High expression of thymidylate synthase leads to resistance to 5-fluorouracil in biliary tract carcinoma in vitro

To evaluate the effect of chemotherapy of 5-fluorouracil (5-FU) in human bi liary tract carcinoma, we studied 5-FU sensitivity, thymidylate synthase (T S) content, and dihydropyrimidine dehydrogenase (DPD) activity in 4 human b iliary tract carcinoma cell lines compared to 12 various digestive carcinom a cell lines of human organs in vitro. 5-FU sensitivity in the cell lines w as analyzed by MTT assay. TS content was analyzed by the [6-H-3]FdUMP bindi ng assay method, and DPD activity was analyzed by thin-layer chromatography (TLC). 5-FU IC50 values of biliary tract carcinoma cell lines were signifi cantly higher than those of the carcinoma cell lines of the other digestive organs: 97, 45, 119, and 194 times the concentration of the other digestiv e, pancreas, colon, and gastric carcinoma cell lines, respectively. TS cont ent of biliary tract carcinoma cell lines was also significantly greater th an that of the carcinoma cell lines of the other organs. No difference in D PD activity, however, was recognized between the carcinoma cell lines of ea ch organ. TS content in the cell lines significantly correlated with 5-FU s ensitivity, but DPD activity did not. Therefore, in the present study, TS e xpression was concluded to influence the high resistance to 5-FU of biliary tract carcinoma in comparison with the carcinomas of the other digestive o rgans.