Vitamin D/Calcium and Oxidative Stress and Inflammation Biomarkers

描述(由申请人提供)： 补钙可减少结直肠腺瘤的复发，血清维生素D水平较高与结直肠癌风险降低有关，结直肠癌是美国癌症死亡的第二大原因。然而，钙和维生素D在人体内的独立和协同抗肿瘤作用尚不清楚。已提出的机制包括保护结肠细胞免受胆汁酸的影响和对细胞周期调节的直接影响。根据基础科学证据，我们假设补充钙和维生素D可以减少人类结肠上皮和血液中的氧化应激和炎症。我们将在最近完成的一项先导性、随机、双盲、安慰剂对照、2x2因素化学预防临床试验(称为“亲代研究”；N=88)中对这一点进行调查，在最近切除的散发性结直肠腺瘤患者中，补充钙(2g/天)和维生素D3(800IU/天)单独和联合使用与安慰剂相比超过6个月。这项初步研究的目的是：1)研究补充钙和维生素D对正常大肠隐窝(HNE、8-OHdG和COX-2)和血浆/血清(F2-异前列腺素、PrSSCys、PrSSG、蛋白质羰基、IL-6、TNFa、干扰素和转化生长因子1)氧化应激和炎症生物标记物的单独和联合影响；2)验证用于人类营养试验的氧化应激/炎症生物标记物，包括血液中的生物标记物是否与正常结肠组织中的生物标记物充分相关，以替代结肠组织中的生物标记物；3)研究氧化应激/炎症标记物与我们的其他生物标记物在外观正常的直肠粘膜中患结直肠癌风险的关系。拟议的工作范围仅限于使用生物样本和来自“家长研究”的问卷数据进行的实验室和统计分析。这项研究提供了一个独特的、具有成本效益的机会来研究一种新的人类饮食-结肠癌假说，并验证生物标志物，这些生物标志物将为研究钙、维生素D和其他饮食因素的抗癌作用以及这些饮食因素是否可以降低结直肠癌风险打开新的机会。

DESCRIPTION (provided by applicant): Calcium supplementation reduces colorectal adenoma recurrence, and higher serum vitamin D levels are associated with reduced risk for colorectal cancer, the second leading cause of cancer deaths in the US. However, the independent and synergistic anti-neoplastic effects of calcium and vitamin D in humans are not clear. Proposed mechanisms have included protection of colonocytes against bile acids and direct effects on cell cycle regulation. Based on basic science evidence, we hypothesize that calcium and vitamin D supplementation decrease oxidative stress and inflammation in humans in the colon epithelium and blood. We will investigate this in a pilot, adjunct study to a recently completed pilot, randomized, double-blind, placebocontrolled, 2x2 factorial chemoprevention clinical trial (termed the 'parent study'; N = 88) of supplemental calcium (2 g/day) and vitamin D3 (800 IU/day), alone and in combination vs. placebo over 6 months in patients with recently resected sporadic colorectal adenomas. The aims of the proposed pilot study are to 1) investigate the separate and joint effects of calcium and vitamin D supplementation on biomarkers of oxidative stress and inflammation in normal colorectal crypts (HNE, 8-OHdG, and COX-2 by novel automated immunohistochemistry and quantitative image analysis methods) and plasma/serum (F2-isoprostanes, PrSSCys, PrSSG, protein carbonyl, IL-6, TNFa, IFN?, and TGF¿1); 2) validate oxidative stress/inflammation biomarkers for use in human nutritional trials, including whether the biomarkers in blood are sufficiently correlated with those in normal colon tissue to be used as surrogates for those in colon tissue; and 3) investigate associations of the oxidative stress/inflammation markers with our other biomarkers of risk for colorectal neoplasms in the normal-appearing rectal mucosa. The proposed scope of work is limited to laboratory and statistical analyses using biological samples and questionnaire data from a 'parent study'. This study offers a unique, cost-effective opportunity to investigate a novel diet-colon cancer hypothesis in humans, and to validate biomarkers that will open new opportunities for investigating anti-carcinogenic effects of calcium and vitamin D and other dietary factors and whether such dietary factors may reduce risk for colorectal cancer.