Colonic mucosal prostaglandin E-2 and cyclooxygenase expression before andafter low aspirin doses in subjects at high risk or at normal risk for colorectal cancer

Development of potential cancer chemopreventive drugs involves the systemat ic evaluation of these drugs in preliminary Phase I and II studies in human beings to identify the optimal drug dose, drug toxicity, and surrogate end point biomarker modulation. Objectives: We tested the hypothesis that aspirin, at a single, once-daily 81-mg dose, will reduce colonic mucosal concentration of prostaglandin estr adiol (E-2) in individuals at high risk for colorectal cancer development s imilar to our prior observations in a young normal-risk population. Methods: Aspirin was administered at a dose of 81 mg once daily for 28 days in a cohort of 92 matched high-risk and normal-risk colorectal cancer subj ects. Prostaglandin E-2 and cyclooxygenase expression mere assayed from dis tal sigmoid biopsies from all of the subjects before and after treatment. Results: The mean prostaglandin E-2 for normal-risk subjects before aspirin treatment was 11.3 +/- 1.7 pg/mug (mean +/- SE) tissue protein and after a spirin treatment was 3.9 +/- 0.91 pg/mug tissue protein (P < 0.0001), In hi gh-risk subjects, mean pretreatment prostaglandin E-2 was 14.3 +/- 1.7 pg/m ug tissue protein and after aspirin treatment was 4.7 +/- 0.70 pg/mug tissu e protein (P < 0.0001), Aspirin treatment did not alter cyclooxygenase-1 pr otein expression. Conclusions: Aspirin treatment at a dose of 81 mg reduces colorectal mucosa l prostaglandin E-2 concentration after 28 daily doses. Risk for colorectal carcinoma did not modify colorectal mucosal baseline or post-aspirin prost aglandin E-2, or cyclooxygenase expression. Colorectal mucosal prostaglandi n concentration mag be used as a "drug-effect surrogate biomarker," that is , a surrogate to assess sufficient delivery and tissue effect of a chemopre ventive agent.