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A Dose-finding Study of Aspirin for Chemoprevention Utilizing Rectal Mucosal Prostaglandin E₂ Levels as a Biomarker¹

Departments of Gastrointestinal Medical Oncology and Digestive Diseases [D. S., M. W., F. A. S.], Carcinogenesis [S. M. F.], and Biostatistics [X. W., K-A. D.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and MacGregor Medical Clinic, Houston, Texas 77054 [N. I., P. S.]

Epidemiological and experimental evidence indicates that aspirin can protect against colorectal cancer. Aspirin inhibits cyclooxygenase enzymes and blocks prostaglandin (PG) biosynthesis. Using rectal PGE₂ levels as a mucosal biomarker, we sought to determine the optimal aspirin dose that would significantly suppress PGE₂ levels for chemoprevention trials. We conducted a randomized, double-blinded study in 60 subjects with prior sporadic colorectal adenoma(s) and evaluated three aspirin doses (81, 325, and 650 mg) or placebo taken daily for 4 weeks. PGE₂ levels in rectal biopsies performed at baseline and week 4 were analyzed by competitive immunoassay. Plasma salicylate levels, pill counts, and subject calendars were used to assess compliance. The 81-mg aspirin dose significantly suppressed PGE₂ levels relative to placebo (P = 0.005) and did so to an equivalent extent as did higher doses (P > 0.4) in evaluable subjects (n = 55) over a 4-week treatment period. Serum salicylate levels were associated with aspirin dose (P = 0.0002). Pill counts and calendars indicated that >98% of doses were taken by all subjects. No adverse events occurred in this short-term study. The 81-mg daily aspirin dose suppressed PGE₂ levels to an equivalent extent as did the 650-mg dose and supports the use of this dose for chemoprevention trials.

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