Aspirin-PC for Chemoprevention of Colorectal Cancer

描述（由申请人提供）：结直肠癌是美国癌症相关死亡的第三大原因。基于大量流行病学研究和最近的前瞻性试验;每日使用阿司匹林与结直肠癌发病率、死亡率和转移扩散到其他器官的显著降低相关。然而，由于易感患者胃肠道出血/溃疡的副作用，这种药物的长期使用受到限制，在某些情况下会导致危及生命的出血。该提案的主要目标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的新药，磷脂酰胆碱（PC）相关阿司匹林（PL 2200），其在临床试验中被证明对GI粘膜比传统阿司匹林更安全，具有等效的生物利用度和治疗功效。使用化学致癌物氧化偶氮甲烷（AOM）诱导啮齿动物的结肠癌临床前模型，将用于评价PL 2200与传统阿司匹林相比的化学预防功效和GI毒性。在这些研究中，我们提出了治疗前和治疗后方案，其中在AOM暴露之前或之后以一定剂量范围口服（Torpac微胶囊）试验药物阿司匹林-PC（PL 2200）、阿司匹林、肠溶包衣（EC）-阿司匹林（最常见的非处方/OTC阿司匹林）和舒林酸（一种具有已知化学预防功效的NSAID）。在安乐死时，我们将测量结肠粘膜的异常隐窝形成（ACF）作为异型增生和试验药物化学预防功效的指标。我们还将通过肉眼和显微镜检查上消化道和下消化道来评估试验药物的GI毒性，并通过测量血细胞比容和粪便血红蛋白来评估GI出血。为了深入了解PL 2200的作用机制，我们将比较测试制剂对受影响的下肠上皮的考克斯-1和考克斯-2抑制活性/表达，以及测试药物抑制血小板血栓烷生成/聚集的功效，因为越来越多的证据表明血小板在结直肠癌生长和转移中起重要的关键调节作用。因此，这些研究将确定使用PL 2200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预防结直肠癌的药物。

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.