Aspirin-PC for Chemoprevention of Colorectal Cancer

阿司匹林-PC 用于结直肠癌的化学预防

• 批准号: 8522788
• 负责人: LENARD M LICHTENBERGER
• 金额: $ 14.73万
• 依托单位: PLX OPCO, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-03 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8522788
• 关键词: Aberrant crypt foci; Adverse drug effect; Adverse effects; Affect; Aftercare; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Aspirin; Azoxymethane; Biological Availability; Blood Platelets; Blood Vessels; Businesses; Cancer Etiology; Cancer Model; Carcinogens; Cardiovascular system; Cell Proliferation; Cessation of life; Chemoprevention; Chemopreventive Agent; Chronic; Clinical; Clinical Trials; Coagulation Process; Colon; Colon Carcinoma; Colorectal Cancer; Colorectal Polyp; Complex; Data; Development; Dinoprostone; Disease; Dose; Drug Costs; Drug Formulations; Drug usage; Dysplasia; Eicosanoids; Enteral; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Epidemiologic Studies; Epithelium; Euthanasia; Event; Gastrointestinal tract structure; Generations; Generic Drugs; Goals; Growth; Healthcare; Heart Diseases; Hematocrit procedure; Hemoglobin; Hemorrhage; Incidence; Lecithin; Life; Light; Lipids; Malignant Neoplasms; Measurement; Measures; Modeling; Mucous Membrane; Neoplasm Metastasis; Observational Study; Oils; Organ; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Platelet aggregation; Play; Pre-Clinical Model; Prostaglandin-Endoperoxide Synthase; Randomized Controlled Trials; Risk; Rodent; Rodent Model; Role; Safety; Sulindac; Testing; Thromboxanes; Time; Toxic effect; Toxicity Tests; Treatment Efficacy; Treatment Protocols; Ulcer; adenoma; angiogenesis; base; cancer chemoprevention; cancer risk; chemical carcinogen; colon carcinogenesis; colorectal cancer prevention; cyclooxygenase 1; cyclooxygenase 2; disorder risk; drug efficacy; drug testing; gastrointestinal; gastrointestinal epithelium; improved; indexing; inhibitor/antagonist; insight; interest; novel; prevent; primary outcome; prospective; public health relevance; soy

DESCRIPTION (provided by applicant): Colorectal cancer is the third leading cause of cancer-related deaths in the U.S. Based on numerous epidemiological studies and recent prospective trials; the use of daily aspirin is associated with a significant reduction in colorectl cancer incidence, deaths and metastatic spread to other organs. However, the chronic use of this drug is limited due to the side effect of gastrointestinal bleeding/ulceration in susceptible patients, in some cases resulting in life-threatening hemorrhage. The main goal of this proposal is to test using a rodent colorectal cancer model a new drug for chemopreventive activity, phosphatidylcholine (PC)-associated aspirin (PL2200) that is documented in clinical trials to be safer to the GI mucosa than traditional aspirin with equivalent bioavailability and therapeutic efficacy. A pre-clinical model of colon cancer in which rodents are induced with a chemical carcinogen, azoxymethane (AOM), will be used to evaluate the chemopreventive efficacy and GI toxicity of PL2200 versus traditional aspirin. In these studies, we propose both pre-treatment and post-treatment protocols where the test drugs Aspirin-PC (PL2200), aspirin, enteric coated (EC)- aspirin (the over-the-counter/OTC aspirin most commonly available and consumed by the public), and sulindac (an NSAID with known chemopreventive efficacy) are orally administered (in Torpac minicapsules) at a range of doses either before or after AOM exposure. At euthanasia we will measure aberrant crypt formation (ACF) of the colonic mucosa as an index of dysplasia and of the test drugs' chemopreventive efficacy. We will also assess the GI toxicity of the test-drugs by inspecting the upper and lower gut macroscopically, microscopically and assess GI bleeding by measuring hematocrit and fecal hemoglobin. To gain insight into the mechanism of action of PL2200 we will compare the COX-1 and COX-2 inhibitory activity/expression of the test formulations on the affected lower gut epithelium, and the test-drugs' efficacy to inhibit platelet thromboxane generation/aggregation, as a growing body of evidence suggests that platelets play an important key regulatory role in colorectal cancer growth and metastasis. These studies, therefore will establish the feasibility of using PL2200 for chemoprevention while lowering the risk of adverse GI events, resulting in the development of an efficacious and safe drug for prevention of colorectal cancer.

描述（由申请人提供）：根据大量流行病学研究和最近的前瞻性试验，结直肠癌是美国癌症相关死亡的第三大原因；每日服用阿司匹林可显著降低结直肠癌的发病率、死亡率和转移性扩散到其他器官。然而，由于易感患者胃肠道出血/溃疡的副作用，该药物的长期使用受到限制，在某些情况下导致危及生命的出血。本研究的主要目的是在啮齿动物结肠直肠癌模型中测试一种具有化学预防活性的新药——磷脂酰胆碱（PC）相关阿司匹林（PL2200），该药物在临床试验中证明比传统阿司匹林对胃肠道粘膜更安全，具有同等的生物利用度和治疗效果。用化学致癌物偶氮氧甲烷（AOM）诱导啮齿动物结肠癌的临床前模型，将用于评估PL2200与传统阿司匹林的化学预防效果和胃肠道毒性。在这些研究中，我们提出了治疗前和治疗后的方案，其中测试药物阿司匹林- pc (PL2200)，阿司匹林，肠溶（EC）阿司匹林（最常见的非处方/OTC阿司匹林）和舒林酸（一种已知具有化学预防功效的非甾体抗炎药）在AOM暴露之前或之后以一定剂量口服（Torpac微型胶囊）。在安乐死时，我们将测量结肠粘膜的异常隐窝形成（ACF），作为不典型增生和试验药物化学预防效果的指标。我们还将通过宏观和微观检查上、下肠道来评估试验药物的胃肠道毒性，并通过测量红细胞压积和粪便血红蛋白来评估胃肠道出血。为了深入了解PL2200的作用机制，我们将比较试验配方对受影响的下肠上皮的COX-1和COX-2抑制活性/表达，以及试验药物抑制血小板血栓素生成/聚集的功效，因为越来越多的证据表明血小板在结直肠癌的生长和转移中起着重要的关键调节作用。因此，这些研究将确立PL2200用于化学预防的可行性，同时降低不良胃肠道事件的风险，从而开发出一种有效、安全的预防结直肠癌的药物。