PC-NSAIDs for Chemoprevention of Colorectal Cancer

描述(申请人提供)：结直肠癌是美国癌症相关死亡的第二大原因。根据一些流行病学研究，每天使用非类固醇抗炎药(NSAID)与显著降低结直肠癌的风险有关。然而，这类药物的长期使用受到限制，因为非类固醇抗炎药的不良反应会导致易感患者的胃肠道出血/溃疡，在某些情况下会导致危及生命的出血。这项建议的主要目标是测试两种新药，这两种药物是一种新型的磷脂酰胆碱(PC)相关的非甾体抗炎药，具有化学预防活性，布洛芬(IBU-PC)和吲哚美辛(INDO-PC)已在临床前研究和试点临床试验(IBU-PC)中被证明比未经修改的非类固醇抗炎药对胃肠道黏膜更安全。在一个已建立的结肠癌模型中，啮齿动物被给予化学致癌物(偶氮甲烷)，将被用来测试IBU-PC和INDO-PC与未经修饰的NSAIDs(如果在AOM暴露之前或之后给予)的化学预防效果，以在5-6周的研究期结束时抑制结肠异常隐窝病灶(ACF)的数量和多样性。将在安乐死时评估胃肠道出血和损伤的措施，以评估测试配方的胃肠道安全性。我们还将研究IBU-PC和INDO-PC抑制结肠癌早期进展的一些潜在的药物作用机制，包括：抑制环氧合酶(COX)活性，减少COX-1，COX-2和MDR-1的表达；以及它们干扰RAS信号事件的能力。这些研究将确定使用IBU-PC或INDO-PC进行化学预防的可行性，同时降低不良胃肠道事件的风险，从而开发一种或多种有效和安全的预防结直肠癌的药物。

DESCRIPTION (provided by applicant): Colorectal cancer is the second leading cause of cancer-related deaths in the U.S. Based on a number of epidemiological studies, the use of a daily non-steroidal anti-inflammatory drug (NSAID) is associated with a significant reduction in risk for colorectal cancer. However, the chronic use of this drug class is limited due to the adverse actions of NSAIDs to induce gastrointestinal bleeding/ulceration in susceptible patients, which in some cases results in life-threatening hemorrhage. The main goal of this proposal is to test two new drugs, which are members of a novel class of phosphatidylcholine (PC)-associated NSAIDs for chemopreventive activity, ibuprofen (IBU- PC) and indomethacin (INDO-PC) that have been documented in preclinical studies and a pilot clinical trial (IBU-PC) to be safer to the GI mucosa than the unmodified NSAID. An established model of colon cancer in which rodents are administered the chemical carcinogen (azoxymethane) will be used to test the chemopreventive efficacy of IBU-PC and INDO-PC versus the unmodified NSAIDs (if administered before or after AOM exposure) to inhibit, at the completion of the 5-6 week study period, the number and multiplicity of colonic aberrant crypt foci (ACF). Measures of GI bleeding and injury will be assessed at euthanasia to assess the GI safety of the test formulations. We will also investigate a number of potential mechanisms of drug action in which IBU-PC and INDO-PC inhibit the early stages of colon cancer progression including: inhibition of: cyclooxygenase (COX) activity, reducing the expression of COX-1, COX-2 and mdr-1; and their ability to disrupt Ras-signaling events. These studies will establish the feasibility of using IBU-PC or INDO-PC for chemoprevention while lowering the risk of adverse GI events, resulting in the development of one or more efficacious and safe drugs for prevention of colorectal cancer.