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Calcium/Vitamin D, Biomarkers & Colon Polyp Prevention

钙/维生素 D、生物标志物

基本信息

批准号：
7468412
负责人：
ROBERD Maner BOSTICK
金额：
$ 47.71万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-01 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7468412
关键词：
Address Affect Animals Apoptosis Ascending colon Attenuated Biological Biological Markers Biopsy Budgets Calcium Calcium Carbonate Cell Cycle Cells Chemoprevention Chemopreventive Agent Cholecalciferol Clinical Chemoprevention Clinical Trials Colon Colonic Polyps Colonoscopy Colorectal Colorectal Adenoma Colorectal Cancer Colorectal Neoplasms Daily Development Double-Blind Method Drug usage E-Cadherin Epithelial Epithelial Cell Proliferation Epithelium Event Excision Funding Gene Expression Genes Genotype Genus Cola Goals Grant Growth Growth Factor Human Image Analysis Immunohistochemistry Incidence Individual Inflammation Inhibition of Apoptosis Knowledge Laboratories Literature MLH1 gene Measurement Measures Mismatch Repair Mission Molecular Mucous Membrane Myocardial Ischemia Non-Steroidal Anti-Inflammatory Agents PTGS2 gene Participant Pathway interactions Patients Phenotype Physiological Placebo Control Placebos Preparation Prevention Randomized Rectum Recurrence Reducing Agents Reporting Risk Sigmoid colon Site Structure Telomerase Testing Time Transforming Growth Factor alpha Vision Visit Vitamin D Vitamin D3 Receptor Vitamins Week Work adenoma autocrine base beta catenin carcinogenesis colon carcinogenesis crypt cell day disorder risk follow-up mortality neoplastic paracrine rectal response telomerase reverse transcriptase

项目摘要

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.

描述（由申请人提供）：钙和维生素 D 可以预防结直肠癌，这具有很强的生物学合理性和动物实验证据，在一项大型人体临床试验中，钙可以显着减少腺瘤复发，观察性文献强烈支持维生素 D 的保护作用。钙和维生素 D 之间密切的生理关系早已为人所知。然而，钙和维生素 D 单独或联合使用对正常人类结直肠上皮的影响仍不清楚。目前还没有涉及维生素 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。目前尚无普遍接受的结直肠癌风险的肿瘤前生物标志物。基于了解结直肠癌分子基础的最新进展，我们开发了一组更新的、可信的、可靠的、免疫组织化学检测的生物标志物，可提供正常结直肠上皮的分子表型：1) 炎症 (COX-2)，2) 涉及结直肠上皮正常结构和功能的基因的表达，这些基因已被发现在两个主要的早期改变结直肠癌发生途径（ARC、β-连环蛋白、E-钙粘蛋白、MLH1）、3）结直肠上皮隐窝细胞的细胞周期事件（长期增殖：端粒酶；细胞凋亡抑制和促进：bcl-2、bax）和 4）自分泌/旁分泌生长促进和抑制因子（TGFα、TGFbeta1）尚未在化学预防试验中进行测试。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（n = 1,964）中添加测量该生物标志物组，该试验测试钙 1,200 mg/天和/或维生素 D31,000 ILJ/天与安慰剂相比在 3-5 年内减少复发性散发性结直肠腺瘤的功效。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，以及这种调节是否可以预测腺瘤复发。对于生物标志物测量，将从 1,328 名 (68%) 参与者的 3 或 5 年随访结肠镜检查中获取外观正常的直肠粘膜活检。此外，在这些参与者的子集（n = 200）中（50/治疗组），将在随机分组时、随机分组后一年以及 3 - 5 年随访结肠镜检查前两周对外观正常的直肠粘膜进行“非准备”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）采集正常粘膜的活组织检查。我们断言，使用生物风险测量（如对缺血性心脏病的测量）将导致结直肠癌发病率和死亡率下降。拟议的项目正是基于这一愿景，并具有相互交织的任务，即研究两种看似合理且证据充分的膳食制剂钙和维生素 D 在调节结直肠肿瘤风险分子表型生物标志物方面的功效，并确定这种调节是否可以预测结直肠肿瘤复发的减少。