TAS-102 is a novel oral
nucleoside antitumor agent containing
trifluridine (FTD) and
tipiracil hydrochloride (TPI). The compound improves overall survival of
colorectal cancer (CRC) patients who are insensitive to standard
chemotherapies. FTD possesses direct antitumor activity since it inhibits
thymidylate synthase (TS) and is itself incorporated into
DNA. However, the precise mechanisms underlying the incorporation into
DNA and the inhibition of TS remain unclear. We found that FTD-dependent inhibition of TS was similar to that elicited by
fluorodeoxyuridine (FdUrd), another clinically used
nucleoside analog. However, washout experiments revealed that FTD-dependent inhibition of TS declined rapidly, whereas FdUrd activity persisted. The incorporation of FTD into
DNA was significantly higher than that of other antitumor
nucleosides. Additionally, orally administered FTD had increased antitumor activity and was incorporated into
DNA more effectively than continuously infused FTD. When
TAS-102 was administered, FTD gradually accumulated in
tumor cell
DNA, in a TPI-independent manner, and significantly delayed
tumor growth and prolonged survival, compared to treatment with
5-FU derivatives.
TAS-102 reduced the Ki-67-positive cell fraction, and swollen nuclei were observed in treated
tumor tissue. The amount of FTD incorporation in
DNA and the antitumor activity of
TAS-102 in xenograft models were positively and significantly correlated. These results suggest that
TAS-102 exerts its antitumor activity predominantly due to its
DNA incorporation, rather than as a result of TS inhibition. The persistence of FTD in the
DNA of
tumor cells treated with
TAS-102 may underlie its ability to prolong survival in
cancer patients.