Peters G J, van der Wilt C L, van Triest B, Codacci-Pisanelli G, Johnston P G, van Groeningen C J, Pinedo H M
Department of Medical Oncology, Free University Hospital, Amsterdam, The Netherlands.
Eur J Cancer. 1995 Jul-Aug;31A(7-8):1299-305. doi: 10.1016/0959-8049(95)00172-f.
Thymidylate synthase is an important target for both fluorinated pyrimidines and for new folate analogues. Resistance to 5-fluorouracil (5FU) can be related to insufficient inhibition of thymidylate synthase. The 5FU-nucleotide FdUMP induces inhibition of thymidylate synthase which is enhanced and retained for longer in the presence of increased folate pools, for which leucovorin is a precursor. In a murine model system, 5FU treatment caused a 4-fold induction of thymidylate synthase levels which may have contributed to resistance. Addition of leucovorin to this treatment prevented this induction and increased the antitumour effect 2-3-fold. In the clinical setting, 5FU administration to patients resulted in approximately 50% inhibition of TS after 48 h. The combination with leucovorin resulted in a more pronounced inhibition after 48 h (approximately 70%). A significant relationship was observed with outcome of treatment; when thymidylate synthase levels were high and inhibition was low, no response was observed. A separate study showed that low thymidylate synthase levels appeared to be an independent prognostic factor for adjuvant therapy.
胸苷酸合成酶是氟嘧啶类药物和新型叶酸类似物的重要作用靶点。对5-氟尿嘧啶（5FU）耐药可能与胸苷酸合成酶抑制不足有关。5FU核苷酸FdUMP可诱导胸苷酸合成酶的抑制，在叶酸池增加（亚叶酸是其前体）的情况下，这种抑制作用会增强且持续时间更长。在小鼠模型系统中，5FU治疗导致胸苷酸合成酶水平升高4倍，这可能是产生耐药的原因之一。在此治疗中加入亚叶酸可防止这种升高，并使抗肿瘤效果提高2至3倍。在临床环境中，给患者使用5FU后48小时，胸苷酸合成酶的抑制率约为50%。与亚叶酸联合使用后，48小时时的抑制作用更为明显（约70%）。观察到治疗结果与之存在显著相关性；当胸苷酸合成酶水平高且抑制率低时，未观察到治疗反应。另一项研究表明，胸苷酸合成酶水平低似乎是辅助治疗的一个独立预后因素。
