PC-NSAIDs for Chemoprevention of Colorectal Cancer

描述（由申请人提供）：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，每天使用非甾体抗炎药（NSAID）与结直肠癌风险的显著降低有关。然而，由于非甾体抗炎药在易感患者中诱发胃肠道出血/溃疡的不良反应，在某些情况下导致危及生命的出血，这类药物的长期使用受到限制。该提案的主要目标是测试两种新药，它们是一类新型的磷脂酰胆碱（PC）相关非甾体抗炎药的化学预防活性，布洛芬（IBU-PC）和吲哚美辛（indomethacin, INDO-PC），已在临床前研究和临床试验（IBU-PC）中记录，对胃肠道粘膜比未改性的非甾体抗炎药更安全。在建立的结肠癌模型中，啮齿动物被给予化学致癌物（偶氮氧甲烷），将用于测试IBU-PC和INDO-PC与未修饰的非甾体抗炎药（如果在AOM暴露之前或之后给予）的化学预防效果，以抑制5-6周研究期结束时结肠异常隐窝灶（ACF）的数量和多样性。将在安乐死时评估GI出血和损伤的措施，以评估测试配方的GI安全性。我们还将研究ibus - pc和INDO-PC抑制结肠癌早期进展的一些潜在药物作用机制，包括：抑制环氧化酶（COX）活性，降低COX-1、COX-2和mdr-1的表达；以及它们破坏ras信号事件的能力。这些研究将确立IBU-PC或INDO-PC用于化学预防的可行性，同时降低不良胃肠道事件的风险，从而开发出一种或多种有效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.