TAS-102 is a new
antimetabolite agent composed of a alpha, alpha, alpha-
trifluorothymidine (FTD; 1 M) and
thymidine phosphorylase inhibitor (TPI; 0.5 M). Here, we investigated the antitumor effect and mechanism of
TAS-102 against
5-FU, or FdUrd, resistant human
cancer cell lines. The respective
tumor growth inhibition rate of orally administered FTD against 5-FU-resistant NUGC-3 was about 70% at a dose level of 200 mg/kg/day; this value was comparable to that against the parental NUGC-3. On the other hand, the
tumor inhibition rates of
5-FU, FdUrd, and
TS-1 against 5-FU-resistant NUGC-3 were lower than those against parental NUGC-3. Similar observations were made in an FdUrd-resistant human
colorectal cancer cell line (DLD-1).
TAS-102 was also effective in 5-FU-less sensitive human
pancreatic cancer cell lines (PAN-12 and BxPC-3) and human
esophagus cancer (T.T.) when compared with
5-FU or UFT. Our hypothesis was that a relatively short and high dosage of
TAS-102 results in an additional mechanism of FTD incorporation into
DNA other than
thymidylate synthase (TS) inhibition. We then examined the effects of FTD on
DNA at the cellular level.
After treatment with FTD or FdUrd, the DNA fragmentation pattern was examined using filter elution and in situ nick translation. Treatment with FTD for 2 h resulted in marked DNA fragmentation. When the
tumor cells were treated with FTD for 72 h or with FdUrd for 2 or 72 h, only a small amount of DNA fragmentation was observed, and the appearance of the
tumor cells did not differ markedly from that of untreated cells. Moreover, the DNA fragmentation rate in the
TAS-102 treatment group was significantly higher than that in the control group in vivo. These results suggest that when
tumor cells are exposed to high concentrations of FTD for short periods of time, FTD manifests its antitumor activity primarily through the induction of DNA fragmentation after FTD incorporation into the
DNA. We conclude that
TAS-102 is expected to manifest antitumor effects against 5-FU-resistant
tumors that are similar to those exerted in 5-FU-sensitive
tumors.