Chemopreventive effects of a selective nitric oxide synthase inhibitor on carcinogen-induced rat esophageal tumorigenesis.
The inducible nitric oxide synthase (iNOS) generates a high concentration of nitric oxide (NO) in tissues. Increased NO production is associated with many disorders including esophageal cancer. Previous studies in our laboratory demonstrated an association between increased iNOS expression and the development of N-nitrosomethylbenzylamine (NMBA)-induced tumors in the rat esophagus. On the basis of these observations, we initiated a bioassay to evaluate the ability of S,S'-1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea (PBIT), a selective iNOS inhibitor, to prevent the progression of esophageal tumors in rats preinitiated with NMBA. Rats were given s.c. injections of NMBA (0.25 mg/kg body weight) three times per week for 5 weeks. One week later, they were fed a synthetic diet containing either 50 or 100 ppm PBIT until the end of the bioassay (25 weeks). PBIT reduced the incidence of esophageal cancer from 96% in NMBA-treated rats to 83% and 77% (P < 0.05) in rats treated with 50 and 100 ppm PBIT, respectively. Tumor multiplicity was reduced from 3.64 +/- 0.42 tumors per esophagus in NMBA-treated rats to 1.79 +/- 0.25 (P < 0.001) and 1.50 +/- 0.24 (P < 0.0001) in rats treated with 50 and 100 ppm PBIT, respectively. PBIT reduced the production of NO in NMBA-induced preneoplastic and papillomatous esophageal lesions when compared with comparable lesions in rats treated with NMBA only. iNOS mRNA expression was not modulated by PBIT. These observations suggest that iNOS plays a role in tumor development and that its selective inhibitor, PBIT, significantly inhibits esophageal tumor progression presumably through reducing the production of NO.
Chen
Tong
T
Division of Environmental Health Sciences, School of Public Health and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
Nines
Ronald G
RG
Peschke
Sarah M
SM
Kresty
Laura A
LA
Stoner
Gary D
GD
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives*; D004435:Eating / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004938:Esophageal Neoplasms / Q000139:chemically induced / Q000208:ethnology / Q000517:prevention & control*; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology*
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D004791:Enzyme Inhibitors; C118852:S,S'-1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea; C014707:nitrosobenzylmethylamine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D013890:Thiourea; D004128:Dimethylnitrosamine