫生意义。在SeT队列中，我们提出了两种方法来研究硒对T2D、胰岛素敏感性和分泌的影响：采用整个队列的流行病学方法；在300名受试者（150名安慰剂组和150名酵母硒组）的亚队列中，使用改良的口服葡萄糖耐量试验，评估硒补充对个体水平胰岛素分泌和敏感性的影响。在二级分析中，我们将调查基线硒水平、遗传背景和/或使用低剂量阿司匹林是否会改变硒对CRA发生或T2D风险的影响。

DESCRIPTION (provided by applicant): Colorectal adenomas (CRAs) are the benign precursors of most cases of colorectal cancer (CRC), a leading cause of cancer deaths; advanced CRAs are those most likely to progress to CRC. Although most CRAs can be removed at colonoscopy, 20-50% of individuals undergoing repeat colonoscopy 3-5 years later have metachronous, i.e. new, CRAs. Furthermore, a proportion of CRCs are not preventable through screening colonoscopy, necessitating alternative preventive strategies, such as chemoprevention. When given as a supplement, selenium (Se), a trace dietary mineral that is incorporated into specialized selenoproteins was previously shown to protect against CRC and prevalent CRAs as secondary endpoints in a non-melanoma skin cancer chemoprevention trial. Chemopreventive agents for CRC can be assessed in randomized controlled trials (RCTs) comparing metachronous CRA rates between intervention and placebo groups with results of effects on CRA recognized by the FDA as a CRC surrogate. No RCTs of Se supplements for CRC chemoprevention or for any other preneoplastic condition as the primary endpoint, have been reported. This application is for 3 years funding to complete The Selenium Trial (SeT); an RCT of Se, 200 5g daily as selenized yeast, for which randomization is completed. The primary study hypothesis is that treatment with Se yeast for 3 to 5 years will reduce the rate of metachronous CRAs without associated serious toxicities. Funding is requested to follow remaining SeT participants through study completion for all 1,800 participants in early 2014, and for data analysis and reporting. A major new study aim has been added to address the suggestion in recent published studies that excessive Se exposure may increase risk for type 2 diabetes (T2D). Although a mechanism for Se-related T2D in human is obscure, animal studies suggest that chronic activation of glutathione peroxidase 1 (GPX1), a potent anti-oxidant selenoprotein, may lead to the development of hyperinsulinemia, hyperglycemia, insulin resistance, and obesity. Therefore, the question of whether or not Se supplementation contributes to T2D has important public health implications. In the SeT cohort, we propose two approaches to studying the effects of Se on T2D, and insulin sensitivity and secretion: an epidemiological approach using the entire cohort; and assessment of the effect of Se supplementation on insulin secretion and sensitivity at the individual level using a modified oral glucose tolerance test in a sub- cohort of 300 subjects (150 on placebo and 150 on Se yeast). In secondary analyses, we will investigate whether or not baseline Se levels, genetic background, and/or use of low-dose aspirin modify Se effects on CRA occurrence or risk for T2D.