Efficacy markers for cisplatin and S-1 in biliary tract carcinoma.

Abstract

334 Background: Gemcitabine (GEM) + cisplatin (CDDP) combination chemotherapy is the first choice for advanced biliary tract carcinoma (BTC). In Japan, the GEM + S-1 therapy has shown promise for the treatment of BTC. Our aim was to investigate the cytotoxic effects of GEM, CDDP and S-1 on BTC cell lines and find an immunohistochemical marker for predicting the efficacy of chemotherapy. Methods: We evaluated the efficacy of GEM, CDDP, and S-1 by means of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of 17 BTC cell lines. Furthermore, we subdivided the cell lines into sensitive and insensitive groups on the basis of the sensitivity of each drug. Moreover, pairwise studies were conducted using the MTT assay, Bliss additivism model, and Combination Index for analysis. Immunohistochemical expression analysis of excision repair cross-complementation group 1 (ERCC1), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), and thymidine phosphorylase (TP) were also performed in each cell line to compare the results of the cytotoxic effects of CDDP and S-1. Results: In the single-agent MTT assays, among the 17 tumor cell lines, 11 were sensitive to GEM, 13 to CDDP, and 11 to S-1. In 5 cell lines, <30% of the cells showed ERCC1 expression; these lines belonged to the CDDP-sensitive group. Conversely, the cell lines with >30% ERCC1-positive cells mostly belonged to the CDDP-insensitive group. CDDP IC50 correlated with the percentage of ERCC1-positive cells (P <.05). In contrast, none of the immunohistochemical markers could be used to select a cutoff level that would point to the sensitivity to S-1. In pairwise MTT assays (combination therapy), we demonstrated the synergy of GEM with CDDP in 9 tumor cell lines (53%) and the synergy of GEM with S-1 in 4 tumor cell lines(24%). Although 3 cell lines with the synergy of GEM with CDDP showed <30% ERCC1-positive cells, there was no correlation between them. Conclusions: ERCC1 expression in <30% of cells may help to identify CDDP-sensitive tumors; however, it is unknown whether expression of ERCC1 can help to predict efficacy of treatment with GEM + CDDP.