Reduction of carcinogenicity of N-nitrosomethylurea by indomethacin and failure of resuming effect of prostaglandin E2 (PGE2) against indomethacin.

Nonsteroid antiinflammatory drugs such as indomethacin may play an important role in preventing the development of chemically induced experimental carcinomas of various organs including the large bowel in rats and mice. This effect might correlate with an inhibition of prostaglandin (PG) synthesis by these drugs. Sprague-Dawley rats were given three intrarectal doses of 4 mg N-nitrosomethyl-urea (MNU) within week 1 to induce large-bowel carcinomas. The experimental groups of rats received a 0.001% aqueous solution of indomethacin ad libitum as drinking water for days 1-8 and/or a subcutaneous injection of 500 micrograms/kg body weight of PGE2 immediately before and 2 h after each MNU dose. They were then maintained on basal diet and plain tap water without further treatment. At autopsy at week 31, the tumor incidence and the mean number of tumors per rat were 90% and 1.7 in untreated rats, 67% and 0.8 in indomethacin-treated rats, and 79% and 1.2 in indomethacin + PGE2-treated rats, respectively. The data indicate that indomethacin reduced the number of large-bowel tumors, while pharmacologic doses of PGE2 failed to reestablish the anticarcinogenic activity of indomethacin. It was concluded that a tolerable therapeutic dose of indomethacin can reduce the carcinogenic activity of MNU in the large bowel.