Nolatrexed (AG-337)

IC50:对L1210\CCRF-CEM和GC3/M TK细胞系的IC50分别为1.0\0.81和1.0 μM.

胸苷酸合成酶(TS)是合成2'-脱氧胸苷-5'-单磷酸的关键酶,2'-脱氧胸苷-5'-单磷酸是用于DNA生物合成的必需前体.因此,该酶是癌症化疗的关键靶标.Nolatrexed (AG-337)是一种非经典胸苷酸合成酶抑制剂.

体外实验:Nolatrexed是依据TS分子模型和叶酸结合位点的X射线晶体学数据设计的.它是一种非经典的TS抑制剂,缺乏末端谷氨酸侧链,在生理pH下不带电荷.Nolatrexed进入细胞不需要特定的运输机制,进入细胞后,不是叶酰聚谷氨酸合成酶的底物[1].

在体实验:使用nolatrexed治疗Bu25TK肿瘤异种移植裸鼠,观察到其抗肿瘤活性时间依赖性增加[1].

临床试验:I期临床研究表明,给予肿瘤患者连续静脉内输注800 mg/m2/d 的Nolatrexed超过5天具有安全性,给药时间与抗肿瘤效应相关[2].

参考文献：
[1] Hughes AN, Rafi I, Griffin MJ, Calvert AH, Newell DR, Calvete JA, Johnston A, Clendeninn N, Boddy AV.  Phase I studies with the nonclassical antifolate nolatrexed dihydrochloride (AG337, THYMITAQ) administered orally for 5 days. Clin Cancer Res. 1999 Jan;5(1):111-8.
[2] Rafi I, Boddy AV, Calvete JA, Taylor GA, Newell DR, Bailey NP, Lind MJ, Green M, Hines J, Johnstone A, Clendeninn N, Calvert AH.  Preclinical and phase I clinical studies with the nonclassical antifolate thymidylate synthase inhibitor nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors. J Clin Oncol. 1998 Mar;16(3):1131-41.