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 biliary tract carcinoma, we studied 5-FU sensitivity, thymidylate synthase (TS) content, and dihydropyrimidine dehydrogenase (DPD) activity in 4 human biliary tract carcinoma cell lines compared to 12 various digestive carcinoma cell lines of human organs in vitro. 5-FU sensitivity in the cell lines was analyzed by MTT assay. TS content was analyzed by the [6-(3)H]FdUMP binding assay method, and DPD activity was analyzed by thin-layer chromatography (TLC). 5-FU IC(50) values of biliary tract carcinoma cell lines were significantly higher than those of the carcinoma cell lines of the other digestive organs: 97, 45, 119, and 194 times the concentration of the other digestive, pancreas, colon, and gastric carcinoma cell lines, respectively. TS content of biliary tract carcinoma cell lines was also significantly greater than that of the carcinoma cell lines of the other organs. No difference in DPD activity, however, was recognized between the carcinoma cell lines of each organ. TS content in the cell lines significantly correlated with 5-FU sensitivity, but DPD activity did not. Therefore, in the present study, TS expression was concluded to influence the high resistance to 5-FU of biliary tract carcinoma in comparison with the carcinomas of the other digestive organs.