A novel combination antimetabolite, TAS-102, exhibits antitumor activity in FU-resistant human cancer cells through a mechanism involving FTD incorporation in DNA.
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.
Emura
Tomohiro
T
Second Cancer Research Laboratory, Hanno Research Center, Taiho Pharmaceutical Co., Ltd., 1-27 Misugidai, Hanno-city, Saitama 357-8527, Japan. t-emura@taiho.co.jp
Suzuki
Norihiko
N
Yamaguchi
Masahiro
M
Ohshimo
Hideyuki
H
Fukushima
Masakazu
M
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000378:metabolism*; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D005467:Floxuridine / Q000494:pharmacology / Q000627:therapeutic use; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011759:Pyrrolidines; D051381:Rats; D011923:Rats, Nude; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism; D013941:Thymine; D014271:Trifluridine / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D014498:Uracil / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D004338:Drug Combinations; D011759:Pyrrolidines; C000613803:trifluridine tipiracil drug combination; D005467:Floxuridine; D014498:Uracil; D013941:Thymine; D014271:Trifluridine; D005472:Fluorouracil