Association of PPAR gamma ligands & colonic neoplasia

描述（由申请人提供）：2型糖尿病（DM）患者患结直肠癌的风险似乎略有增加。糖尿病的治疗包括饮食疗法、胰岛素和/或口服药物。过氧化物酶体增殖物激活受体（PPARs）是转录因子的核激素受体超家族的成员，其活性由小的亲脂性配体（例如类固醇激素）的高亲和力结合调节。一类新的糖尿病药物噻唑烷二酮类（TZD）与PPARs的/亚型结合。这些药物的一个独特特征是改善胰岛素敏感性。 结肠上皮细胞表达高水平的PPARgamma蛋白。先前的体外和体内研究表明，PPARgamma可能影响从正常结肠粘膜到良性腺瘤性息肉并最终到浸润性癌症的发展和进展。这些研究中的大多数表明TZD PPARgamma配体具有潜在的化学保护作用。例如，致癌作用的动物模型证明在PPARgamma配体存在下异常隐窝病灶和肠肿瘤的产生减少。尽管TZD广泛用于治疗2型DM，但缺乏这些化合物对人类结肠肿瘤作用的数据。然而，我们的初步数据表明，1年或更长时间暴露于TZDs可能会降低2型糖尿病患者患结直肠癌的风险。 拟定的研究是一项回顾性病例对照研究，嵌套在来自北方加州Kaiser Permanente的糖尿病患者队列中，这些患者自TZD在美国上市之前就一直接受Kaiser医生的治疗。从该队列中，大约4,000例在1999年至2005年期间接受结肠镜检查的患者将根据结肠镜检查结果分为3组：晚期腺瘤性瘤变、早期腺瘤性瘤变和无腺瘤性瘤变。此外，将根据第二次乙状结肠镜检查时远端结肠中是否存在腺瘤性瘤变对大约6，000例接受了连续乙状结肠镜检查的患者进行分类。将比较各组在结肠镜检查或第二次乙状结肠镜检查前使用TZD的情况。因此，我们将评估化合物对从正常粘膜到腺瘤性瘤形成的进展的作用。我们的研究结果将使我们能够将现有的体外和体内观察结果转化为完整的人类结肠，并可能导致进一步的化学预防策略。

DESCRIPTION (provided by applicant): Patients with type 2 diabetes mellitus (DM) appear to have a small increased risk of colorectal cancer. Treatment of DM can include diet therapy, insulin, and or oral medications. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of transcription factors whose activities are regulated by high affinity binding of small lipophilic ligands such as steroid hormones. A new class of diabetic drugs, the thiazolidinediones (TZDs), binds to the, /subtype of the PPARs. A unique feature of these drugs is improvement in insulin sensitivity. Colonic epithelial cells express high levels of PPARgamma, protein. Prior in vitro and in vivo studies have suggested that PPARgamma may influence the development and progression from normal colon mucosa to benign adenomatous polyps and eventually to invasive cancer. The majority of these studies suggest a potential chemoprotective effect of TZD PPARgamma ligands. For example, animal models of carcinogenesis demonstrate reduced production of aberrant crypt foci and intestinal tumors in the presence of PPARgamma ligands. Despite widespread use of TZDs to treat type 2 DM, data on the effect of these compounds on colonic neoplasia in humans are lacking. However, our preliminary data suggests that 1 year or greater exposure to TZDs may reduce the risk of colorectal cancer among patients with type 2 DM. The proposed study is a retrospective case-control study nested within the cohort of diabetic patients from Kaiser Permanente Northern California who have been in the care of Kaiser physicians since before the marketing of TZDs in the US. From this cohort, approximately 4,000 patients who have undergone colonoscopy between 1999 and 2005 will be categorized into 1 of 3 groups according to the findings at colonoscopy: advanced adenomatous neoplasia, early adenomatous neoplasia, and no adenomatous neoplasia. In addition, approximately 6,000 patients who have undergone serial sigmoidoscopies will be categorized according to the presence or absence of adenomatous neoplasia in the distal colon on the second sigmoidoscopy. Use of TZDs prior to the colonoscopy or second sigmoidoscopy will be compared among the groups. As such, we will assess the effect of the compounds on the progression from normal mucosa to adenomatous neoplasia. Our results will allow us to translate the existing in vitro and in vivo observations to the intact human colon and could lead to further chemoprevention strategies.