Effect of subacute ibuprofen dosing on rectal mucosal prostaglandin E-2 levels in healthy subjects with a history of resected polyps

Nonsteroidal antiinflammatory drugs are among the most promising chemopreve ntive agents for colorectal cancer. Although the mechanism by which nonster oidal antiinflammatory drugs exert such effects remains to be further chara cterized, their best known pharmacological effect is inhibition of prostagl andin synthetase, which leads to decreases in tissue prostaglandin levels. We conducted a randomized, double-blind, controlled study to examine the ef fect of daily ibuprofen treatment on the rectal mucosal prostaglandin E-2 ( PGE(2)) levels in healthy subjects with a history of resected polyps. Study participants (n = 27) completed a 2-week run-in period and were then rando mized to take a single, daily dose of ibuprofen (300 or 600 mg) or of a pla cebo for 4 weeks. Rectal biopsy specimens were taken before and after the r un-in period and at 2 and 4 weeks after the ibuprofen/ placebo treatment. N otably large between- and within-subject variability in the rectal mucosal PGE(2) content was seen. The changes in PGE(2) levels after ibuprofen/ plac ebo treatment correlated with the baseline PGE, content. After adjustment o f the baseline values, 2 weeks of 300 mg/day of ibuprofen treatment resulte d in significantly more suppression of PGE(2) levels than that observed aft er the placebo treatment (55% versus 22% suppression from baseline; P = 0.0 33). Although other ibuprofen treatment schedules and doses appeared to res ult in suppression in the PGE(2) levels, the suppression was not statistica lly significant because of the large variability in this measurement. Becau se lower doses are associated with fewer adverse effects, a dose of 300 mg of ibuprofen/day should be considered for future Phase n chemoprevention st udies. Stratifying study participants, based on their baseline PGE(2) level s and inclusion of a larger number of study subjects, are recommended for f uture trials where the rectal mucosal PGE(2) level is to be used as a surro gate end point biomarker.