Abstract 781: Efficacy of trifluridine for 5-fluorouracil-resistant human gastric cancer cell lines and their mechanisms

Abstract

Abstract Background: TAS-102 is a novel oral nucleoside antitumor agent consisting of trifluridine (FTD) and tipiracil hydrochloride (TPI). TAS-102 was found to significantly improve the overall survival of patients with metastatic colorectal cancer who were refractory to treatment with a fluoropyrimidine, irinotecan, and oxaliplatin in a double-blind randomized phase II study. Although significant survival benefits from 5-fluorouracil (5-FU)-based chemotherapy have also been reported in patients with gastric cancer, many patients experience recurrences after several courses of 5-FU-based chemotherapy. The resistance of gastric tumors to 5-FU therapy is thus a major clinical problem. In this study, the efficacy of FTD against 5-FU-resistant human gastric cancer cell lines was investigated. Method: 5-FU-resistant cell lines established by continuously exposing the parent cell lines (MKN-45, MKN-74, and KATOIII) to escalating concentrations (1-5 μM) of 5-FU over a 1-year period were used. The sensitivities of the cell lines to FTD were evaluated using a crystal violet staining assay. To elucidate the mechanism by which resistance is overcome, the mRNA levels of TK1, which converts FTD into an active monophosphate form, and hENT1, which is involved in the cellular uptake of FTD, were determined using RT-PCR. Results: The resistant cell lines KATOIII/5FU, MKN74/5FU, and MKN45/5FU exhibited a 2.0-fold, 4.8-fold, and 14.2-fold resistance to 5-FU, compared with their parent cell lines, respectively. MKN-45/5FU also showed a 3.7-fold resistance to FTD, whereas MKN-74/5FU (1.0-fold) and KATOIII/5FU (1.2-fold) showed no cross-resistance to FTD. The TK1 mRNA level was decreased by 40% in the MKN-45/5FU cells, compared with the parent cell line. Furthermore, this cell line showed a 60% decrease in the mRNA level for hENT1. In contrast, the hENT1 mRNA level increased by 1.6-fold in the KATOIII/5FU cells, with a 50% decrease in the TK1 mRNA level. The TK1 and hENT1 mRNA levels in MKN-74/5FU were increased by 1.9-fold and 1.7-fold, respectively. Conclusion: FTD was able to overcome the resistance to 5-FU in 2 out of 3 resistant cell lines in vitro, with MKN45/5FU exhibiting a partial cross-resistance to FTD. These results suggest that TAS-102 might be a promising chemotherapeutic agent for the treatment of gastric cancer relapses after 5-FU-based treatment. Furthermore, TK1 and hENT1 might be involved in FTD-related cytotoxicity. Citation Format: Kazuaki Matsuoka, Takashi Kobunai, Teiji Takechi. Efficacy of trifluridine for 5-fluorouracil-resistant human gastric cancer cell lines and their mechanisms. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 781. doi:10.1158/1538-7445.AM2014-781