Calcium, Vitamin D, and Markers of Adenomatous Polyps

描述（由申请人提供）：钙和维生素D对预防结直肠癌有很强的生物学合理性和动物实验证据，在一项大型人类临床试验中，钙显著减少了腺瘤的复发（然而，先前报道的观察性证据，尽管总体上是支持的，但不一致），观察性文献强烈支持维生素D的保护。钙和维生素D之间的密切生理关系早已为人所知。然而，除了钙可能减少结肠直肠上皮细胞增殖外，钙和维生素D单独或联合对正常人类结肠直肠上皮的影响尚不清楚。目前还没有关于维生素D单独或联合钙与人类结直肠癌化学预防相关的临床试验。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的最新了解，我们开发了一组更新的、合理的、可靠的、免疫组织化学检测的生物标志物，提供了正常结肠上皮的分子表型：1)炎症（COX-2）， 2)参与结肠直肠上皮正常结构和功能的基因的表达，这些基因在2个主要的结直肠癌发生途径（ARC, B-catenin, E-cadherin, MSH2, MLH1）的早期被发现改变，3)更完整地了解结肠直肠上皮隐窝细胞的细胞周期事件(短期和长期增殖：MIB-1和端粒酶，分化：p21；抑制和促进细胞凋亡：bcl-2， bax和bak)，以及4)自分泌/旁分泌生长因子(TGFa, TGFB1，尚未在化学预防试验中进行测试。为了满足这些需求，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、2 × 2因子的化学预防试验（n = 88），在最近切除散发性腺瘤性结直肠息肉的患者中，单独或联合使用钙2000 mg/天和维生素D3 800 lU/天与安慰剂相比，持续6个月，以研究它们对患者的影响。一些个体（COX-2， ARC, MSH2, MLH1, MIB-1, hTERT, p21, bcl-2， bax和bak）和结直肠癌风险生物标志物面板的组合成分。我们还将检查按非甾体抗炎药使用和Bsm I维生素D受体基因型分层的研究结果。治疗效果大小和可变性的初步估计将用于完善生物标志物小组和研究设计，并计算潜在的全面研究所需的样本量。在此，我们建议将B-catenin， E-cadherin， TGFa和TGFB1添加到该试验的生物标志物面板中。我们断言，使用风险的生物学测量，就像缺血性心脏病一样，将导致结直肠癌发病率和死亡率的下降。拟议的项目是基于这一愿景，并具有探索两种合理且证据充分支持的膳食剂钙和维生素D在调节结肠直肠癌风险的一组合理的分子表型生物标志物方面的功效的相互交织的任务。

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.