Cytotoxicity of trifluridine correlates with the thymidine kinase 1 expression level

Yuki Kataoka, Makoto Iimori, Shinichiro Niimi, Hiroshi Tsukihara, Takeshi Wakasa, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Hiroyuki Kitao

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Trifluridine (FTD), a tri-fluorinated thymidine analogue, is a key component of the oral antitumor drug FTD/TPI (also known as TAS-102), which is used to treat refractory metastatic colorectal cancer. Thymidine kinase 1 (TK1) is thought to be important for the incorporation of FTD into DNA, resulting in DNA dysfunction and cytotoxicity. However, it remains unknown whether TK1 is essential for FTD incorporation into DNA and whether this event is affected by the expression level of TK1 because TK1-specific-deficient human cancer cell lines have not been established. Here, we generated TK1-knock-out human colorectal cancer cells using the CRISPR/Cas9 genome editing system and validated the specificity of TK1 knock-out by measuring expression of AFMID, which is encoded on the same locus as TK1. Using TK1-knock-out cells, we confirmed that TK1 is essential for cellular sensitivity to FTD. Furthermore, we demonstrated a correlation between the TK1 expression level and cytotoxicity of FTD using cells with inducible TK1 expression, which were generated from TK1-knock-out cells. Based on our finding that the TK1 expression level correlates with sensitivity to FTD, we suggest that FTD/TPI might efficiently treat cancers with high TK1 expression.

Original languageEnglish
Article number7964
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

All Science Journal Classification (ASJC) codes

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