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）：结交癌是美国与癌症相关死亡的第二大原因，基于许多流行病学研究，使用每日非甾体类抗炎药（NSAID）的使用与大肠癌的风险大幅降低有关。但是，由于NSAID在易感患者中诱导胃肠道出血/溃疡的不良作用，该药物类别的长期使用受到限制，在某些情况下，这会导致威胁生命的出血。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）相关的NSAID，用于化学预防活性，Ibuprofen（IBU-PC）和Indomethacin（Ibu-pc）和Indophacin（Indo-pc），这些NSAID已在临时研究和临时研究中已被记录为Inmodical clifiparical clifipial clifipial clifipial clifipial clifipal clibos clie climodical climodical climodica clie to ibu-cluc cly to ibu-pc。 NSAID。固定的结肠癌模型，在该模型中，将使用化学致癌物（甲氧烷）来测试IBU-PC和Indo-PC的化学预防效果，而在5-6周的次数中，在5-6周的次数中，在抑制5-6周的次数和倍数次数的情况下（如果在AOM暴露之前或之后）抑制col的NSAID（如果在AOM暴露之前或之后进行）。胃肠道出血和伤害的措施将在安乐死评估，以评估测试配方的胃肠道安全性。我们还将研究一些潜在的药物作用机制，其中IBU-PC和Indo-PC抑制结肠癌进展的早期阶段，包括：抑制：环氧酶（COX）活性，降低COX-1，COX，COX，COX-2和MDR-1的表达；以及他们破坏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，同时降低发生不良GI事件的风险，从而发展一种或更多有效，安全的药物来预防结直肠癌。