Superior antitumour activity of S-1 in tumours with a high dihydropyrimidine dehydrogenase activity
Superior antitumour activity of S-1 in tumours with a high dihydropyrimidine dehydrogenase activity
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DOI：
10.1016/s0959-8049(03)00513-6
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发表时间：
2003-11-01
影响因子：
8.4
通讯作者：
Shirasaka, T
中科院分区：
文献类型：
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作者：
Fujiwara, H;Terashima, M;Shirasaka, T
为了阐明S-1（1 M替加氟、0.4 M 5-氯-2、4-二羟基吡啶和1 M草酸钾）在5-氟尿嘧啶（5-FU）代谢的磷酸化和降解途径方面增强抗肿瘤活性的机制，我们研究了肿瘤胸苷酸合成酶（TS）含量、二氢嘧啶脱氢酶（DPD）活性、TS抑制率(TS-IR) 和 5-FU 掺入四种人胃癌异种移植物（MKN-28、MKN-74、GCIY 和 GT3TKB）中的 RNA (F-RNA)，并将 S-1 获得的结果与 5-FU 和 UFT（IM 替加氟、4 M 尿嘧啶）获得的结果进行比较。在第0、4和8天，以50 mg/kg的剂量对小鼠腹膜内（i.p.）施用3次。S-1和UFT分别以10和24 mg/kg的剂量口服，每天一次，连续9天。抗肿瘤活性被评估为每只动物中肿瘤生长的最大抑制。在具有高 DPD 活性的肿瘤（GCIY 和 GT3TKB）中，S-1 显示出比 5-FU 和 UFT 更好的抗肿瘤活性。 5-FU和UFT组的抗肿瘤活性与TS含量和DPD活性呈负相关。然而，在 S-I 组中没有观察到这种相关性。在 GCIY 和 GT3TKB 异种移植物中，S-I 组的 TS-IR 显着高于 5-FU 或 UFT 组。在 GT3TKB 异种移植物中，S-1 组的 F-RNA 水平显着高于 5-FU 或 UFT 组。 S-1 的卓越细胞毒性似乎归因于对 DNA 合成的抑制增加和对具有高 DPD 活性的肿瘤的 RNA 功能的增强阻断。 (C) 2003 Elsevier Ltd. 保留所有权利。
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 (I 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-I group. In GCIY and GT3TKB xenografts, TS-IR was significantly higher in the S-I 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. (C) 2003 Elsevier Ltd. All rights reserved.