The number of 5-fluoro-2'-deoxyuridine-5'-monophosphate binding sites and reduced folate pool in human colorectal carcinoma tissues: changes after tegafur and uracil treatment.
Thymidylate synthase (TS) is a target enzyme of 5-fluorouracil and is inhibited by 5-fluoro-dUMP (FdUMP) to form an inactive ternary complex. We investigated the changes in the number of FdUMP binding sites in human colorectal carcinoma tissues after treatment with 5-fluorouracil derivatives and also examined the mechanisms underlying these changes. The number of FdUMP binding sites was significantly increased in patients who received tegafur and uracil preoperatively [UFT (+) group, n = 14] compared with those who did not [UFT (-) group, n = 36; P < 0.0001]. No amplification of the TS gene was observed in the carcinoma tissues in either group. The level of TS mRNA in the carcinoma tissues showed no significant difference between UFT (-) and UFT (+) groups. There was a significant correlation between the level of TS mRNA and TS in the UFT (-) group, as shown by simple linear regression analysis (P < 0.05). In the UFT (+) group, 9 of 12 cases showed TSf corresponding to their level of TS mRNA. It seemed that the augmentation of TStot is the result of accumulation of ternary complex. Thus, TS inhibition by FdUMP will be insufficient in the absence of methylenetetrahydrofolate in the cytosol, because translation of TS from TS mRNA has been shown to continue in the presence of FdUMP.
Omura
K
K
Department of Surgery (1), Kanazawa University School of Medicine, Japan.
Kawakami
K
K
Kanehira
E
E
Nagasato
A
A
Kawashima
S
S
Tawaraya
K
K
Watanabe
S
S
Hirano
K
K
Shirasaka
T
T
Watanabe
Y
Y
D001483:Base Sequence; D001665:Binding Sites / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000235:genetics; D005468:Fluorodeoxyuridylate; D006801:Humans; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis; D005641:Tegafur / Q000494:pharmacology*; D013763:Tetrahydrofolates / Q000032:analysis; D013940:Thymidylate Synthase / Q000032:analysis* / Q000187:drug effects / Q000235:genetics; D014498:Uracil / Q000494:pharmacology*
D012333:RNA, Messenger; D013763:Tetrahydrofolates; D005468:Fluorodeoxyuridylate; D005641:Tegafur; D014498:Uracil; D013940:Thymidylate Synthase