Hertel L W, Boder G B, Kroin J S, Rinzel S M, Poore G A, Todd G C, Grindey G B
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285.
Cancer Res. 1990 Jul 15;50(14):4417-22.
A new pyrimidine antimetabolite, 2',2'-difluorodeoxycytidine, Gemcitabine (LY188011, dFdCyd) has been synthesized and evaluated in experimental tumor models. dFdCyd is a very potent and specific deoxycytidine analogue. The concentration required for 50% inhibition of growth is 1 ng/ml in the CCRF-CEM human leukemia cell culture assay. Concurrent addition of deoxycytidine to the cell culture system provides about a 1000-fold decrease in biological activity. The inhibition of growth of human leukemia cells in culture led to the in vivo evaluation of this compound as a potential oncolytic agent. Maximal activity in vivo was seen with dFdCyd when administered on an every third day schedule. 1-beta-D-Arabinofuranosylcytosine, administered on a daily for 10-day schedule, was directly compared to dFdCyd in this evaluation. dFdCyd demonstrated good to excellent antitumor activity in eight of the eight murine tumor models evaluated. 1-beta-D-Arabinofuranosylcytosine was substantially less active or had no activity in these same tumor models. This in vivo activity against murine solid tumors supports the conclusion that dFdCyd is an excellent candidate for clinical trials in the treatment of cancer.
一种新的嘧啶抗代谢物，2',2'-二氟脱氧胞苷，吉西他滨（LY188011，dFdCyd）已被合成并在实验性肿瘤模型中进行了评估。dFdCyd是一种非常强效且特异的脱氧胞苷类似物。在CCRF - CEM人白血病细胞培养试验中，50%抑制生长所需的浓度为1 ng/ml。向细胞培养系统中同时添加脱氧胞苷会使生物活性降低约1000倍。培养的人白血病细胞生长受到抑制促使对该化合物作为潜在溶瘤剂进行体内评估。当按每三天一次的给药方案给药时，dFdCyd在体内表现出最大活性。在该评估中，将按每天给药持续10天的方案给药的1-β-D-阿拉伯呋喃糖基胞嘧啶与dFdCyd直接进行了比较。在评估的8种小鼠肿瘤模型中，有8种模型显示dFdCyd具有良好至优异的抗肿瘤活性。在这些相同的肿瘤模型中，1-β-D-阿拉伯呋喃糖基胞嘧啶的活性显著较低或无活性。这种对小鼠实体瘤的体内活性支持了dFdCyd是癌症治疗临床试验的优秀候选药物这一结论。
