Calcium/Vitamin D, Biomarkers & Colon Polyp Prevention

描述(由申请人提供)： 钙和维生素D预防结直肠癌有很强的生物学可信性和动物实验证据，在人类的大型临床试验中，钙可显著减少腺瘤复发，观察性文献有力地支持了维生素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类结直肠上皮的影响仍不清楚。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，这些基因已被发现在两个主要的结直肠癌发生途径(ARC，β-catenin，E-cadherin，MLH1)的早期改变，3)大肠上皮隐窝细胞中的细胞周期事件(长期增殖：端粒酶；抑制和促进细胞凋亡：bcl-2，bax)，以及4)自分泌/旁分泌生长促进和抑制因子(TGFpha，TGFbeta1)，尚未在化学预防试验中进行测试。为了满足这些需求，我们将在正在进行的一项多中心、随机、双盲、安慰剂对照、2x2因素临床试验(n=1,964)中增加测量这个生物标志物小组，以测试钙1,200毫克/天和/或维生素D31,000 ILJ/天与安慰剂在减少3-5年内散发性结直肠癌复发方面的有效性，以确定钙和/或维生素D是否可以有利地调节生物标志物小组，以及这种调节是否可以预测腺瘤复发。对于生物标记物的测量，1328名(68%)的参与者将在3年或5年的结肠镜检查中获得外观正常的直肠粘膜的活检组织。此外，在这些参与者中的一组(n=200)(每组50人)中，外观正常的直肠黏膜的活组织检查将在随机分组后一年以及3-5年随访结肠镜检查前两周进行，在后续的结肠镜检查期间也将从三个结肠部位(直肠、乙状结肠中段和近端升结肠)进行活体检查。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。拟议的项目是基于这一愿景，并交织在一起的任务是调查两种看似合理且得到充分支持的膳食制剂在调节一组看似合理的结直肠肿瘤风险的分子表型生物标志物方面的有效性，并确定这种调节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.