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: 8837775
• 负责人: LENARD M LICHTENBERGER
• 金额: $ 14.69万
• 依托单位: PLX OPCO, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-06 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8837775
• 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; 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）：基于许多流行病学研究和最近的前瞻性试验，大肠癌是美国与癌症相关死亡的第三主要原因；每日阿司匹林的使用与结尾癌的发生率，死亡和转移性扩散到其他器官有关。但是，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，在某些情况下导致威胁生命的出血。该提案的主要目的是使用啮齿动物结直肠癌模型测试一种用于化学预防活性，磷脂酰胆碱（PC）相关的阿司匹林（PL2200）的新药物，该药物在临床试验中记录在临床试验中，对GI Mucosa比传统的阿司匹林更安全，并具有等效的生物利用率和治疗效率。结肠癌的临床前模型，其中啮齿动物是用化学致癌物（aom）诱导的，将用于评估PL2200与传统阿司匹林的化学预防效果和GI毒性。 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在AOM暴露之前或之后。在安乐死，我们将测量结肠粘膜的异常隐窝形成（ACF），作为发育不良的指数和测试药物的化学预防效果。我们还将通过测量血细胞比容和粪便血红蛋白来评估宏观宏观和下型宏观宏观和下肠道的肠道毒性，并评估胃肠道出血。为了深入了解PL2200的作用机制，我们将比较COX-1和COX-C-2抑制活性/表达在受影响的下肠上皮上皮上的测试公式的表达，以及测试毒被抑制血小板螺旋藻的产生/聚集的疗效，证据的证据的增长表明，血小板的生长是重要的，并且具有重要的键盘癌的作用。因此，这些研究将确定使用PL2200进行化学预防的可行性，同时降低不良GI事件的风险，从而开发出一种有效且安全的药物来预防结直肠癌。