[Mechanism for synergistic antitumor effect in the combination of 5-fluorouracil with cisplatin in vivo tumor models: from the view of biochemical modulation of 5-fluorouracil].
The mechanism for 5-fluorouracil (5-FU) and cisplatin (CDDP) synergism was investigated in experimental tumor models in rodents in vivo. The reduced folates such as 5, 10-methylenetetrahydrofolate (CH2FH4) and tetrahydrofolate (FH4) which play a significant role in the metabolism of 5-FU were increased about 2 to 3 fold 5 in P388 and Yoshida sarcoma cells of rodents at 24 hours following intraperitoneal administration of CDDP (5 mg/kg), and tritiated 2'-deoxyuridine incorporation into DNA fraction of the CDDP-treated cells was more strongly inhibited than that of non-treated cells after incubation with 5-FU, which indicated the increased formation of a tight ternary complex between thymidylate synthase, FdUMP derived from 5-FU and elevated CH2FH4. The combination of single intraperitoneal CDDP and 6 day-continuous infusion of 5-FU and/or 7 consecutive oral administration 5-FU derivative, BOF-A2, enhanced synergistically the antitumor activity against solid Yoshida sarcomas in rats as compared to each drug alone. These data suggest that CDDP play an important role as not only an effector but also a modulator in biochemical modulation of 5-FU in cellular methionine metabolism and by resultant elevation of intracellular reduced folates.
Shirasaka
T
T
Institute for Pathogenic Biochemistry in Medicine, Taiho Pharmaceutical Co. Ltd, Saitama, Japan.
Shimamoto
Y
Y
Ohshimo
H
H
Kimura
A
A
Fukushima
M
M
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004247:DNA / Q000187:drug effects; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007941:Leukemia P388 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D012517:Sarcoma, Yoshida / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D004247:DNA; D002945:Cisplatin; D005472:Fluorouracil