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Analyses of the Molecular Determinant of Cell Fate Induced by an Antimetabolite, Trifluridine

片岡, 裕貴 筑波大学 DOI:10.15068/0002008134

2023.09.04

概要

Trifluridine (FTD), a tri-fluorinated thymidine analogue, is a key component of the
novel oral antitumor drug FTD/Tipiracil (TPI); based on international phase III clinical
trials, this drug can be used to treat refractory metastatic colorectal cancer [7] and
metastatic gastric cancer [8]. The tri-phosphorylated form of FTD [9] is reported to be
incorporated into DNA through its replication during the S phase [9, 10, 12], resulting
in DNA dysfunction and cytotoxicity.
Thymidine kinase 1 (encoded by TK1 [13]) is a cytosolic nucleoside kinase that is part
of the thymidine salvage pathway and mainly phosphorylates thymidine [14, 15]. Based
on its chemical structure, FTD is reported to be phosphorylated by TK1, and this
modification is suggested to be essential for its cytotoxicity. Indeed, TK1 seems to be
associated with the cytotoxicity of FTD [16, 17]; however, the cell lines used in these
previous reports were generated by random mutagenesis and not fully validated.
Furthermore, although TK1-deficient cells play a key role in determining the
importance of TK1 for FTD cytotoxicity, TK1-specific-deficient human cancer cell
lines have not been established.
This study generated TK1-specific-knock-out human colorectal cancer cell lines and
demonstrated that TK1 is essential for cellular sensitivity to FTD. Moreover, to the best
of my knowledge, I have provided the first evidence that the TK1 expression level
correlates with FTD sensitivity. ...

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