Using vitamin D glucuronide pro-drugs to prevent/treat colon cancer

使用维生素 D 葡萄糖醛酸前药预防/治疗结肠癌

• 批准号: 8434622
• 负责人: Jesse Paul Goff
• 金额: $ 43.58万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8434622
• 关键词: A/J Mouse; APC gene; Adverse effects; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Azoxymethane; Bacteria; Beta-glucuronidase; Binding; Blood; Blood Circulation; Calcifediol; Calcitriol; Calcium; Cancer Etiology; Cancer Model; Carcinogens; Cells; Cessation of life; Chronic; Cleaved cell; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Colorectal Neoplasms; Crohn' s disease; Data; Development; Diet; Distal; Dose; Drug Targeting; Effectiveness; Enzymes; Epidemiologic Studies; Event; Fatty acid glycerol esters; Fiber; Gene Expression; Gene Targeting; Genetic Transcription; Glucuronides; Growth; Histologic; Homeostasis; Hormonal; Hormones; Human; Hypercalcemia; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestinal Neoplasms; Intestines; Irritants; Life; Link; Modeling; Mus; Mutation; Oncogenic; Parents; Patients; Play; Population; Process; Prodrugs; Property; Reporting; Resistance; Risk; Role; Serum; Small Intestines; Sodium Dextran Sulfate; System; Testing; Therapeutic; Time; Tissues; Toxic effect; Tumor Burden; Ulcerative Colitis; United States; Vitamin D; Vitamin D3 Receptor; Vitamins; analog; cancer cell; cancer diagnosis; carcinogenesis; colon carcinogenesis; design; feeding; human disease; in vivo; mouse model; prevent; public health relevance; response; targeted delivery; tumor; tumor growth

DESCRIPTION (provided by applicant): Growth of colon cancer cells, both in vitro and in vivo, has been shown to be inhibited by the active hormonal form of vitamin D, 1,25-dihydroxyvitamin D3. Unfortunately, doses of 1,25-dihydroxyvitamin D3 required to effectively treat colon tumors in vivo also stimulate the vitamin's classic effects on calcium homeostasis, resulting in the development of life-threatening hypercalcemia. Our preliminary data indicate, contrary to accepted dogma, very little 1,25-dihydroxyvitamin D3 administered either orally or injected subcutaneously actually reaches the colon to alter the transcription of target genes. We have approached these problems by synthesizing a pro-drug form of 1,25-dihydroxyvitamin D3. The pro-drug is capable of delivering high amounts of the hormone directly to the colon without substantially increasing blood concentrations of 1,25-dihydroxyvitamin D3, thus reducing the risk of a hypercalcemic response. This was achieved by conjugating a glucuronide to the hormone in a ¿-linkage that renders it biologically inactive and resistant to mammalian digestive enzymes. Upon reaching the lower intestinal tract, however, ¿-glucuronidase enzymes produced by resident bacterial populations cleave off the glucuronide and release the active hormone. The current proposal will determine whether using the glucuronide pro-drug system to target delivery of 1,25-dihydroxyvitamin D3 to the lower intestinal tract can slow or prevent the development of colorectal tumors without inducing systemic hypercalcemic toxicity. Chronic inflammation contributes to the development of carcinogenesis; people suffering from ulcerative colitis and Crohn's disease have an increased risk of developing colon cancer. Aim 1 will determine the efficacy of the vitamin D glucuronide pro-drug in preventing or limiting the formation and size of colon tumors induced by azoxymethane/dextran sodium sulfate in a mouse model of inflammation-associated carcinogenesis. Mutations in the adenomatous polyposis coli (Apc) gene, originally linked to familial forms of colon cancer, have also been identified in the preponderance of human colon tumors. Aim 2 will determine the effects of the glucuronide in preventing or limiting the formation and size of colon tumors in ApcMin/+ mice that carry a mutation in the mouse Apc gene and serve as a model of sporadic human colon cancer. Prior studies using 1,25-dihydroxyvitamin D3 or its analogs in the treatment of colon cancer have been limited by the development of hypercalcemia and sub-therapeutic amounts reaching the colon. The strength of the current proposal is the ability to target delivery of high concentrations of 1,25- dihydroxyvitamin D3 directly to the colon so its effects on colon carcinogenesis can be assessed in the absence of hypercalcemia.

描述（由申请人提供）：体外和体内结肠癌细胞的生长已被维生素D的活性激素形式1,25-二羟基维生素D3所抑制。不幸的是，体内有效治疗结肠肿瘤所需的1,25-二羟基维生素D3剂量也会刺激维生素对钙稳态的经典作用，导致危及生命的高钙血症的发展。我们的初步数据表明，与公认的教条相反，口服或皮下注射的1,25-二羟基维生素D3实际上很少到达结肠以改变目标基因的转录。我们通过合成1,25-二羟基维生素D3的前药物形式来解决这些问题。前药能够将大量激素直接输送到结肠，而不会显著增加血液中1,25-二羟基维生素D3的浓度，从而降低高钙血症反应的风险。这是通过将葡萄糖醛酸苷与激素结合在一个¿-连锁中实现的，该连锁使其具有生物活性并对哺乳动物消化酶具有抗性。然而，一旦到达下肠道，由常驻细菌群产生的-葡萄糖醛酸酶就会分解葡萄糖醛酸并释放出活性激素。目前的提案将确定使用葡萄糖醛酸苷前药系统靶向递送1,25-二羟维生素D3到下肠道是否可以在不诱导全身高钙血症毒性的情况下减缓或防止结直肠肿瘤的发展。慢性炎症有助于癌变的发生；患有溃疡性结肠炎和克罗恩病的人患结肠癌的风险增加。目的1将在炎症相关癌变小鼠模型中确定维生素D葡糖苷前药在预防或限制偶氮氧甲烷/葡聚糖硫酸钠诱导的结肠肿瘤形成和大小方面的功效。大肠腺瘤性息肉病（Apc）基因的突变，最初与家族形式的结肠癌有关，也在人类结肠肿瘤的优势中被发现。目的2将确定葡萄糖醛酸盐在预防或限制携带小鼠Apc基因突变的ApcMin/+小鼠结肠肿瘤的形成和大小方面的作用，并作为散发性人类结肠癌的模型。先前使用1,25-二羟基维生素D3或其类似物治疗结肠癌的研究受到高钙血症的发展和到达结肠的亚治疗量的限制。目前的建议的优势在于能够将高浓度的125 -二羟基维生素D3直接输送到结肠，因此可以在没有高钙血症的情况下评估其对结肠癌的影响。