PC-NSAIDs for Chemoprevention of Colorectal Cancer

PC-NSAIDs 用于结直肠癌的化学预防

基本信息

批准号：
8539588
负责人：
LENARD M LICHTENBERGER
金额：
$ 7.14万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-03 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8539588
关键词：
Aberrant crypt foci Adverse effects Anti-Inflammatory Agents Anti-inflammatory Aspirin Azoxymethane Cancer Etiology Carcinogens Cessation of life Chemoprevention Chemopreventive Agent Chronic Clinical Clinical Trials Colon Carcinoma Colorectal Cancer Complex Data Depressed mood Development Disease Dose Drug Costs Drug Formulations Drug effect disorder Drug usage Enzyme Inhibitor Drugs Enzyme Inhibitors Epidemiologic Studies Euthanasia Event Exposure to Gastrointestinal tract structure Generic Drugs Goals Healthcare Hemorrhage Ibuprofen Indomethacin Injury Lecithin Life Link Lipids Malignant Neoplasms Measures Modeling Mucous Membrane Non-Steroidal Anti-Inflammatory Agents Parents Patients Pharmaceutical Preparations Phospholipids Property Prostaglandin-Endoperoxide Synthase Prostaglandins Rattus Reporting Risk Rodent Rodent Model Safety Signal Transduction Staging Testing Ulcer base cancer risk chemical carcinogen colon carcinogenesis colorectal cancer prevention cyclooxygenase 1 cyclooxygenase 2 disorder risk gastrointestinal in vivo Model member novel preclinical study prevent safety testing soy tumor progression

项目摘要

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.

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。根据多项流行病学研究，每日使用非甾体类抗炎药 (NSAID) 与显着的死亡率相关。降低结直肠癌的风险。然而，由于非甾体抗炎药会在易感患者中诱发胃肠道出血/溃疡，在某些情况下导致危及生命的出血，因此长期使用此类药物受到限制。该提案的主要目标是测试两种新药，即布洛芬 (IBU-PC) 和吲哚美辛 (INDO-PC)，它们属于新型磷脂酰胆碱 (PC) 相关 NSAID 的化学预防活性，已在临床前研究和试点临床试验 (IBU-PC) 表明比未改良的 NSAID 对胃肠道粘膜更安全。已建立的结肠癌模型，其中给啮齿类动物施用化学致癌剂（氧化偶氮甲烷），将用于测试 IBU-PC 和 INDO-PC 相对于未修饰的 NSAID（如果在 AOM 暴露之前或之后施用）的化学预防功效，以抑制在完成 5-6 周研究期间，结肠异常隐窝病灶 (ACF) 的数量和多重性。将在安乐死时评估胃肠道出血和损伤的测量，以评估测试制剂的胃肠道安全性。我们还将研究 IBU-PC 和 INDO-PC 抑制结肠癌进展早期的许多潜在药物作用机制，包括：抑制：环氧合酶 (COX) 活性，减少 COX-1、COX- 的表达2 和 mdr-1；以及它们破坏 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，从而开发出一种或多种有效且安全的药物来预防结直肠癌。