Van Triest B, Peters G J
Department of Oncology, University Hospital VU, Amsterdam, The Netherlands.
Oncology. 1999 Oct;57(3):179-94. doi: 10.1159/000012030.
In this review, we describe the role of thymidylate synthase (TS) as a determinant of chemotherapeutic response. TS is an essential enzyme for the de novo synthesis of thymidylate and subsequent DNA synthesis. TS has been used as a target for cancer chemotherapy in the development of fluoropyrimidines such as 5-fluorouracil (5FU) and 5-fluorodeoxyuridine and novel folate-based TS inhibitors such as ZD1694 (Tomudex, Raltitrexed), LY231514, AG337 (Thymitaq) and GW1843U89. All these antifolates have different transport mechanisms and various polyglutamylation and accumulation patterns which are all important for drug sensitivity. An update of clinical studies with TS inhibitors (antifolate-based TS inhibitors and 5FU combination studies) will be given and new perspectives for clinical development will be discussed. The prognostic or predictive value of TS (in vitro, in vivo and in patients) will be reviewed, focusing on colorectal cancer.
在本综述中，我们描述了胸苷酸合成酶（TS）作为化疗反应决定因素的作用。TS是胸苷酸从头合成及后续DNA合成所必需的一种酶。在氟嘧啶（如5-氟尿嘧啶（5FU）和5-氟脱氧尿苷）以及新型基于叶酸的TS抑制剂（如ZD1694（Tomudex，雷替曲塞）、LY231514、AG337（Thymitaq）和GW1843U89）的研发中，TS已被用作癌症化疗的靶点。所有这些抗叶酸药物都有不同的转运机制以及各种多聚谷氨酸化和蓄积模式，这些对药物敏感性都很重要。将给出TS抑制剂的临床研究最新情况（基于抗叶酸的TS抑制剂和5FU联合研究），并讨论临床开发的新前景。将综述TS（体外、体内及患者体内）的预后或预测价值，重点关注结直肠癌。
