A potential important role for thymidylate synthetase inhibition on antitumor activity of fluoropyrimidine and raltitexed.
BACKGROUND
Because thymidylate synthetase (TS) is a key enzyme in DNA synthesis, it has been used as a target for cancer chemotherapy.


METHODS
We investigated the combined antitumor activity of raltitexed, 5-FU and UFT on human tumor xenografts in nude mice and examined changes in TS activity and 5-FU-bound RNA (F-RNA) levels. Human gastric (SC-1-NU) or colon (HT-29) carcinoma xenografts were transplanted subcutaneously into nude mice, and drugs administered intraperitoneally (raltitexed and 5-FU) or perorally (UFT) daily for 5 days, and repeated once after a 2-day interval.


RESULTS
The antitumor effects were mostly equivalent between the treatment groups despite the different drugs and sequence orders. TS inhibition rates correlated with the tumor inhibition rate, which was statistically significant, while F-RNA levels did not correlate with antitumor activity.


CONCLUSIONS
Our results indicated that the combination of fluoropyrimidine-related agents should be directed towards increased TS inhibition rather than increased F-RNA levels.
Kabeshima
Yasuo
Y
Department of Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Kubota
Tetsuro
T
Watanabe
Masahiko
M
Saikawa
Yoshiro
Y
Nishibori
Hideki
H
Hasegawa
Hirotoshi
H
Kitajima
Masaki
M
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000201:enzymology; D005641:Tegafur / Q000008:administration & dosage; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014498:Uracil / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D011799:Quinazolines; D013876:Thiophenes; D005641:Tegafur; D014498:Uracil; D013940:Thymidylate Synthase; C068874:raltitrexed; D005472:Fluorouracil