Omura K, Kawakami K, Kanehira E, Nagasato A, Kawashima S, Tawaraya K, Watanabe S, Hirano K, Shirasaka T, Watanabe Y
Department of Surgery (1), Kanazawa University School of Medicine, Japan.
Cancer Res. 1995 Sep 1;55(17):3897-901.
Thymidylate synthase (TS) is a target enzyme of 5-fluorouracil and is inhibited by 5-fluoro-dUMP (FdUMP) to form an inactive ternary complex. We investigated the changes in the number of FdUMP binding sites in human colorectal carcinoma tissues after treatment with 5-fluorouracil derivatives and also examined the mechanisms underlying these changes. The number of FdUMP binding sites was significantly increased in patients who received tegafur and uracil preoperatively [UFT (+) group, n = 14] compared with those who did not [UFT (-) group, n = 36; P < 0.0001]. No amplification of the TS gene was observed in the carcinoma tissues in either group. The level of TS mRNA in the carcinoma tissues showed no significant difference between UFT (-) and UFT (+) groups. There was a significant correlation between the level of TS mRNA and TS in the UFT (-) group, as shown by simple linear regression analysis (P < 0.05). In the UFT (+) group, 9 of 12 cases showed TSf corresponding to their level of TS mRNA. It seemed that the augmentation of TStot is the result of accumulation of ternary complex. Thus, TS inhibition by FdUMP will be insufficient in the absence of methylenetetrahydrofolate in the cytosol, because translation of TS from TS mRNA has been shown to continue in the presence of FdUMP.
胸苷酸合成酶（TS）是5-氟尿嘧啶的靶酶，可被5-氟脱氧尿苷一磷酸（FdUMP）抑制，从而形成无活性的三元复合物。我们研究了用5-氟尿嘧啶衍生物治疗后人结肠直肠癌组织中FdUMP结合位点数量的变化，并探讨了这些变化的潜在机制。与未接受替加氟和尿嘧啶术前治疗的患者[替加氟尿嘧啶联合制剂（-）组，n = 36；P < 0.0001]相比，接受替加氟尿嘧啶联合制剂术前治疗的患者[替加氟尿嘧啶联合制剂（+）组，n = 14]的FdUMP结合位点数量显著增加。两组癌组织中均未观察到TS基因扩增。替加氟尿嘧啶联合制剂（-）组和替加氟尿嘧啶联合制剂（+）组癌组织中TS mRNA水平无显著差异。简单线性回归分析显示，替加氟尿嘧啶联合制剂（-）组中TS mRNA水平与TS之间存在显著相关性（P < 0.05）。在替加氟尿嘧啶联合制剂（+）组中，12例中有9例的TSf与其TS mRNA水平相对应。似乎总TS的增加是三元复合物积累的结果。因此，在胞质溶胶中缺乏亚甲基四氢叶酸的情况下，FdUMP对TS的抑制作用将不足，因为已证明在存在FdUMP的情况下，TS mRNA仍可继续翻译出TS。
