[Analysis of the mechanism of increased antitumor activity of UFT after combined treatment with CDDP].
Previously we have reported the efficacy of the combination therapy of UFT with CDDP against several human cancer xenografts implanted in nude mice. Among all cell lines tested, KM20C (Human colon adenocarcinoma) has shown the most pronounced synergistic antitumor effect after administration of CDDP prior to UFT. The effect of CDDP administered after UFT and that of either drug alone were weaker. To clarify the mechanism of this synergistic effect, the change of the poolsize of reduced folate in KM20C, induced by CDDP treatment, was measured. The pretreatment with CDDP increased the poolsize of CH2-H4 folate and H4 folate and increased the binding of FdUMP to the dTMP synthase of an intact cells. Based on the above data, it was concluded that the enhancement of cell sensitivity to UFT was caused by the CDDP-induced increase of the reduced folate pool, in consequence leading a better binding of FdUMP generated from UFT to dTMP synthase, a target enzyme for the antitumor activity of fluorinated pyrimidines.
Oie
S
S
Biological Research Laboratory, Taiho Pharmaceutical Co., Ltd.
Okabe
H
H
Takeda
S
S
Yamada
Y
Y
D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000473:pathology*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D005641:Tegafur / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014498:Uracil / Q000494:pharmacology
D005641:Tegafur; D014498:Uracil; D002945:Cisplatin