Effects of a low dose leucovorin with 5-fluorouracil derivative on colorectal tumors induced with 1,2-dimethylhydrazine in rats.
Thymidylate synthase, which is a key enzyme involved in the de novo pathway for pyrimidine nucleotide synthesis, is inhibited by 5-fluorodeoxyuridine monophosphate, forming an inactive ternary complex with intracellular folate. We investigated the effect of a 5-fluorouracil derivative (UFT) with or without low dose leucovorin on the number of 5-fluorodeoxyuridine monophosphate binding sites, thymidine kinase activity and intracellular folate concentration in 1,2-dimethylhydrazine-induced rat colorectal carcinomas. A 10-day administration of UFT with or without leucovorin enhanced the thymidine kinase activity and the number of 5-fluorodeoxyuridine monophosphate binding sites, with an increase of thymidylate synthase mRNA expression. Thymidylate synthase inhibition was slightly increased as the intracellular folate concentration increased. These results indicate that thymidylate synthase inhibition increases when the intracellular folate is exogenously supplemented and maintained at an adequate concentration.
Kuwa
K
K
Medical Research Institute, Tokyo Medical and Dental University, Japan.
Sakamoto
S
S
Mitamura
T
T
Kudo
H
H
Suzuki
S
S
Fukushima
M
M
D019813:1,2-Dimethylhydrazine; D000818:Animals; D001483:Base Sequence; D001835:Body Weight; D002273:Carcinogens; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D017931:DNA Primers; D005472:Fluorouracil / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D002955:Leucovorin / Q000008:administration & dosage / Q000627:therapeutic use*; D009929:Organ Size; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism
D002273:Carcinogens; D017931:DNA Primers; D012333:RNA, Messenger; D013940:Thymidylate Synthase; D013937:Thymidine Kinase; D019813:1,2-Dimethylhydrazine; D002955:Leucovorin; D005472:Fluorouracil