Selenium Colorectal Cancer Chemoprevention Trials

描述（由申请人提供）：结直肠腺瘤（CRA）是大多数结直肠癌（CRC）病例的良性前体，CRC是癌症死亡的主要原因;晚期CRA最有可能进展为CRC。尽管大多数CRA可以在结肠镜检查时被移除，但在3-5年后接受重复结肠镜检查的个体中有20-50%具有异时性，即新的CRA。此外，一部分CRC不能通过筛查结肠镜来预防，需要替代预防策略，如化学预防。当作为补充剂给予时，硒（Se），一种掺入专门硒蛋白的微量膳食矿物质，先前在非黑色素瘤皮肤癌化学预防试验中被证明可以预防CRC和普遍的CRA作为次要终点。CRC的化学预防剂可以在随机对照试验（RCT）中进行评估，这些试验比较了干预组和安慰剂组之间的异时CRA率，并对FDA认可的CRA作为CRC替代物的效果进行了评估。没有关于硒补充剂用于CRC化学预防或任何其他癌前疾病作为主要终点的RCT报告。本申请是3年的资金，以完成硒试验（SeT）;一项随机对照试验的硒，200 5克，每天作为硒化酵母，其中随机化完成。主要研究假设是用硒酵母治疗3至5年将降低异时CRA的发生率，而没有相关的严重毒性。要求提供资金，以跟踪剩余的SeT参与者，直到2014年初完成所有1，800名参与者的研究，并进行数据分析和报告。增加了一个主要的新研究目的，以解决最近发表的研究中的建议，即过量的硒暴露可能会增加2型糖尿病（T2 D）的风险。尽管硒相关T2 D在人类中的机制尚不清楚，但动物研究表明，谷胱甘肽过氧化物酶1（GPX 1）（一种有效的抗氧化硒蛋白）的慢性激活可能导致高胰岛素血症、高血糖症、胰岛素抵抗和肥胖症的发生。因此，硒补充是否有助于T2 D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Se对T2 D以及胰岛素敏感性和分泌的影响：使用整个队列的流行病学方法;以及在300名受试者的子队列中使用改良的口服葡萄糖耐量试验在个体水平上评估Se补充对胰岛素分泌和敏感性的影响（150名接受安慰剂，150名接受Se酵母）。在二次分析中，我们将研究基线硒水平、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T2 D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.