Schedule-dependent synergy and antagonism between high-dose 1-beta-D-arabinofuranosylcytosine and asparaginase in the L5178Y murine leukemia.
Schedule-dependent synergy and antagonism between high-dose 1-beta-D-arabinofuranosylcytosine and asparaginase in the L5178Y murine leukemia.
复制标题
L5178Y 小鼠白血病中高剂量 1-β-D-阿拉伯呋喃糖基胞嘧啶和天冬酰胺酶之间的时间表依赖性协同作用和拮抗作用。
作者：
S. Schwartz;B. Morgenstern;R. Capizzi
使用小鼠白血病L5178 Y在体内和体外研究了给药方案对1-β-D-阿拉伯呋喃糖基胞嘧啶（ara-C）和天冬酰胺酶的组合的生化和治疗效果的影响。用阿糖胞苷（10（-6）M）或天冬酰胺酶（0.5 IU/ml）体外处理细胞8小时，分别产生45%和24%的活力;同时暴露于两种药物导致25%的活力，亚加性效应。用天冬酰胺酶在ara-C之前或ara-C在天冬酰胺酶之前连续8小时体外处理分别导致43%和8%的活力，表明强烈的时间表依赖性。从体内药物诱导的细胞生长抑制中恢复的最佳时间间隔为120小时。在接种10（6）个细胞后3天，用天冬酰胺酶、阿糖胞苷或两种药物同时治疗白血病小鼠，平均存活时间分别为16、21和18天（对照组平均存活时间为10天）。两种药物之间间隔120小时，用阿糖胞苷治疗，然后用天冬酰胺酶治疗，24只60天存活者中有20只。相反，当天冬酰胺酶先于阿糖胞苷时，平均存活时间仅为23天，没有60天的存活者。任何一种组合的最大体重减轻仅为10%。药理学拮抗作用的机制包括天冬酰胺酶诱导的细胞摄取减少和ara-C掺入大分子。明显的协同作用与天冬酰胺酶处理的时间有关，当在细胞从阿糖胞苷作用中恢复之前连续施用天冬酰胺酶时，出现“最佳治疗效果”。由于这两种药物都可能是抗白血病联合用药的组成部分，因此了解这种药物相互作用将优化临床治疗。
The effect of schedule of drug administration on the biochemical and therapeutic effects of the combination of 1-beta-D-arabinofuranosylcytosine (ara-C) and asparaginase was investigated in vivo and in vitro using the murine leukemia L5178Y. Treatment of cells in vitro with either ara-C (10(-6) M) or asparaginase (0.5 IU/ml) for 8 hr resulted in 45 and 24% viability, respectively; simultaneous exposure to both drugs resulted in 25% viability, a subadditive effect. Sequential 8-hr in vitro treatments with asparaginase preceding ara-C or ara-C preceding asparaginase resulted in 43 and 8% viability, respectively, indicating strong schedule dependency. Recovery from drug-induced inhibition of cell growth in vivo suggested an optimal interval of 120 hr. Treatment of leukemic mice with asparaginase, ara-C, or both drugs simultaneously 3 days after inoculation of 10(6) cells resulted in mean survival times of 16, 21, and 18 days, respectively (control mean survival time, 10 days). With a 120-hr interval between the two drugs, treatment with ara-C followed by asparaginase resulted in 20 of 24 sixty-day survivors. In contrast, when asparaginase preceded ara-C, there was a mean survival time of only 23 days with no 60-day survivors. Maximal weight loss with either combination was only 10%. Mechanisms for the pharmacological antagonism include asparaginase-induced decreased cellular uptake and incorporation of ara-C into macromolecules. The apparent synergy is related to the timing of asparaginase treatment, the "optimal therapeutic effect" occurring when sequential asparaginase is administered before the cells recover from the ara-C effect. Since both drugs are probable components of antileukemic combinations, understanding of such drug-drug interactions would optimize clinical therapy.