Chemoprevention of IBD-Associated Colon Cancer

描述(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被归因于炎性介质引起的氧化应激以及粘膜修复过程中结肠上皮的增殖造成的遗传损害。通过结肠镜筛查，IBD相关肿瘤可以在早期被发现，而且有可能治愈。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，并最终应导致相当大的成本节约。最近的动物研究表明，抑制T细胞介导的结肠炎可以降低结肠癌的风险。我们的研究表明，口服菠萝酶，一种从菠萝中提取的蛋白酶混合物，显著降低IL-10缺陷小鼠的自发性结肠炎的发生率和已建立的T细胞介导的结肠炎的严重程度。我们实验室和其他人之前的体外研究表明，菠萝酶可以减少T细胞的增殖、信号转导和细胞因子的产生。其体内外抗炎作用依赖于其蛋白水解性。这项建议旨在验证一种假设，即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相关结肠癌的风险。这些特定的目的将确定菠萝酶对慢性T细胞介导的结肠炎小鼠的炎症和结肠肿瘤发展的影响。炎症的严重程度和结肠肿瘤的发生率将通过组织学来确定。将确定DNA中与炎症相关的氧化损伤以及与治疗相关的对信号转导和关键生物标记物表达的影响，以直接评估菠萝酶在炎症和结直肠癌发生关键途径上的影响。拟议的研究将进一步阐明可以导致新的干预措施来预防IBD相关结肠癌的机制，为IBD患者及其家人带来巨大好处。

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.