Abstract 1306: Combined efficacy of trifluridine and SN-38 in a 5-FU-resistant human colorectal cancer cell line

Abstract

Abstract Background: In 2015, the FDA approved TAS-102 (also named TFTD)—a 1:0.5 molar ratio of trifluridine (FTD), an antitumor agent, and tipiracil (TPI), a thymidine phosphorylase inhibitor—for the treatment of refractory metastatic colorectal cancer. In this study, we investigated whether cytotoxicity was enhanced when FTD was used simultaneously or sequentially with SN-38, which is an active metabolite of irinotecan hydrochloride (CPT-11). Method: The colorectal cancer cell line DLD-1 and 5-FU-resistant DLD-1/5-FU were treated with one of four combinations of SN-38 and FTD: (1) exposure to only 0.1-2.0 μM FTD or only 0.0005-0.02 μM SN-38 for 24 hours; (2) simultaneous exposure to 0.1-2.0 μM FTD and 0.01 μM SN-38 for 24 hours, followed by no drug exposure for 24 hours; (3) sequential exposure to 0.1-2.0 μM FTD for 24 hours followed by 0.01 μM SN-38 for 24 hours; or (4) sequential exposure to 0.01 μM SN-38 for 24 hours followed by 0.1-2.0 μM FTD for 24 hours. All treatments were evaluated by the colony formation assay. Results: The 5-FU-resistant DLD-1/5-FU demonstrated no cross-resistance to both FTD and SN-38. Survival fractions (SFs) of DLD-1 and DLD-1/5-FU after simultaneous exposure to 0.5 μM FTD and 0.01 μM SN-38 were 0.30 and 0.26, respectively, which were lower compared to those after exposure to FTD alone (0.92 and 0.94, respectively). After sequential exposure to 0.5 μM FTD followed by 0.01 μM SN-38 or vice versa, SFs of DLD-1 were 0.49 and 0.36, respectively, and those of DLD-1/5-FU were 0.47 and 0.22, respectively; in both cases, SFs were lower than those after exposure to FTD alone (0.92 and 0.94, respectively). Taken together, sequential exposure to SN-38 followed by FTD was more effective in both cell lines. Conclusion: Simultaneous and sequential exposure to FTD and SN-38 were effective against both parent and 5-FU-resistant cell lines. These results suggest that a combination of TAS-102 and CPT-11 might be useful to relapsed colorectal cancer after 5-FU-based treatment. TableDLD-1, mean ± SD, survial fractions, n = 3 (independently)FTD (μM)FTD schedule (1)FTD + SN-38 schedule (2)FTD ⇒ SN-38 schedule (3)SN-38 ⇒ FTD schedule (4)0.01.00 ± 0.001.00 ± 0.001.00 ± 0.001.00 ± 0.000.11.04 ± 0.030.37 ± 0.050.64 ± 0.100.42 ± 0.180.50.92 ± 0.080.30 ± 0.110.49 ± 0.120.36 ± 0.161.00.79 ± 0.060.29 ± 0.120.27 ± 0.120.25 ± 0.092.00.50 ± 0.110.20 ± 0.070.05 ± 0.070.04 ± 0.02DLD-1/5FU, mean ± SD, survial fractions, n = 3 (independently)FTD (μM)FTD schedule (1)FTD + SN-38 schedule (2)FTD ⇒ SN-38 schedule (3)SN-38 ⇒ FTD schedule (4)0.01.00 ± 0.001.00 ± 0.001.00 ± 0.001.00 ± 0.000.11.01 ± 0.050.25 ± 0.110.65 ± 0.060.31 ± 0.220.50.94 ± 0.060.26 ± 0.120.47 ± 0.030.22 ± 0.141.00.92 ± 0.070.22 ± 0.120.25 ± 0.040.17 ± 0.072.00.61 ± 0.150.14 ± 0.070.09 ± 0.010.05 ± 0.01 Citation Format: Kazuaki Matsuoka, Takashi Kobunai, Teiji Takechi. Combined efficacy of trifluridine and SN-38 in a 5-FU-resistant human colorectal cancer cell line. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1306.