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.
Colorectal cancer is the third leading cause of cancer-related deaths in the U.S. There is sufficient clinical information available to support the use of aspirin as a chemopreventive agent in patients at risk for this disease, but the side effects of this drug to cause bleeding and ulceration of the gastrointestinal (GI) tract, limit its widespread use. The drug under development in this proposal, PL2200, is an aspirin that is chemically complexed with a lipid (phosphatidylcholine) to make it much safer for the GI tract, while still maintaining ts chemopreventive action. PL2200 has the potential to save healthcare dollars by providing a relatively low cost drug that can prevent a fatal disease (colorectal cancer) and avoid life-threatening side effects (bleeding).