Prolonged and enhanced suppression of thymidylate synthase by weekly 24-h infusion of high-dose 5-fluorouracil.

摘要: We have recently demonstrated that HDFL (high-dose 5-FU 2600 mg m-2 week-1 and leucovorin 500 week-1, weekly 24-h infusion) is highly active in the treatment of gastric cancer. To further clarify possible mechanism underlying improved activity compared with conventional regimens, we conducted vitro studies examining effect these regimens on differential regulation thymidylate synthase (TS) NCI-N87, a human cancer cell line. The expected serum concentrations are 100-200 mM (lasting for less than 30 min) 5-10 24 h) (bolus injection or short intravenous infusion 370-500 m-2) respectively. Western blot analysis revealed exposure NCI-N87 to 2.5-10.0 resulted dose-dependent depletion free TS, lasting more h. In contrast, 30-min 200 12-h TS. Moreover, higher S-phase blockade enhanced cytotoxicity. both modes treatment, initial rapid TS was accompanied by increment higher-molecular-weight molecule, suggesting formation ternary complex key action during this period. Northern showed steady-state mRNA not affected either schedules. conclude cells low concentration better suppression degree blockade, cytotoxicity high 5-FU. These results may help explain clinical efficacy regimens.