PC-NSAIDs for Chemoprevention of Colorectal Cancer

PC-NSAIDs 用于结直肠癌的化学预防

• 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
• 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

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) 可显着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，这两种药物已在临床前研究和初步临床试验 (IBU-PC) 中得到记录，比未经修饰的药物对胃肠道粘膜更安全。 非甾体抗炎药。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，以在 5-6 周的研究期结束时抑制结肠异常隐窝病灶 (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一些潜在药物作用机制，包括： 抑制：环氧合酶 (COX) 活性，减少 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。 公共卫生相关性：结直肠癌是美国癌症相关死亡的第二大原因。有足够的临床信息支持使用 非甾体抗炎药（NSAID）作为有这种疾病风险的患者的化学预防剂，但此类药物引起胃肠道（GI）出血和溃疡的副作用限制了其广泛使用。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）进行化学复合，使它们对胃肠道更加安全，同时仍然保持其化学预防作用。布洛芬-PC 和吲哚美辛-PC 可以通过提供相对低成本的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），从而节省医疗费用。