Effects of combined administration of DPD-inhibitory oral fluoropyrimidine, S-1, plus paclitaxel on gene expressions of fluoropyrimidine metabolism-related enzymes in human gastric xenografts.
BACKGROUND
S-1 is the most effective oral fluoropyrimidine derivative widely used for patients with gastric carcinoma in Japan. Although S-1 plus taxane has been a promising candidate as an effective chemotherapeutic regimen, the mechanisms of its additive or synergistic anticancer effects and changes in gene expression after the administration of these agents have not yet been fully elucidated.


METHODS
Experimental chemotherapy was performed using human gastric carcinoma xenografts, MKN-45 and TMK-1, to examine anticancer effects and gene expressions of fluoropyrimidine metabolism-related enzymes including thymidine phosphorylase (TP), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), and uridine phosphorylase (UP). Nude mice were treated with S-1, paclitaxel, and their combination. After treatment, in vivo antitumor effects of S-1, paclitaxel alone, and their combination and the effects on gene expressions of enzymes involved in 5-fluorouracil metabolism were examined using the RT-PCR method.


RESULTS
The combined use of S-1 and paclitaxel showed additive to synergistic antitumor effects on both gastric cancer xenografts. While consistent upregulation of dThPase and DPD gene expression was exhibited after administration of S-1, no further increase of dThPase gene expression after combined use of S-1 with paclitaxel was observed. There was no increase in TS gene expression after the administration of either S-1 alone or paclitaxel alone.


CONCLUSIONS
These results provide some insight into the mechanism and/or rationale underlying the additive to synergistic effect of combined administration of S-1 and paclitaxel in gastric carcinoma.
Sakurai
Yoichi
Y
Department of Surgery, Fujita Health University School of Medicine, 1-98 Dengakugakubo Kutsukake-cho, 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; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000187:drug effects; D004338:Drug Combinations; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009962:Orotate Phosphoribosyltransferase / Q000187:drug effects; D010094:Oxonic Acid / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D005641:Tegafur / Q000494:pharmacology*; D013939:Thymidine Phosphorylase / Q000187:drug effects; D013940:Thymidylate Synthase / Q000187:drug effects; D014543:Uridine Phosphorylase / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D009962:Orotate Phosphoribosyltransferase; D014543:Uridine Phosphorylase; D013939:Thymidine Phosphorylase; D017239:Paclitaxel; D005472:Fluorouracil