Combined efficacy and mechanism of trifluridine and SN-38 in a 5-FU-resistant human colorectal cancer cell lines.

ABSTRACT

Trifluridine/tipiracil (FTD/TPI or TFTD, also known as TAS-102) with a molar ratio of 10.5, is a novel combination of FTD, an antineoplastic thymidine analog, and TPI, an inhibitor of thymidine phosphorylase. It has been approved as a treatment for unresectable advanced or recurrent colorectal cancer. Irinotecan (CPT-11) is an active agent in colorectal cancer. The administration order of drugs is a critical issue in clinical combination therapy. In this study, we evaluated the in vitro simultaneous and sequential combination efficacy of FTD and SN-38, an active metabolite of CPT-11, against human colorectal 5-fluorouracil (5-FU) resistant cell line DLD-1/5-FU and the parental cells DLD-1. The sequential exposure to SN-38 for 24 h followed by sequential exposure to FTD for 24 h or vice versa was more effective for cell survival than the simultaneous exposure of both drugs for 24 h. Furthermore, compared with simultaneous exposure, sequential exposure induced DNA damage, G2/M cell cycle arrest with increasing sub-G1 positive cells, and apoptosis in both DLD-1 and DLD-1/5-FU cells. In particular, in DLD-1/5-FU cells, sequential exposure to SN-38 followed by FTD induced apoptosis more than FTD followed by SN-38. Thus, the sequential treatment with SN-38 followed by FTD may be useful for the combination therapy of FTD/TPI and CPT-11 against relapsed colorectal cancer after 5-FU-based chemotherapy.