SUPPRESSION OF HUMAN COLORECTAL MUCOSAL PROSTAGLANDINS - DETERMINING THE LOWEST EFFECTIVE ASPIRIN DOSE

Background: A variety of studies have supported the finding that regul ar intake of aspirin (acetylsalicylic acid) or nonsteroidal anti-infla mmatory agents san affect colorectal cancer carcinogenesis, These agen ts inhibit the synthesis of prostagiandins, High levels of prostagland ins are observed in colon cancer tissues. Purpose: Experiments were pl anned to determine the lowest dose of aspirin that can markedly suppre ss the levels of mucosal prostaglandins E-2 and F-2 alpha in colorecta l mucosa and to determine whether a relationship exists between een th ese levels and plasma levels of both acetylsalicylic acid and its meta bolite, salicylic acid. Methods: Healthy men and women aged 18 years o r older participated in the study. The participants took a single, dai ly dose of aspirin (40.5, 81, 162, 324, or 648 mg) or a placebo for 14 days. Colorectal biopsy specimens were taken at baseline, 24 hours af ter the first dose of aspirin, and 24-30 hours and 72-78 hours after t he last, i.e., fourteenth, daily dose of aspirin. The biopsy specimens were assayed for prostaglandins E-2 and F-2 alpha by use of a competi tive enzyme immunoassay, Plasma concentrations of acetylsalicylic acid and salicylic acid were determined by use of high-performance liquid chromatography, All P values are two-sided. Results: A total of 65 sub jects (10 receiving placebo, groups of 10 each receiving 40.5, 81, 162 , or 324 mg of aspirin, and a group of 15 receiving 648 mg of aspirin) completed the protocol. One subject reported unacceptable drug-induce d toxic effects and did not complete the protocol; other subjects repo rted acceptable side effects. The lowest dose to significantly suppres s colorectal mucosal prostaglandin E-2 concentrations from baseline at 24 hours after the first dose (by 22.6 %; P = .002) and at 24-30 hour s after the last close (by 14.2%; P = .021) nas 162 mg. At 92-78 hours after the last dose, there was significant suppression for subjects r eceiving 81 mg (by 23.7%; P = .008). The lowest dose to significantly suppress colorectal mucosal prostaglandin F-2 alpha concentrations fro m baseline at 24 hours after the first dose (by 18.3%; P = .832) was 3 24 mg, The lowest dose causing a marked reduction in the level of pros taglandin F-2 alpha at 23-30 hours (by 15.1%; P = .003) and 72-78 hour s (by 23.0%; P = .0002) after the last dose was 40.5 mg, NO detectable amounts of acetylsalicylic acid or salicylic acid were present in the plasma at any of tile biopsy time points. Conclusions: The lowest dos es of aspirin taken daily for 14 days to significantly suppress concen trations of colorectal mucosal prostaglandins E-2 and F-2 alpha were 8 1 and 40.5 mg, respectively. The suppression occurred without detectab le amounts of aspirin or salicylic acid in the plasma at the time poin ts studied. On the basis bf these observations, we recommend a single, daily dose of 81 mg of aspirin in future studies of this drug as a ch emopreventive agent far colorectal cancer.