A specific inducible nitric oxide synthase inhibitor, ONO-1714 attenuates inflammation-related large bowel carcinogenesis in male Apc(Min/+) mice

Int J Cancer. 2007 Aug 1;121(3):506-13. doi: 10.1002/ijc.22736.


It is generally assumed that inflammation influences carcinogenesis. We previously reported that dextran sodium sulfate (DSS) strongly enhances colon carcinogenesis in the Apc(Min/+) mice and the over-expression of inducible nitric oxide synthase (iNOS) contributes to this enhancement. In the current study, we investigated the effect of a selective iNOS inhibitor, ONO-1714 on colitis-related colon carcinogenesis in the Apc(Min/+) mouse treated with DSS. Male C57BL/6J Apc(Min/+) and Apc(+/+) mice were exposed to 1% DSS in their drinking water for 7 days. ONO-1714 was given to the mice at a dose level of 50 or 100 ppm in diet for 5 weeks (during the administration of DSS). The tumor inhibitory effects by ONO-1714 were assessed at week 5 by counting the incidence and multiplicity of colonic neoplasms. Additionally, we assessed serum lipid levels and colonic mRNA expression for cyclooxygenase (COX)-2, iNOS, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta. Feeding with ONO-1714 significantly inhibited the occurrence of colonic adenocarcinoma in a dose-dependent manner in the Apc(Min/+) mice. In addition, the treatment with ONO-1714 significantly lowered the serum triglyceride levels and mRNA expression levels of COX-2, TNFalpha and IL-1beta of colonic mucosa in the DSS-treated Apc(Min/+) mice. Neither ONO-1714 nor DSS affected the colonic pathology in the Apc(+/+) mice. Our findings may suggest that ONO-1714 could therefore serve as an effective agent for suppression of colitis-related colon cancer development in the Apc(Min/+) mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / prevention & control*
  • Adenomatous Polyposis Coli / genetics
  • Amidines / administration & dosage
  • Amidines / pharmacology*
  • Animals
  • Colitis / chemically induced
  • Colitis / complications*
  • Colonic Neoplasms / prevention & control*
  • Cyclooxygenase 2 / metabolism
  • Dextran Sulfate
  • Dose-Response Relationship, Drug
  • Heterocyclic Compounds, 2-Ring / administration & dosage
  • Heterocyclic Compounds, 2-Ring / pharmacology
  • Interleukin-1beta / metabolism
  • Intestinal Mucosa / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nitric Oxide Synthase Type II / antagonists & inhibitors*
  • RNA, Messenger / analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Triglycerides / blood
  • Tumor Necrosis Factor-alpha / metabolism


  • 7-chloro-3-imino-5-methyl-2-azabicyclo(4.1.0)heptane
  • Amidines
  • Heterocyclic Compounds, 2-Ring
  • Interleukin-1beta
  • RNA, Messenger
  • Triglycerides
  • Tumor Necrosis Factor-alpha
  • Dextran Sulfate
  • Nitric Oxide Synthase Type II
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2