Chemoprevention of biliary carcinogenesis in Syrian hamsters by the novel carboxamide derivative IS-741 after initiation with N-nitrosobis(2-oxopropyl)amine (BOP)

To elucidate the possible inhibitory effect of a novel carboxamide derivati ve (IS-741) on biliary carcinogenesis, Syrian hamsters were subjected to ch olecystoduodenostomy and ligation of the distal end of the common duct, and then given a regular diet (group I) or a diet containing 200 p.p.m. of IS- 741 (group II), All hamsters were subcutaneously injected with N-nitrosobis (2-oxopropyl)amine until 10 weeks after surgery, and continued to feed on t heir respective dietary regimen until termination of the experiment at 16 w eeks after surgery, Biliary adenocarcinomas were evaluated histologically, Non-cancerous and cancerous hepatobiliary tract tissues were analyzed for p hospholipase A(2) (PLA(2)) activity, myeloperoxidase (MPO) activity, and th e concentrations of prostaglandin (PG), i.e., prostaglandin E-2, 6-ketopros taglandin F(1)alpha and thromboxane B-2. IS-741 significantly inhibited the development and multiplicity of hepatobiliary adenocarcinomas and reduced the proliferating cell nuclear antigen labeling indices in non-cancerous he patobiliary tissues, compared with group I, The anticancerous effect of IS- 741 was associated with a significant inhibition of PLA(2) and MPO levels i n non-cancerous tissues of the extrahepatic biliary tract and the liver, an d in cancerous tissue of the liver, Furthermore, IS-741 reduced the product ion of PGs in non-cancerous hepatobiliary tissues, compared with group I, A lthough the precise mechanism of action of IS-741 in preventing biliary tum origenesis remains to be elucidated, it is likely to be related to modulati on of arachidonic acid metabolism and/or suppression of neutrophil accumula tion.