Accumulating evidences indicate that over production of nitric oxide (NO) is involved
in the pathogenesis of colorectal cancer in both rodents and humans. Inducible nitric oxide
synthase (iNOS) is responsible for the over production of NO in a variety of parenchymal
cells and macrophages. Min (multiple intestinal neoplasia) mice, which have germ-line
nonsense mutation at codon 850 of Apc gene, spontaneously develop multiple adenomas
in small and large intestines at the age of 10～12 weeks. In the present study we utilized
ApcMin/+ mice to investigate the role of iNOS on the intestinal adenoma development. We
have found that iNOS protein are expressed in normal mucosa of small and large
intestines of most Min mice. In order to suppress iNOS we administered S,S'-1,4-p
henylene-bis(1,2-ethanediyl)bis-isothiourea (dihydrobromide) (PBIT), a selective iNOS
inhibitor in diet (50 ppm). The number of adenomas in small intestines significantly
decreased in ApcMin/+ mice receiving PBIT in diet. The tumor incidence and multiplicity in
colorectal tissues also significantly decreased in PBIT-given mice, comparing with those
receiving control diet. Immunohistochemical expression of iNOS was decreased in
intestinal tissues from PBIT-given mice, comparing with those from control mice. These
results suggest that NO produced by iNOS plays an important role as an endogenous
factor in the development of intestinal polyposis in mice and PBIT, a selective iNOS
inhibitor, may act as a potential chemopreventive agent for colorectal cancers.

Keywords: Apc, iNOS, Min mouse, NO, 1,4-PBIT, Polyp