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：
8401434
负责人：
LENARD M LICHTENBERGER
金额：
$ 7.6万
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/8401434
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. PUBLIC HEALTH RELEVANCE: Colorectal cancer is the second leading cause of cancer-related deaths in the U.S. There is sufficient clinical information available to support the use of nonsteroidal anti-inflammatory drugs (NSAIDs) as chemopreventive agents in patients at risk for this disease, but the side effect of this class of drugs to cause bleeding and ulceration of the gastrointestinal (GI) tract, limits their widespread use. The drugs under development in this proposal are Ibuprofen and Indomethacin that are chemically complexed with a lipid (phosphatidylcholine) to make them much safer for the GI tract, while still maintaining their chemopreventive action. Ibuprofen-PC and Indomethacin-PC have the potential to save healthcare dollars by providing relatively low cost drugs that can prevent a fatal disease (colorectal cancer) and also avoid life-threatening side effects (bleeding).

描述（由申请人提供）：结直肠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）与显着有关降低结直肠癌的风险。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。该提案的主要目的是测试两种新药，它们是一种新型的磷脂酰胆碱（PC）相关的NSAID，用于化学预防活性，ibuprofen（IBU- PC）和Indomethacin（Indopc）（Indo-PC）临床前研究和试验临床试验（IBU-PC）比未修饰的NSAID更安全。既定的结肠癌模型，其中啮齿动物被施用化学致癌物（甲氧烷烷）将用于测试IBU-PC和Indo-PC的化学预防效果5-6周研究期的完成，结肠异常隐窝灶（ACF）的多样性。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-的表达2和MDR-1;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。公共卫生相关性：大肠癌是美国与癌症相关死亡的第二大原因，有足够的临床信息可供支持使用非甾体类抗炎药（NSAIDS）作为患有这种疾病风险的患者的化学预防剂，但是这类药物的副作用会导致胃肠道（GI）散发出血和溃疡，从而限制了其广泛使用。该提案中正在开发的药物是布洛芬和吲哚美辛，它们与脂质（磷脂酰胆碱）化学复合，使其在GI段中更安全，同时仍保持其化学预防作用。布洛芬-PC和吲哚美辛 - PC通过提供相对较低的成本药物来预防致命疾病（结直肠癌），并避免危及生命的副作用（出血），从而有可能节省医疗保健费用。