Calcium/Vitamin D, Biomarkers & Colon Polyp Prevention

描述（由申请人提供）： 有很强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，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，钙和维生素D单独或联合对正常人结肠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）已经发现，参与结直肠上皮正常结构和功能的基因的表达在两个主要疾病的早期发生改变，结直肠癌发生途径（ARC、β-连环蛋白、E-钙粘蛋白、MLH 1），3）结直肠上皮隐窝细胞中的细胞周期事件（长期增殖：端粒酶;凋亡抑制和促进：bcl-2、bax），和4）自分泌/旁分泌生长促进和抑制因子（TGF α、TGF β 1），其尚未在化学预防试验中测试。为了满足这些需求，我们将在一项正在进行的多中心、随机、双盲、安慰剂对照、2x2析因临床试验中增加测量该生物标志物组（n = 1，964）测试钙1，200 mg/天和/或维生素D31，000 IU/天相对于安慰剂在3-5年内减少复发性散发性结肠直肠腺瘤的功效，以确定钙和/或维生素D是否可以有利地调节生物标志物组以及这种调节是否预测腺瘤复发。对于生物标志物测量，将在3年或5年随访结肠镜检查时从1，328名（68%）参与者中获得正常外观的直肠粘膜活检。此外，在这些参与者的一个子集（n = 200）中，（50/治疗组），将在随机化时、随机化后1年和3 - 5年随访结肠镜检查前2周“非准备”采集外观正常的直肠粘膜活检;在后续结肠镜检查期间，还将从三个结肠部位（直肠、中乙状结肠和近端升结肠）获取正常外观粘膜的活组织检查。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，并交织调查两个合理的和证据充分支持的饮食剂，钙和维生素D，在调制一个合理的面板的分子表型生物标志物的风险，结直肠肿瘤的疗效任务，并确定这种调制是否预测减少结直肠肿瘤的复发。

DESCRIPTION (provided by applicant): There is strong biologic 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, and the observational literature strongly supports protection from vitamin D. A close physiological relationship between calcium and vitamin D has long been known. Yet, 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 two major colorectal carcinogenesis pathways (ARC, beta-catenin, E-cadherin, MLH1), 3) cell cycle events in colorectal epithelial crypt cells (long-term proliferation: telomerase; apoptosis inhibition and promotion: bcl-2, bax), and 4) autocrine/paracrine growth promotion and inhibition factors (TGFalpha, TGFbeta1,) that has not yet been tested in a chemoprevention trial. To address these needs, we will add measuring this biomarker panel to an ongoing multi- center, randomized, double-blind, placebo-controlled, 2x2 factorial clinical trial (n = 1,964) testing the efficacy of calcium 1,200 mg/day and/or vitamin D31,000 ILJ/day vs placebo in reducing recurrent sporadic colorectal adenomas over 3-5 years, in order to determine whether calcium and/or vitamin D can favorably modulate the panel of biomarkers and whether this modulation predicts adenoma recurrence. For the biomarker measurements, biopsies of normal- appearing rectal mucosa will be obtained from 1,328 (68%) of participants at 3- or 5-year follow-up colonoscopy. In addition, on a subset (n = 200) of these participants (50/treatment group), biopsies of normal-appearing rectal mucosa will be taken 'non-prep' at randomization, one year following randomization, and two weeks prior to 3 - 5 year follow-up colonoscopy; biopsies of normal appearing mucosa will also be taken from three colon sites (rectum, mid- sigmoid colon, and proximal ascending colon) during follow-up colonoscopies. 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 investigating the efficacy of two plausible and evidentially well-supported dietary agents, calcium and vitamin D, in modulating a plausible panel of molecular phenotypic biomarkers of risk for colorectal neoplasia, and determining whether this modulation predicts reduced recurrence of colorectal neoplasms.