Calcium, Vitamin D, and Markers of Adenomatous Polyps

钙、维生素 D 和腺瘤性息肉标志物

• 批准号: 6943335
• 负责人: ROBERD Maner BOSTICK
• 金额: $ 7.65万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-21 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6943335
• 关键词: adenomatous polyps; biomarker; cadherins; cancer prevention; cancer risk; chemoprevention; clinical research; colorectal neoplasms; dietary calcium; genetic polymorphism; genetic susceptibility; human tissue; intestinal mucosa; nonsteroidal antiinflammatory agent; nutrition aspect of cancer; nutrition related tag; patient oriented research; preneoplastic state; transforming growth factors; vitamin D; vitamin D receptors

DESCRIPTION (provided by applicant): There is strong biological plausibility and animal experimental evidence for protection against colorectal cancer by calcium and vitamin D, calcium significantly reduced adenoma recurrence in a large clinical trial in humans (yet the previously reported observational evidence, although generally supportive, is inconsistent), and the observational literature strongly supports protection from vitamin D. A close physiological relationship between calcium and vitamin D has long been known. Yet, other than a possible reduction of colorectal epithelial cell proliferation by calcium, the effects of calcium and vitamin D, individually or jointly, on the normal human colorectal epithelium remain unknown. There have been no clinical trials involving vitamin D individually or jointly with calcium related to colorectal cancer chemoprevention in humans. There are currently no generally accepted pre-neoplastic biomarkers of risk for colorectal cancer. Based on recent advances in understanding the molecular basis of colorectal cancer, we developed a panel of newer, plausible, reliable, immunohistochemically detected biomarkers that provides molecular phenotyping of the normal appearing colorectal epithelium: 1) inflammation (COX-2), 2) the expression of genes involved in the normal structure and function of the colorectal epithelium that have been found to be altered early in the 2 major colorectal carcinogenesis pathways (ARC, B-catenin, E-cadherin, MSH2, MLH1), 3) a more complete picture of the cell cycle events in colorectal epithelial crypt cells (short and long-term proliferation: MIB-1 and telomerase; differentiation: p21; apoptosis inhibition and promotion: bcl-2, bax, and bak), and 4) autocrine/paracrine growth factors (TGFa, TGFB1 that has not yet been tested in a chemoprevention trial. To address these needs, we are currently conducting a preliminary, randomized, double-blind, placebo-controlled, 2x2 factorial chemoprevention trial (n = 88) of calcium 2,000 mg/day and vitamin D3 800 lU/day, alone and in combination vs placebo over 6 months in patients with recent removal of sporadic adenomatous colorectal polyps, to investigate their effects on.several of the individual (COX-2, ARC, MSH2, MLH1, MIB-1, hTERT, p21, bcl-2, bax, and bak) and combined components of our colorectal cancer risk biomarker panel. We will also examine study results stratified by NSAID use and Bsm I vitamin D receptor genotypes. The preliminary estimates of treatment effect sizes and variabilities will be used to refine the biomarker panel and study design and to calculate the needed sample size for a potential full-scale study. Herein, we propose adding B-catenin, E-cadherin, TGFa, and TGFB1 to the biomarker panel for this trial. We assert that using biological measurements of risk, as they have for ischemic heart disease, will result in a decline in colorectal cancer incidence and mortality. The proposed project is borne of this vision, and has intertwined missions of exploring the efficacy of 2 plausible and evidentially well-supported dietary agents, calcium and vitamin D, on the modulation of a plausible panel of molecular phenotypic biomarkers of risk for colorectal neoplasia.

描述（由申请人提供）：有强有力的生物相容性和动物实验证据表明钙和维生素D可预防结直肠癌，在一项大型人体临床试验中，钙可显著降低腺瘤复发（然而，先前报告的观察性证据，尽管总体上支持，但不一致），观察性文献强烈支持维生素D的保护作用。钙和维生素D之间的密切生理关系早已为人所知。然而，除了钙可能减少结直肠上皮细胞增殖外，钙和维生素D单独或联合对正常人结直肠上皮的影响仍然未知。目前还没有涉及维生素D单独或与钙联合用于人类结直肠癌化学预防的临床试验。目前还没有普遍接受的结直肠癌风险的肿瘤前生物标志物。基于对结直肠癌分子基础理解的最新进展，我们开发了一组更新的、合理的、可靠的、化学检测的生物标志物，其提供了正常表现的结直肠上皮的分子表型：1）炎症（考克斯-2），（二）参与结直肠上皮正常结构和功能的基因表达在2 - 10年的早期被发现改变，结直肠癌发生的主要途径（ARC、B-连环蛋白、E-钙粘蛋白、MSH2、MLH1），3）更完整地描述结直肠上皮隐窝细胞中的细胞周期事件（短期和长期增殖：MIB-1和端粒酶;分化：p21;凋亡抑制和促进：bcl-2、bax和bak），和4）自分泌/旁分泌生长因子（TGF α、TGF β 1，其尚未在化学预防试验中测试。为了解决这些需求，我们目前正在进行一项初步的、随机的、双盲的、安慰剂对照的、2x2因子的化学预防试验（n = 88），在最近切除了散发性腺瘤性结直肠息肉的患者中，单独使用钙2,000 mg/天和维生素D3 800 IU/天以及与安慰剂联合使用6个月，以研究它们对几个个体的影响。（考克斯-2、ARC、MSH2、MLH1、MIB-1、hTERT、p21、bcl-2、bax和bak）和我们的结直肠癌风险生物标志物组的组合组分。我们还将检查按NSAID使用和Bsm I维生素D受体基因型分层的研究结果。治疗效应量和变异性的初步估计值将用于完善生物标志物组和研究设计，并计算潜在全规模研究所需的样本量。在此，我们建议将B-连环蛋白、E-钙粘蛋白、TGFa和TGFB1添加到本试验的生物标志物组中。我们断言，使用风险的生物学测量，就像他们对缺血性心脏病的测量一样，将导致结直肠癌发病率和死亡率的下降。拟议的项目是承担这一愿景，并有交织的使命，探索2个合理的和证据充分支持的饮食代理，钙和维生素D，对一个合理的面板的分子表型生物标志物的风险结肠直肠肿瘤的调制的功效。