Changes of gene expression of thymidine phosphorylase, thymidylate synthase, dihydropyrimidine dehydrogenase after the administration of 5'-deoxy-5-fluorouridine, paclitaxel and its combination in human gastric cancer xenografts.
BACKGROUND
Although a variety of combination chemotherapies has been tested in gastric carcinoma, the most effective chemotherapeutic regimen and the precise mechanisms underlying anticancer agent combination have not yet been sufficiently elucidated.


METHODS
Experimental chemotherapy was performed using human gastric carcinoma xenografts, MKN-45 and TMK-1, to examine the anticancer effects and gene expressions of the enzymes involved in 5-fluorouracil metabolism, thymidine phosphorylase (dThdPase), thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD). Nude mice were treated with 5'-deoxy-5-fluorouridine (5'-dFUrd), or paclitaxel alone or in combination. The in vivo antitumor effects on gene expressions of the enzymes were examined using the quantitative real-time RT-PCR method.


RESULTS
The combined use of 5'-dFUrd and paclitaxel showed additive to synergistic antitumor effects on both gastric cancer xenografts. There were significant differences of the gene expressions of dThdPase, TS, and DPD between the xenografts. The expression of dThdPase mRNA was consistently up-regulated by the administration of paclitaxel, while no constant direction of TS mRNA and DPD mRNA change was found in the xenografts.


CONCLUSIONS
A synergistic antitumor effect of the combined administration of 5'-dFUrd and paclitaxel was found in gastric cancer xenografts and up-regulation of dThdPase mRNA may be an important underlying mechanism especially in tumors with high gene expression of this enzyme.
Sakurai
Yoichi
Y
Department of Surgery, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan. ysakurai@fujita-hu.ac.jp
Yoshida
Ikuo
I
Kamoshida
Shingo
S
Inaba
Kazuki
K
Isogaki
Jun
J
Komori
Yoshiyuki
Y
Uyama
Ichiro
I
Tsutsumi
Yutaka
Y
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology*; D001835:Body Weight; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D005467:Floxuridine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D013939:Thymidine Phosphorylase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D013940:Thymidylate Synthase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D012333:RNA, Messenger; D005467:Floxuridine; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D013939:Thymidine Phosphorylase; D017239:Paclitaxel; C025034:doxifluridine