Efficacy of 25-hydroxyvitamin D3 in colon cancer chemoprevention

25-羟基维生素D3在结肠癌化学预防中的功效

• 批准号: 7624959
• 负责人: RAJENDRA G MEHTA
• 金额: $ 37.49万
• 依托单位: IIT RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-05 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7624959
• 关键词: Aberrant crypt foci; Adenocarcinoma; Animals; Azoxymethane; Calcifediol; Calcitriol; Cancer Model; Carcinogens; Cell Line; Chemopreventive Agent; Cholecalciferol; Clinical; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Data; Development; Diet; Dietary intake; Distal; Dose; Enzymes; Epidemiology; Epithelial Cells; Exposure to; Genus Cola; Hormones; Human; Hypercalcemia; Incidence; Intake; Knock-out; Knockout Mice; Knowledge; Laboratories; Mediating; Mixed Function Oxygenases; Modeling; Mus; Mutate; Pharmaceutical Preparations; Plasma; Polyps; Prevention; Prevention therapy; Relative (related person); Research Personnel; Risk; Role; Serum; Signal Pathway; Signal Transduction; Sunlight; Toxic effect; Tumor Burden; Up-Regulation; Vitamin D; Vitamin D Analog; Vitamin D3 Receptor; Vitamins; Woman; analog; cancer cell; cancer chemoprevention; carcinogenesis; colon cancer cell line; colon carcinogenesis; colorectal cancer prevention; design; in vivo; inhibitor/antagonist; novel; prevent; receptor expression; research study; response; tumor progression

DESCRIPTION (provided by applicant): The role of vitamin D in colorectal cancer (CRC) prevention is well recognized. Epidemiological evidence demonstrates an inverse relationship between vitamin D, both dietary intake and exposure to sunlight, and risk of developing colon cancer. Similarly, decreased plasma levels of 25-hydroxyvitamin D3 [25(OH)D3] have been shown to correlate with increased polyp formation in distal colons of women. Experimental evidence has found that treatment of animals with the active metabolite of vitamin D, 1,25-dihydroxyvitamin D3, reduces colon tumor burden. However, 1,25(OH)2D3 causes hypercalcemia. In view of this numerous analogs of vitamin D have been synthesized. Yet only a handful of these analogs have been successfully used for the prevention and therapy of colon cancer. In our laboratory we synthesized a novel vitamin D analog, 1a-hydroxy-24-ethyl-cholecalciferol [1cc(OH)D5]. The preliminary results showed that this agent at non-toxic levels significantly decreases the formation of aberrant crypt foci (ACF) by 85% in mice exposed to the carcinogen azoxymethane (AOM). Recently, it has been observed that 1a-hydroxylase, required to convert non-toxic 25(OH)D3 to 1,25(OH)2D3- is present in colonic epithelial cells. This suggests that 25(OH)D3 alone may serve as potential chemopreventive agent. Finally, the role of vitamin D receptor (VDR) remains to be fully elucidated. Our preliminary data indicates that vitamin D's role in CRC chemopreventive activity requires VDR expression, and that aberrant (3Jcatenin may be modified by up- regulation of VDR. Thus, we hypothesize that 25(OH)D3 will serve as a colon chemopreventive agent with its actions mediated primarily via VDR. Our specific aims are to: (1 A) Determine the dose response of 25(OH)D3 in suppressing the development of AOM-induced ACF and adenocarcinomas in CF-1 mice; (1B) Evaluate the relative efficacy of 25(OH)D3, 1a(OH)D5, and 1,25(OH)2D3 in colon carcinogenesis. For this aim the AOM-induced CRC model will be used; (2) Assess the role VDR, 1a(OH)ase, and 24-hydroxylase in ACF and CRC progression. For these studies an AOM-induced carcinogenesis model using VDR knockout and their wild-type counterparts will be used to evaluate the responsiveness to 25(OH)D3; and (3) Investigate the mediating role of VDR in the wnt/(3-catenin signaling pathway and its relation to vitamin D actions. The studies will provide a rationale for using 25(OH)D3 for the prevention of colon carcinogenesis.

描述（由申请人提供）：维生素 D 在预防结直肠癌 (CRC) 中的作用已得到广泛认可。流行病学证据表明，维生素 D、饮食摄入量和阳光照射与患结肠癌的风险之间呈负相关。同样，25-羟基维生素 D3 [25(OH)D3] 血浆水平降低已被证明与女性远端结肠息肉形成增加相关。实验证据发现，用维生素 D 的活性代谢物 1,25-二羟基维生素 D3 治疗动物可减轻结肠肿瘤负担。然而，1,25(OH)2D3 会导致高钙血症。鉴于此，已经合成了许多维生素D类似物。然而，这些类似物中只有少数已成功用于预防和治疗结肠癌。在我们的实验室中，我们合成了一种新型维生素 D 类似物，1a-羟基-24-乙基-胆钙化醇 [1cc(OH)D5]。初步结果表明，在暴露于致癌物质氧化偶氮甲烷 (AOM) 的小鼠中，这种无毒水平的药剂可显着减少 85% 的异常隐窝病灶 (ACF) 形成。最近，观察到结肠上皮细胞中存在将无毒的 25(OH)D3 转化为 1,25(OH)2D3- 所需的 1a-羟化酶。这表明 25(OH)D3 单独可以作为潜在的化学预防剂。最后，维生素 D 受体 (VDR) 的作用仍有待充分阐明。我们的初步数据表明，维生素 D 在 CRC 化学预防活性中的作用需要 VDR 表达，并且异常的（3J 联蛋白）可能会通过 VDR 的上调而被修饰。因此，我们假设 25(OH)D3 将作为结肠化学预防剂，其作用主要通过 VDR 介导。我们的具体目标是： (1 A) 确定 25(OH)D3 的剂量反应 抑制 CF-1 小鼠中 AOM 诱导的 ACF 和腺癌的发展； (1B) 评估 25(OH)D3、1a(OH)D5 和 1,25(OH)2D3 在结肠癌发生中的相对功效。为此，将使用 AOM 引发的 CRC 模型； (2) 评估 VDR、1a(OH)ase 的作用，以及 ACF 和 CRC 进展中的 24-羟化酶。对于这些研究，使用 VDR 敲除及其野生型对应物的 AOM 诱导的致癌模型将用于评估对 25(OH)D3 的反应性； (3) 研究 VDR 在 wnt/(3-catenin 信号通路中的介导作用及其与维生素 D 作用的关系。这些研究将为使用 25(OH)D3 用于预防结肠癌。