Lambe C U, Averett D R, Paff M T, Reardon J E, Wilson J G, Krenitsky T A
Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709, USA.
Cancer Res. 1995 Aug 1;55(15):3352-6.
Earlier studies have shown guanine arabinoside (ara-G) is an effective agent against growth of T-cell lines and freshly isolated human T-leukemic cells. However, poor water solubility of ara-G limits clinical use. 2-Amino-6-methoxypurine arabinoside (506U) is a water-soluble prodrug converted to ara-G by adenosine deaminase. 506U is not a substrate for deoxycytidine kinase, adenosine kinase, or purine nucleoside phosphorylase and is phosphorylated by mitochondrial deoxyguanosine kinase at a rate 4% that of ara-G phosphorylation. Mitochondrial DNA polymerase was the least sensitive to ara-GTP inhibition of the five human DNA polymerases tested. [3H]506U was anabolized to ara-G 5'-phosphates in CEM cells but not to phosphorylated metabolites of 506U. 506U was selective for transformed T over B cells and also inhibited growth in two of three monocytic lines tested. 506U given i.v. to cynomolgus monkeys was rapidly converted to ara-G; the ara-G had a half-life of approximately 2 h. 506U had in vivo dose-dependent efficacy against human T-cell tumors in immunodeficient mice. A Phase 1 trial of 506U against refractory hematological malignancies is now in progress at two study sites.
早期研究表明，阿糖鸟苷（ara-G）是一种针对T细胞系和新鲜分离的人T白血病细胞生长的有效药物。然而，阿糖鸟苷的水溶性差限制了其临床应用。2-氨基-6-甲氧基嘌呤阿拉伯糖苷（506U）是一种水溶性前药，可被腺苷脱氨酶转化为阿糖鸟苷。506U不是脱氧胞苷激酶、腺苷激酶或嘌呤核苷磷酸化酶的底物，并且被线粒体脱氧鸟苷激酶磷酸化的速率是阿糖鸟苷磷酸化速率的4%。在所测试的五种人DNA聚合酶中，线粒体DNA聚合酶对阿糖鸟苷三磷酸（ara-GTP）抑制的敏感性最低。[3H]506U在CEM细胞中被合成代谢为阿糖鸟苷5'-磷酸，但不会代谢为506U的磷酸化代谢产物。506U对转化的T细胞比对B细胞具有选择性，并且还抑制了所测试的三个单核细胞系中的两个的生长。静脉注射给食蟹猴的506U迅速转化为阿糖鸟苷；阿糖鸟苷的半衰期约为2小时。506U在免疫缺陷小鼠中对人T细胞肿瘤具有体内剂量依赖性疗效。一项针对难治性血液系统恶性肿瘤的506U的1期试验目前正在两个研究地点进行。
