Vitamin D/Calcium and Oxidative Stress and Inflammation Biomarkers

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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.