Involvement of Prostaglandin E₂ in Bile Acid-caused Promotion of Colon Carcinogenesis and Anti-promotion by the Cyclooxygenase Inhibitor Indomethacin

Abstract

The mechanism of the anti-promoting effect of the prostaglandin (PG) synthesis inhibitor indomethacin in colon carcinogenesis was investigated. Male Sprague-Dawley rats received 0.002% water solution of indomethacin as drinking water freely for 3 days, then a subcutaneous injection of various doses of PGE₂ and/or an intrarectal instillation of 12μmol of sodium deoxycholate as a colon tumor promoter. Ornithine decarboxylase (ODC), a marker of tumor promotion, in the distal colonic mucosa was assayed at 4hr after deoxycholate instillation. Indomethacin significantly suppressed the deoxycholate-augmented increase of ODC activity, while exogenous PGE₂ restored or further increased the augmented ODC activity. The amount of PGE₂ and the level of ODC activity were well correlated. However, PGE₂ alone without deoxycholate did not increase the activity. Deoxycholate markedly increased colonic mucosal PGE₂ at 1hr after the instillation, and indomethacin decreased it. The results indicate that PGE₂, the production of which is stimulated in the colonic mucosa by deoxycholate, is involved in the induction of colonic mucosal ODC. This is probably why PG synthesis inhibitors may inhibit the tumor promotion and prevent cancer development in the colon.