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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}

Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University and Medical Service, James H. Quillen Veterans Affairs Medical Center, Johnson City, Tennessee 37604 [K. K.]; Departments of Family and Preventive Medicine [C. L. R.] and Medicine [C. R. B.], University of California at San Diego, San Diego, California 92093; Department of Clinical Cancer Prevention, M. D. Anderson Cancer Center, Houston, Texas 77030 [I. S.]; Departments of Family Medicine [M. T. R.], Radiation Oncology [D. N.], Internal Medicine [K. B., J. B., M. P-G., D. E. B.], and Pharmacology [D. E. B.], University of Michigan Medical Center, Ann Arbor, Michigan 48109; and Veterans Affairs Medical Center, Ann Arbor, Michigan 48109 [D. E. B.]

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.

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