RRC ID 41996
著者 Fujiwara H, Terashima M, Irinoda T, Takagane A, Abe K, Nakaya T, Yonezawa H, Oyama K, Takahashi M, Saito K, Takechi T, Fukushima M, Shirasaka T.
タイトル Superior antitumour activity of S-1 in tumours with a high dihydropyrimidine dehydrogenase activity.
ジャーナル Eur J Cancer
Abstract To elucidate the mechanism of the enhanced antitumour activity of S-1 (1 M tegafur, 0.4 M 5-chloro-2, 4-dihydroxypyridine, and 1 M potassium oxonate) in terms of the phosphorylation and degradation pathways of 5-fluorouracil (5-FU) metabolism, we investigated tumoral thymidylate synthase (TS) content, dihydropyrimidine dehydrogenase (DPD) activity, the TS inhibition rate (TS-IR), and 5-FU incorporated into RNA (F-RNA) in four human gastric cancer xenografts (MKN-28, MKN-74, GCIY and GT3TKB) and compared the results obtained with S-1 with those obtained with 5-FU and UFT (1 M tegafur, 4 M uracil). 5-FU was administered intraperitoneally (i.p.) to mice at a dose of 50 mg/kg, three times, on days 0, 4 and 8. S-1 and UFT were administered orally at doses of 10 and 24 mg/kg, respectively, once a day, for 9 consecutive days. Antitumour activity was evaluated as the maximum inhibition of tumour growth in each animal. S-1 showed a better antitumour activity than 5-FU and UFT in tumours with a high DPD activity (GCIY and GT3TKB). There were inverse correlations between the antitumour activity and both TS content and DPD activity in the 5-FU and UFT groups. However, no such correlations were observed in the S-1 group. In GCIY and GT3TKB xenografts, TS-IR was significantly higher in the S-1 group than in the 5-FU or UFT groups. In GT3TKB xenografts, the F-RNA level was significantly higher in the S-1 group than in the 5-FU or UFT groups. The superior cytotoxicity of S-1 appears to be attributable to both an increased inhibition of DNA synthesis and an enhanced blockade of RNA function against tumours with a high DPD activity.
巻・号 39(16)
ページ 2387-94
公開日 2003-11-1
DOI 10.1016/s0959-8049(03)00513-6
PII S0959804903005136
PMID 14556932
MeSH Animals Antineoplastic Combined Chemotherapy Protocols / therapeutic use* Cell Line, Tumor Dihydrouracil Dehydrogenase (NADP) / metabolism* Dose-Response Relationship, Drug Drug Combinations Fluorouracil / metabolism* Fluorouracil / pharmacokinetics Male Mice Mice, Inbred BALB C Mice, Nude Oxonic Acid / administration & dosage Pyridines / administration & dosage RNA, Neoplasm / metabolism Stomach Neoplasms / enzymology* Tegafur / administration & dosage Thymidylate Synthase / analysis Thymidylate Synthase / antagonists & inhibitors* Xenograft Model Antitumor Assays
IF 7.275
引用数 31
WOS 分野 ONCOLOGY
リソース情報
ヒト・動物細胞 GCIY(RCB0555) GT3TKB(RCB0885) MKN28(RCB1000) MKN74(RCB1002)