Calcium, Vitamin D, and Markers of Adenomatous Polyps

描述(由申请人提供)：有很强的生物学可信和动物实验证据表明，钙和维生素D可以预防结直肠癌，在人类的大型临床试验中，钙可以显著减少腺瘤的复发(然而先前报道的观察证据虽然普遍支持，但并不一致)，观察文献强烈支持预防维生素D。钙和维生素D之间的密切生理关系早已为人所知。然而，除了钙可能降低大肠上皮细胞的增殖外，钙和维生素D单独或联合对正常人类大肠上皮细胞的影响尚不清楚。在人类中，还没有单独或联合使用维生素D和钙与结直肠癌化学预防有关的临床试验。目前还没有被普遍接受的结直肠癌风险的癌前生物标志物。基于对结直肠癌分子基础认识的最新进展，我们开发了一组新的、可信的、可靠的免疫组织化学检测的生物标志物，它们提供了正常大肠上皮的分子表型：1)炎症(COX-2)，2)与正常结构和功能有关的基因的表达，这些基因在两条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)更完整的大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：bcl2、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、双盲、安慰剂对照的2x2因素化学预防试验(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 800Lu/天，以及联合使用安慰剂超过6个月，以调查它们对结直肠癌风险生物标志物小组中的几个个体(COX-2、ARC、MSH2、MLH1、MIB-1、hTERT、p21、BCL-2、BAX和BAK)和联合成分的影响。我们还将检查按非甾体抗炎药使用和BSM I维生素D受体基因分型的研究结果。对治疗效果大小和变异性的初步估计将用于改进生物标志物面板和研究设计，并计算潜在全面研究所需的样本量。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记物小组中。我们断言，使用生物学的风险测量方法，就像对缺血性心脏病一样，将导致结直肠癌发病率和死亡率的下降。拟议的项目承载了这一愿景，并交织着探索两种看似合理且得到明显支持的膳食制剂在调节一组看似合理的大肠肿瘤风险分子表型生物标记物方面的有效性。

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.