Inhibitory effects of mofezolac, a cyclooxygenase-1 selective inhibitor, on intestinal carcinogenesis.

Abstract

Cyclooxygenase (COX)-2, one enzyme isoform responsible for producing prostanoids from arachidonic acid, contributes to colon carcinogenesis. Recently, genetic disruption of COX-1, the other isoform, was shown to decrease the number of intestinal polyps and prostaglandin E(2) levels in intestinal mucosa, like the case with COX-2 gene disruption, in Min mice. We therefore investigated whether a COX-1 selective inhibitor, mofezolac, suppresses intestinal carcinogenesis in rodents. F344 male rats, receiving azoxymethane (AOM, 15 mg/kg body wt) s.c. injections at 5 and 6 weeks of age, were fed a diet containing 600 or 1200 p.p.m. mofezolac for 4 weeks. The number of aberrant crypt foci (ACFs) per rat and the bromodeoxyuridine labeling index of the crypt epithelium were dose-dependently decreased by administration of mofezolac, the value for the former at 1200 p.p.m. being 60% of control value. When Apc gene knockout mice (APC1309 mice) were given 600 or 1200 p.p.m. mofezolac in their diet for 8 weeks, the numbers of intestinal polyps were also dose-dependently decreased, with reduction to 59% of that in the control diet group at the higher dose. Nimesulide, a COX-2 selective inhibitor used as positive control, showed similar suppressive effects on the development of ACFs in AOM-treated rats and polyps in Apc gene knockout mice. The data indicate that both COX-1 and COX-2 can contribute to intestinal tumorigenesis.

• Authors: Tomohiro Kitamura, Toshihiko Kawamori, Naoaki Uchiya, Masaki Itoh, Tetsuo Noda, Mamoru Matsuura, Takashi Sugimura, Keiji Wakabayashi
• Journal: Carcinogenesis (Carcinogenesis) Vol. 23 Issue 9 Pg. 1463-6 (Sep 2002) ISSN: 0143-3334 [Print] England
• PMID: 12189188 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors
• Isoenzymes
• Isoxazoles
• Membrane Proteins
• Sulfonamides
• Cyclooxygenase 1
• Cyclooxygenase 2
• Prostaglandin-Endoperoxide Synthases
• Ptgs1 protein, mouse
• Ptgs1 protein, rat
• Azoxymethane
• mofezolac
• nimesulide

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Azoxymethane
• Carcinogenicity Tests
• Cyclooxygenase 1
• Cyclooxygenase 2
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors (therapeutic use)
• Disease Models, Animal
• Female
• Genes, APC (physiology)
• Intestinal Neoplasms (chemically induced, prevention & control)
• Isoenzymes (antagonists & inhibitors)
• Isoxazoles (therapeutic use)
• Male
• Membrane Proteins
• Mice
• Mice, Knockout
• Prostaglandin-Endoperoxide Synthases
• Rats
• Rats, Inbred F344
• Sulfonamides (therapeutic use)