Chemoprevention of IBD-Associated Colon Cancer

IBD 相关结肠癌的化学预防

• 批准号: 7195393
• 负责人: Laura P. Hale
• 金额: $ 24.85万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-29 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7195393
• 关键词: chemoprevention; colitis; colon; colon neoplasms; cysteine endopeptidases; inflammation

DESCRIPTION (provided by applicant): Patients with inflammatory bowel disease (IBD) have a 20 to 30-fold increased risk of colorectal cancer relative to the general population. This increased cancer risk has been attributed to genetic damage from oxidative stress caused by inflammatory mediators combined with the proliferation of colonic epithelium during mucosal repair. IBD-associated neoplasia can be detected at an early, potentially curable stage by colonoscopic screening. However, safe and effective new strategies for preventing colon cancer would be of great benefit to IBD patients and should ultimately lead to considerable cost savings. Recent animal studies have shown that inhibiting T cell-mediated colon inflammation can decrease the risk of colon cancer. Our studies show that oral administration of bromelain, a proteinase mixture derived from pineapple, significantly decreases both the incidence of spontaneous colitis and the severity of established T cell-mediated colitis in IL-10-deficient mice. Previous in vitro studies by our laboratory and others have shown that bromelain decreases T cell proliferation, signal transduction, and cytokine production. Its anti-inflammatory effects in vitro and in vivo depend on its proteolytic activity. This proposal is designed to test the hypothesis that bromelain treatment will decrease the risk of IBD-associated colon cancer by decreasing the genetic damage caused by T cell-mediated inflammation. The specific aims will determine the effect of bromelain on inflammation and development of colon neoplasia in mice with chronic T cell-mediated colitis. The severity of inflammation and the incidence of colonic neoplasia will be determined histologically. Inflammation-associated oxidative lesions in DNA and treatment-related effects on signal transduction and critical biomarker expression will be determined to directly assess effects of bromelain on pathways critical to inflammation and colorectal carcinogenesis. The proposed studies will further elucidate mechanisms that can lead to novel interventions to prevent IBD-associated colon cancers, providing great benefit to IBD patients and their families.

描述（由申请人提供）：与普通人群相比，炎症性肠病 (IBD) 患者患结直肠癌的风险增加 20 至 30 倍。这种癌症风险的增加归因于炎症介质引起的氧化应激以及粘膜修复过程中结肠上皮增殖造成的遗传损伤。通过结肠镜筛查，可以在早期、可能治愈的阶段检测到 IBD 相关肿瘤。然而，安全有效的预防结肠癌的新策略将对 IBD 患者大有裨益，并最终应节省大量成本。最近的动物研究表明，抑制 T 细胞介导的结肠炎症可以降低患结肠癌的风险。我们的研究表明，口服菠萝蛋白酶（一种源自菠萝的蛋白酶混合物）可显着降低 IL-10 缺陷小鼠自发性结肠炎的发病率和已形成的 T 细胞介导的结肠炎的严重程度。我们实验室和其他实验室之前的体外研究表明，菠萝蛋白酶可降低 T 细胞增殖、信号转导和细胞因子的产生。其体外和体内的抗炎作用取决于其蛋白水解活性。该提案旨在检验菠萝蛋白酶治疗将通过减少 T 细胞介导的炎症引起的遗传损伤来降低 IBD 相关结肠癌风险的假设。具体目标将确定菠萝蛋白酶对患有慢性 T 细胞介导的结肠炎的小鼠的炎症和结肠瘤形成的影响。炎症的严重程度和结肠瘤形成的发生率将通过组织学来确定。将确定 DNA 中与炎症相关的氧化损伤以及治疗相关对信号转导和关键生物标志物表达的影响，以直接评估菠萝蛋白酶对炎症和结直肠癌发生的关键途径的影响。拟议的研究将进一步阐明可能导致预防 IBD 相关结肠癌的新干预措施的机制，为 IBD 患者及其家人带来巨大利益。