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，每日使用非甾体抗炎药（NSAID）与结直肠癌风险显著降低相关。然而，由于NSAID在易感患者中诱导胃肠道出血/溃疡的不良作用，在某些情况下导致危及生命的出血，因此该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，这两种新药是一类新的磷脂酰胆碱（PC）相关NSAID的化学预防活性成员，布洛芬（IBU-PC）和吲哚美辛（INDO-PC）已在临床前研究和初步临床试验（IBU-PC）中记录为对GI粘膜比未修饰的NSAID更安全。将使用啮齿动物给予化学致癌物（氧化偶氮甲烷）的已建立的结肠癌模型来测试IBU-PC和INDO-PC相对于未修饰的NSAID（如果在AOM暴露之前或之后给药）在5-6周研究期结束时抑制结肠异常隐窝病灶（ACF）的数量和多样性的化学预防功效。将在人道处死时评估胃肠道出血和损伤的指标，以评估供试制剂的胃肠道安全性。我们还将研究IBU-PC和INDO-PC抑制结肠癌早期进展的许多潜在药物作用机制，包括：抑制环氧合酶（考克斯）活性，降低考克斯-1、考克斯-2和mdr-1的表达;以及它们破坏Ras信号传导事件的能力。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GI事件的风险，从而开发一种或多种有效且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.