Peters G J, van Groeningen C J, Laurensse E J, Pinedo H M
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
Eur J Cancer. 1991;27(3):263-7. doi: 10.1016/0277-5379(91)90512-c.
Inhibition of thymidylate synthase (TS) by the 5-fluorouracil (5-FU) metabolite FdUMP is considered to be the main mechanism of action of 5-FU. TS from colorectal tumours and normal colon mucosa from 10 untreated patients was studied. There was a large variation in the activity of tumour TS both at 1 and 10 mumol/l of its substrate dUMP; in normal mucosa this variation was less. Inhibition by 10 nmol/l FdUMP in tumours varied from 80 to 90% at 1 mumol/l dUMP; in normal mucosa, inhibition varied from 10 to 80%. The number of FdUMP binding sites ranged from 0.1 to 1 in tumours but such binding sites were not detectable in normal mucosa. The ratio between TS activity and FdUMP binding sites varied considerably in tumours but not in normal mucosa. The deviations from normal kinetics may represent a mutant TS form. Alterations in TS may partly account for differences in response to 5-FU.
5-氟尿嘧啶（5-FU）代谢产物氟尿嘧啶脱氧核苷酸（FdUMP）对胸苷酸合成酶（TS）的抑制作用被认为是5-FU的主要作用机制。对10例未经治疗患者的结直肠肿瘤及正常结肠黏膜中的TS进行了研究。在其底物脱氧尿苷一磷酸（dUMP）浓度为1和10μmol/L时，肿瘤TS的活性存在很大差异；在正常黏膜中，这种差异较小。在肿瘤中，当dUMP浓度为1μmol/L时，10nmol/L FdUMP的抑制率在80%至90%之间；在正常黏膜中，抑制率在10%至80%之间。肿瘤中FdUMP结合位点的数量在0.1至1之间，但在正常黏膜中未检测到此类结合位点。肿瘤中TS活性与FdUMP结合位点之间的比例差异很大，但正常黏膜中并非如此。与正常动力学的偏差可能代表一种突变的TS形式。TS的改变可能部分解释了对5-FU反应的差异。
