Colonic mucosal prostaglandin e₂ and cyclooxygenase expression before and after low aspirin doses in subjects at high risk or at normal risk for colorectal cancer^{1, 2}

Development of potential cancer chemopreventive drugs involves the systematic 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 estradiol (E₂) in individuals at high risk for colorectal cancer development similar 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 subjects. Prostaglandin E₂ and cyclooxygenase expression were assayed from distal sigmoid biopsies from all of the subjects before and after treatment. Results: The mean prostaglandin E₂ for normal-risk subjects before aspirin treatment was 11.3 ± 1.7 pg/μg (mean ± SE) tissue protein and after aspirin treatment was 4.9 ± 0.91 pg/μg tissue protein (P & 0.0001). In high-risk subjects, mean pretreatment prostaglandin E₂ was 14.4 ± 1.7 pg/μg tissue protein and after aspirin treatment was 4.7 ± 0.70 pg/μg tissue protein (P & 0.0001). Aspirin treatment did not alter cyclooxygenase-1 protein expression. Conclusions: Aspirin treatment at a dose of 81 mg reduces colorectal mucosal prostaglandin E₂ concentration after 28 daily doses. Risk for colorectal carcinoma did not modify colorectal mucosal baseline or post-aspirin prostaglandin E₂, or cyclooxygenase expression. Colorectal mucosal prostaglandin concentration may be used as a "drug-effect surrogate biomarker," that is, a surrogate to assess sufficient delivery and tissue effect of a chemopreventive agent.