Chemoprevention of colonic aberrant crypt foci by an inducible nitric oxide synthase-selective inhibitor

Inducible nitric oxide synthase (INOS) is overexpressed in colonic tumors o f humans and also in rats treated with a colon carcinogen. iNOS appear to r egulate cyclooxygenase-2 (COX-2) expression and production of proinflammato ry prostaglandins, which are known to play a key role in colon tumor develo pment. Experiments were designed to study the inhibitory effects of S,S '-1 ,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea (PBIT) a selective iNOS-spe cific inhibitor, measured against formation of azoxymethane (AOM)-induced c olonic aberrant crypt foci (ACF), Beginning at 5 weeks of age, male F344 ra ts were fed experimental diets containing 0 or 50 p.p.m. of PBIT, or 2000 p .p.m. of curcumin (non-specific INOS inhibitor). One week later, rats were injected s.c. with AOM (15 mg/kg body wt, once weekly for 2 weeks), At 17 w eeks of age, all rats were killed, colons were evaluated for ACF formation and colonic mucosa was assayed for isoforms of COX and NOS activities. Both COX and iNOS activities in colonic mucosa of the AOM-treated rats were sig nificantly induced. Importantly, 50 p.p.m. PBIT suppressed AOM-induced colo nic ACF formation to 58% (P < 0.0001) and crypt multiplicity containing fou r or more crypts per focus to 78% (P < 0.0001); it also suppressed AOM-indu ced iNOS activity. Curcumin inhibited colonic ACF formation by 45% (P < 0.0 01), These observations suggest that iNOS may play a key regulatory role in colon carcinogenesis. Developing iNOS-specific inhibitors may provide a se lective and safe chemopreventive strategy for colon cancer treatment.