https://scholars.lib.ntu.edu.tw/handle/123456789/487386
標題: | Prolonged and enhanced suppression of thymidylate synthase by weekly 24-h infusion of high-dose 5-fluorouracil | 作者: | KUN-HUEI YEH Shiou-Hwei Yeh CHIH-HUNG HSU TONG-MEI WANG Ma I.-F. ANN-LII CHENG |
公開日期: | 2000 | 出版社: | Churchill Livingstone | 卷: | 83 | 期: | 11 | 起(迄)頁: | 1510-1515 | 來源出版物: | British Journal of Cancer | 摘要: | We have recently demonstrated that HDFL (high-dose 5-FU 2600 mg m-2 week-1 and leucovorin 500 mg m-2 week-1, weekly 24-h infusion) is highly active in the treatment of gastric cancer. To further clarify the possible mechanism underlying the improved activity of HDFL compared with conventional 5-FU regimens, we conducted in vitro studies examining the effect of these regimens on the differential regulation of thymidylate synthase (TS) in NCI-N87, a human gastric cancer cell line. The expected serum concentrations of 5-FU are 100-200 mM (lasting for less than 30 min) and 5-10 mM (lasting for 24 h) for the conventional 5-FU regimens (bolus injection or short intravenous infusion of 5-FU 370-500 mg m-2) and the HDFL regimens, respectively. Western blot analysis revealed that 24-h exposure of NCI-N87 to 2.5-10.0 mM of 5-FU resulted in a dose-dependent depletion of free TS, lasting for more than 24 h. In contrast, 30-min exposure of NCI-N87 to 200 mM of 5-FU resulted in a less than 12-h depletion of free TS. Moreover, 24-h exposure to 5-FU resulted in a higher S-phase blockade and enhanced cytotoxicity. In both modes of 5-FU treatment, the initial rapid depletion of free TS was accompanied by a rapid increment of a higher-molecular-weight TS molecule, suggesting that rapid formation of the ternary complex was the key mechanism of 5-FU action during this period. Northern blot analysis showed that the steady-state mRNA of TS was not affected by either of the schedules. We conclude that 24-h exposure of gastric cancer cells to low concentration of 5-FU resulted in better suppression of free TS, a higher degree of S-phase blockade, and enhanced cytotoxicity compared to 30-min exposure to high concentration of 5-FU. These in vitro results may help explain the improved clinical efficacy of HDFL regimens compared to conventional 5-FU regimens. (C) 2000 Cancer Research Campaign. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-0033665764&doi=10.1054%2fbjoc.2000.1456&partnerID=40&md5=962657e20c2fe92f633f646a452d45a4 https://scholars.lib.ntu.edu.tw/handle/123456789/487386 |
ISSN: | 0007-0920 | DOI: | 10.1054/bjoc.2000.1456 | SDG/關鍵字: | fluorouracil; folinic acid; messenger RNA; thymidylate synthase; article; cancer cell culture; cell cycle S phase; concentration response; controlled study; drug cytotoxicity; drug effect; drug mechanism; enzyme conformation; human; human cell; in vitro study; incubation time; molecular weight; Northern blotting; priority journal; protein analysis; protein expression; stomach cancer; treatment planning; Western blotting |
顯示於: | 腫瘤醫學研究所 |
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