PPAR GAMMA AGONISTS FOR THE PREVENTION OF COLON CANCER

流行病学研究强烈地将非甾体抗炎药（NSAID）的使用与降低结肠癌风险联系起来。非甾体抗炎药可以预防结肠癌。然而，可能存在其他解释。某些非甾体抗炎药是转录因子核受体超家族成员过氧化物酶体增殖物激活受体（ppar）的配体。全面研究PPAR γ激动剂作为结肠癌可能的化学预防剂。结肠癌是第二种癌症。待验证的假设是PPAR γ激动剂（PPAR γ是PPAR在结肠上皮和结肠肿瘤中高度表达的一种形式）将对结肠具有化学预防作用。我提出了两个目标来验证这一假设：大鼠结肠上皮蛋白表达。探讨对正常和结肠癌治疗的啮齿动物结肠的影响。我们将测试曲格列酮、吡格列酮、罗格列酮、BRL 49653和抗炎非甾体抗炎药、吲哚美辛和布洛芬。这些研究的结果将提供结肠中PPAR γ表达水平升高与激活它的化合物之间的直接联系。在目的2中，我们将在大鼠结肠中以抑制异常隐窝灶（ACF）作为中间终点。这些研究旨在确定PPAR γ激动剂是否在体内是肿瘤发生的抑制剂。二级研究将评估这些化合物对结肠细胞增殖和凋亡率的影响。这些研究将确定PPAR γ作为化学预防药物开发的可能靶点。

Epidemiological studies strongly associate non-steroidal anti- inflammatory drug (NSAID) use with reduced risk for colon cancer. NSAIDS prevent colon cancer. However, alternative explanations may exist. Certain NSAIDS are ligands for peroxisome proliferator-activated receptors (PPARs), members of the nuclear receptor superfamily of transcription factors. The overall investigating agonists of PPAR gamma as possible chemopreventives for colon cancer. Colon cancer is the second cancer. The hypothesis to be tested is that agonists of PPAR gamma, a form of PPAR highly expressed in the colon epithelium and colon tumors, will be chemopreventive for he colon. I propose two aims to test the hypothesis, protein expression in rat colon epithelium. Effects on normal and colon carcinogen-treated rodent colon will be explored. We will test troglitazone, pioglitazone, rosiglitazone, BRL 49653 and the anti-inflammatory NSAIDs, indomethacin and ibuprofen. Results from these studies will provide a direct link between the reportedly elevated expression levels of PPAR gamma in the colon and compounds that activate it. In Aim 2, we will determine in the rat colon using inhibition of aberrant crypt foci (ACF) as an intermediate endpoint. These studies are aimed at determining whether PPAR gamma agonists are inhibitors of tumorigenesis in vivo. Secondary studies will assess the effects of these compounds on colonic cell proliferation and apoptotic rates. These studies will define PPAR gamma as a possible target for chemopreventive drug development.