Chemoprevention of IBD-Associated Colon Cancer

描述（由申请人提供）：炎症性肠病（IBD）患者患结直肠癌的风险比一般人群高20至30倍。这种增加的癌症风险归因于由炎症介质引起的氧化应激引起的遗传损伤以及粘膜修复期间结肠上皮的增殖。IBD相关的肿瘤可以通过结肠镜筛查在早期发现，可能是可治愈的。然而，预防结肠癌的安全有效的新策略将对IBD患者大有益处，并最终导致可观的成本节约。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结肠癌的风险。我们的研究表明，口服菠萝蛋白酶（一种来自菠萝的蛋白酶混合物）可显著降低IL-10缺陷小鼠自发性结肠炎的发病率和已建立的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先前的体外研究表明，菠萝蛋白酶降低T细胞增殖、信号转导和细胞因子产生。其在体外和体内的抗炎作用取决于其蛋白水解活性。该提案旨在验证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中的炎症和结肠瘤形成的影响。炎症的严重程度和结肠肿瘤的发生率将通过组织学确定。将确定DNA中的炎症相关氧化损伤和对信号转导和关键生物标志物表达的治疗相关影响，以直接评估菠萝蛋白酶对炎症和结直肠癌发生关键途径的影响。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患者及其家属提供巨大益处。

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.