Chemoprevention of colitis-associated colon cancer

结肠炎相关结肠癌的化学预防

• 批准号: 7218103
• 负责人: E. AUBREY THOMPSON
• 金额: $ 7.38万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-04 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7218103
• 关键词: Accounting; Affect; American; Animal Model; Apoptotic; Area; Backcrossings; Carboplatin/Cyclophosphamide; Carcinogens; Cations; Cessation of life; Chemoprevention; Chemopreventive Agent; Chronic; Clinical Trials; Colectomy; Colitis; Colon; Colon Carcinoma; Corn Oil; Data; Development; Diet; Dietary Fats; Doctor of Philosophy; Enrollment; Epithelial Cells; Epithelium; Etiology; Event; Fatty acid glycerol esters; Fish Oils; Genetic; Genus Cola; Hybrids; Inbred C57BL Mice; Incidence; Inflammation; Inflammatory Bowel Diseases; Intestines; Isoenzymes; Kidney; Knock-out; Knockout Mice; Laboratories; Link; Lipids; Location; Malignant - descriptor; Malignant Neoplasms; Mediating; Mus; Numbers; Omega-3 Fatty Acids; Operative Surgical Procedures; PKC-betaII; PPAR gamma; Patients; Peroxisome Proliferator-Activated Receptors; Polyunsaturated Fatty Acids; Predisposing Factor; Proliferative Index; Protocols documentation; Publishing; Risk; Risk Factors; Role; Signal Transduction; Staging; Testing; Tweens; Ulcerative Colitis; Work; cyclophosphamide/doxorubicin/lomustine protocol; indexing; interest; lifetime risk; pre-clinical; prevent; prophylactic; receptor; research study; size; tumor

DESCRIPTION (provided by applicant): Ulcerative colitis is the single major risk factor for the development of colitis-associated colon cancer (CAC). Lifetime risk accruals for CAC may be as high as 43%, and CAC accounts for 1 in 6 deaths due to inflammatory bowel diseases. There is no known non-surgical chemopreventive strategy for CAC, although there is compelling evidence that diets that are rich in n-3 polyunsaturated fatty acids (n-3 PUFA, also known as (3 PUFA) suppress both colonic inflammation and carcinogen-induced colon cancer. These observations suggest that diets that are rich in n-3 PUFA may be effective means to prevent progression from inflammation to colon cancer, and one of our objectives is to test this hypothesis in a newly developed animal model of CAC. Our working hypothesis holds that the chemopreventive effects of n-3 PUFA are mediated, at least in part, by two lipid receptors: protein kinase C-beta II (PKC(ll) and peroxisome proliferator-activated receptor-gamma (PPAR(). Both of these entities have been shown to be important in the etiology of sporadic colon cancer, but their role in dietary lipid signaling in the colon has not been defined, and their role in CAC has not been investigated. We will utilize genetic knockout mice to determine if the tumor-suppressive effects of n-3 PUFA are dependent upon the expression of PKCpll or PPAR( in the colonic epithelium. Completion of these experiments will provide pre-clinical proof-of-principle for the use of dietary lipids in chemoprevention of CAC and will define the biologically plausible mechanisms that may account for alteration of CAC risk by essential dietary lipids. Confirmation of our hypotheses will provide essential pre-clinical proof-of-principle in support of clinical trials to determine if dietary n-3 PUFA prevents progression from colonic inflammation to CAC, will identify the role of PKC(ll and PPAR( in CAC, and may ultimately provide an alternative means of chemoprevention to patients who presently have no alternative to colectomy.

描述（由申请人提供）：溃疡性结肠炎是结肠炎相关结肠癌（CAC）发展的单一主要危险因素。 CAC 的终生风险累积可能高达 43%，并且 CAC 占炎症性肠病死亡的六分之一。目前还没有已知的针对 CAC 的非手术化学预防策略，尽管有令人信服的证据表明富含 n-3 多不饱和脂肪酸（n-3 PUFA，也称为 (3 PUFA)）的饮食可以抑制结肠炎症和致癌物诱发的结肠癌。这些观察结果表明，富含 n-3 PUFA 的饮食可能是预防炎症进展为结肠癌的有效方法，并且 我们的目标之一是在新开发的 CAC 动物模型中检验这一假设。我们的工作假设认为，n-3 PUFA 的化学预防作用至少部分是由两种脂质受体介导的：蛋白激酶 C-β II (PKC(II) 和过氧化物酶体增殖物激活受体-γ (PPAR())。这两个实体已被证明在 散发性结肠癌的病因学，但它们在结肠膳食脂质信号传导中的作用尚未确定，并且它们在 CAC 中的作用尚未得到研究。我们将利用基因敲除小鼠来确定 n-3 PUFA 的肿瘤抑制作用是否依赖于结肠上皮中 PKCpll 或 PPAR( 的表达。这些实验的完成将为以下方面提供临床前原理验证： 膳食脂质在 CAC 化学预防中的应用，并将定义可能解释必需膳食脂质改变 CAC 风险的生物学合理机制。我们假设的证实将提供必要的临床前原理验证，以支持临床试验，以确定膳食 n-3 PUFA 是否可以预防结肠炎症进展为 CAC，并将确定 PKC(ll 和 PPAR（在 CAC 中，最终可能为目前无法替代结肠切除术的患者提供一种化学预防的替代方法。