薬理と治療

Abstract

Background　A high incidence of adenocarcinomas in colorectum can be induced by weekly subcutaneous injection of 1,2-dimethylhydrazine in rats. Administration of dextran sulfate sodium subsequent to a single intraperitoneal injection of azoxymethane can induce chronic ulcerative colitis in mice, resulting in an increase in incidence of high-grade dysplasia and adenocarcinomas of colorectum. Thymidylate synthase and thymidine kinase, key enzymes in the de novo and salvage pathways for pyrimidine nucleotide synthesis, respectively, are highly active in rapidly proliferating tissues. Methods　In the present study, we investigated the roles of these enzymes in colorectal carcinogenesis in two experimental animal model series. Results　Well and poorly differentiated adenocarcinomas showed high activity of thymidine kinase in distal colon and high activity of thymidylate synthase in proximal colon in rats, respectively. Colorectal carcinogenesis developed with the increasing duration of chemically induced diarrhea in carcinogen-pretreated mice. On the contrary, sulphasalazine, anti-ulcerative colitis drug, markedly reduced the tumorous regions with high-grade dysplasia in the colorectum of mice. Conclusions　These two isolated animal models may provide valuable insight into the mechanisms involved in colorectal carcinogenesis; i.e. repeated carcinogen exposure or repeated mucosal necrosis-regeneration in ulcerative colitis facilitates colorectal carcinogenesis.