van der Wilt C L, Peters G J
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
Pharm World Sci. 1994 Apr 15;16(2):84-103. doi: 10.1007/BF01880660.
Thymidylate synthase forms the target for anticancer therapy with fluoropyrimidines. Anticancer activity can be increased by the use of different modulators of fluoropyrimidine metabolism, which lead to an enhanced inhibition of thymidylate synthase. In vitro and in vivo studies with fluoropyrimidines and two of these modulators, folinic acid (leucovorin) and interferon, are summarized. The promise of these preclinical results is reflected by the response data of several clinical trials. The biochemical effects of these modulators are described and illustrated by the fluoropyrimidine-mediated inhibition of thymidylate synthase in tumour samples, which is clearly enhanced by folinic acid. The regulation of thymidylate synthase synthesis may also be crucial for total blockade of thymidylate synthase activity. This regulation may be influenced by interferon-gamma. Although the addition of modulators increases the activity of fluoropyrimidines at the level of thymidylate synthase, most solid tumours, especially colorectal carcinomas, are resistant to these combinations. For this reason, new, more potent inhibitors of thymidylate synthase have been developed, the antifolates. Preclinical data show that some of these compounds have good antitumour activity, but they still have to prove their value in the clinic. These two approaches, the use of modulators and new compounds, have shown activity preclinically and the extension of these findings to clinical studies stresses the importance of thymidylate synthase as a target in fluoropyrimidine therapy of solid tumours.
胸苷酸合成酶是氟嘧啶类抗癌治疗的靶点。使用不同的氟嘧啶代谢调节剂可增强抗癌活性，这些调节剂能增强对胸苷酸合成酶的抑制作用。本文总结了氟嘧啶类药物以及其中两种调节剂（亚叶酸（甲酰四氢叶酸）和干扰素）的体外和体内研究。多项临床试验的应答数据反映了这些临床前研究结果的前景。文中描述了这些调节剂的生化作用，并通过氟嘧啶介导的对肿瘤样本中胸苷酸合成酶的抑制作用进行了说明，亚叶酸可明显增强这种抑制作用。胸苷酸合成酶合成的调节对于完全阻断胸苷酸合成酶活性可能也至关重要。这种调节可能受γ干扰素影响。尽管添加调节剂可在胸苷酸合成酶水平上增强氟嘧啶类药物的活性，但大多数实体瘤，尤其是结直肠癌，对这些联合用药具有抗性。因此，已开发出新型、更有效的胸苷酸合成酶抑制剂——抗叶酸药物。临床前数据表明，其中一些化合物具有良好的抗肿瘤活性，但它们仍需在临床中证明其价值。这两种方法，即使用调节剂和新型化合物，在临床前已显示出活性，将这些研究结果扩展至临床研究强调了胸苷酸合成酶作为实体瘤氟嘧啶治疗靶点的重要性。
