Vitamin D and Colorectal Cancer

维生素 D 与结直肠癌

基本信息

批准号：
7591734
负责人：
RICHARD V BENYA
金额：
$ 34.58万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7591734
关键词：
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole Aberrant crypt foci Affect Animals Attenuated Azoxymethane Biological Markers Biopsy Calcium Cancer Etiology Carcinogens Cell Line Cell Proliferation Chemoprevention Chemopreventive Agent Cholecalciferol Colon Colon Carcinoma Colonic Adenoma Colonoscopy Colorectal Cancer Data Databases Diagnostic Neoplasm Staging Diet Dietary Supplementation Endoscopic Biopsy Enrollment Enzymes Epidemiology Epithelial Cells Equipment Genetic Polymorphism Human Hypercalcemia Immunohistochemistry Intake Lesion Liquid substance Malignant - descriptor Malignant Neoplasms Mixed Function Oxygenases Mucous Membrane Mus Neoplasm Metastasis Patient Self-Report Patients Pharmaceutical Preparations Placebos Population Predisposition Process Publishing Questionnaires Receptor Activation Receptor Gene Relative (related person)Research Rodent Serum Subcutaneous Injections Time United States Vitamin D Vitamin D Analog Vitamin D3 Receptor Vitamins Woman adenoma base cancer chemoprevention cancer risk colorectal cancer screening drug efficacy instrumentation men novel patient population prevent receptor expression tumor progression

项目摘要

DESCRIPTION (provided by applicant): This proposal is dedicated to 1), establishing the efficacy of vitamin D for colorectal cancer (CRC) chemoprevention in humans; and 2), identifying the vitamin D congener most efficacious for CRC chemoprevention. Animal studies indicate that the active metabolite of vitamin D 1,25(OH)2D3 reduces the number and size of colon cancers; while epidemiological data show an inverse relationship between vitamin D intake and CRC risk. However 1,25(OH)2D3 causes hypercalcemia. We therefore synthesized a novel vitamin D analog, 11-hydroxy-24-ethyl-cholecalciferol [11(OH)D5]. In our preliminary data we show that this novel compound is non-toxic yet decreases the formation of aberrant crypt foci (ACF) by 85% in mice exposed to the carcinogen azoxymethane (AOM). We have recently demonstrated that cyp27A1 [required to convert cholecalciferol to 25(OH)D3] as well as cyp27B1 [required to convert 25(OH)D3 to 1,25(OH)2D3] are present in epithelial cells lining the normal human colon. This suggests that non-toxic and widely available cholecalciferol may be sufficient to prevent CRC. However, the CRC chemopreventive efficacy of cholecalciferol has not been assessed in humans; nor has the efficacy of this drug been assessed in comparison to 25(OH)D3, 1,25(OH)2D3, or to our novel drug 11(OH)D5. Chemoprevention studies typically use colonic adenomas as a CRC biomarker. Yet adenomas are relatively fixed lesions such that studies using them as a biomarker require years and large numbers of patients to complete. In contrast, we use magnification chromo-colonoscopy (MCC) for CRC screening, allowing us to routinely enumerate ACF number in humans. Since ACF are more fluid lesions that are present in greater numbers than adenomas, ACF are increasingly used as a surrogate CRC marker. Our hypothesis is that activation of the vitamin D receptor early in the process of CRC malignant transformation can prevent or attenuate tumor progression. Our aims are to: 1), establish the efficacy of vitamin D for CRC chemoprevention by evaluating the ability of cholecalciferol to reduce ACF's in humans; and 2), compare this with 25(OH)D3, 1,25(OH)2D3 and our novel drug 11(OH)D5 in mice exposed to AOM. Overall these studies will allow us to definitively determine the suitability of vitamin D in CRC chemoprevention, as well as assess the relative efficacy of a novel non-calcemic vitamin D analog for CRC chemoprevention. Colorectal cancer (CRC) is the second most common malignancy in men and women in the United States. Although vitamin D has been suspected to prevent CRC for nearly 30 years, it has never been directly evaluated in humans. Typically CRC chemoprevention studies use colonic adenomas as a biomarker, but these studies require hundreds to thousands of patients, and take years to complete. In contrast, aberrant crypt foci (ACF), the earliest histopathological lesions associated with malignant transformation in the colon, are more prevalent and are more fluid than adenomas. Hence this proposal is dedicated to assessing known and novel vitamin D analogs for their CRC chemopreventative efficacy using alteration in ACF number as our primary end-point.

描述（由申请人提供）：该提案专门针对1），确立了维生素D对人类结直肠癌（CRC）化学预防的功效；和2），确定对CRC化学预防最有效的维生素d同类体。动物研究表明，维生素D 1,25（OH）2d3的活性代谢产物减少了结肠癌的数量和大小。尽管流行病学数据显示维生素D摄入量与CRC风险之间存在反比关系。但是，1,25（OH）2d3引起高钙血症。因此，我们合成了一种新型的维生素D类似物，11-羟基-24-乙基 - 胆碱核酸[11（OH）D5]。在我们的初步数据中，我们表明这种新颖的化合物无毒，但在暴露于致癌甲氧基甲烷（AOM）的小鼠中，异常隐窝灶（ACF）的形成减少了85％。我们最近证明了CYP27A1 [将胆固醇酚转化为25（OH）D3]以及CYP27B1 [需要将25（OH）D3转换为25（OH）D3至1,25（OH）2D3]，这是在正常人类结肠内的上皮细胞中存在的。这表明无毒和广泛可用的胆固醇可能足以防止CRC。但是，尚未在人类中评估CRC化学预防疗效。与25（OH）D3、1,25（OH）2d3或我们的新型药物11（OH）D5相比，该药物的疗效也没有评估。化学预防研究通常使用结肠腺瘤作为CRC生物标志物。然而，腺瘤是相对固定的病变，因此使用它们作为生物标志物的研究需要数年和大量患者才能完成。相比之下，我们使用放大染色性骨镜检查（MCC）进行CRC筛查，从而使我们常规地列举了人类的ACF数量。由于ACF是比腺瘤更多的流体病变，因此ACF越来越多地用作替代CRC标记。我们的假设是，在CRC恶性转化过程的早期，维生素D受体的激活可以预防或减轻肿瘤的进展。我们的目的是：1），通过评估胆石钙化降低人类ACF的能力来确定维生素D对CRC化学预防的功效；和2），将其与25（OH）D3，1,25（OH）2d3和我们新颖的药物11（OH）D5在暴露于AOM的小鼠中进行比较。总体而言，这些研究将使我们能够确定维生素D在CRC化学预防中的适用性，并评估新型非钙质血症维生素D模拟对CRC化学预防的相对疗效。结直肠癌（CRC）是美国男性和女性第二常见的恶性肿瘤。尽管怀疑维生素D已被怀疑可以预防CRC近30年，但它从未在人类中进行直接评估。通常，CRC化学预防研究使用结肠腺瘤作为生物标志物，但是这些研究需要数百至数千名患者，并且需要数年才能完成。相反，与结肠中恶性转化相关的最早的组织病变病变异常的隐窝灶（ACF）比腺瘤更为普遍，更流畅。因此，该建议致力于评估已知和新颖的维生素D类似物，以使用ACF数量的改变作为我们的主要终点，以评估其CRC化学预防疗效。