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性结肠癌(CAC)发展的单一主要危险因素。CAC的终生风险累计值可能高达43%，CAC占因炎症性肠病死亡的六分之一。目前还没有针对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)的饮食既能抑制结肠炎，又能抑制致癌物质诱导的结肠癌。这些观察表明，富含n-3多不饱和脂肪酸的饮食可能是防止从炎症进展到结肠癌的有效手段，我们的目标之一是在新开发的CAC动物模型中测试这一假说。我们的工作假说认为，n-3多不饱和脂肪酸的化学预防作用至少部分是通过两种脂质受体介导的：蛋白激酶C-βII(PKC(11))和过氧化物酶体增殖物激活受体-γ(PPAR())。这两种物质已被证明在散发性结肠癌的病因学中具有重要作用，但它们在结肠中的饮食脂质信号中的作用尚未确定，它们在CAC中的作用也未被研究。我们将利用基因敲除小鼠来确定n-3PUFA的肿瘤抑制作用是否依赖于结肠上皮中PKCpl1或PPAR()的表达。这些实验的完成将为饮食脂质在化学预防CAC中的使用提供临床前的原则证明，并将确定可能解释基本饮食脂质改变CAC风险的生物学上可信的机制。我们的假说的确认将为临床试验提供必要的临床前原则证明，以确定膳食n-3多不饱和脂肪酸是否可以防止从结肠炎向CAC的进展，将确定PKC(11和PPAR)在CAC中的作用，并最终可能为目前没有结肠切除术替代方案的患者提供一种替代的化学预防手段。