Avramis V I, Biener R, Krailo M, Finklestein J, Ettinger L, Willoughby M, Siegel S E, Holcenberg J S
Division of Hematology-Oncology, Childrens Hospital of Los Angeles, California 90027.
Cancer Res. 1987 Dec 15;47(24 Pt 1):6786-92.
The pharmacodynamic parameters of 1-beta-D-arabinofuranosylcytosine (ara-C) in patient plasma and its active anabolite 1-beta-D-arabinofuranosylcytosine-5-triphosphate (ara-CTP) in circulating and bone marrow blast cells were studied in 20 pediatric patients with acute leukemia. ara-C (3 g/m2) was administered as a short-term infusion over 3 h every 12 h for a total of eight doses. The peak plasma concentration of ara-C ranged from 0.02 to 5.6 microM after the first dose of ara-C. The area under the concentration-time curve (AUC) of ara-C in plasma ranged from 302 to 20,298 microMh after the first dose of ara-C. The half-life of elimination (t1/2,el) of ara-C from plasma was 2.4 +/- 1.5 h in three patients with acute nonlymphoblastic leukemia (ANLL) and 4.78 +/- 4.1 h in 9 patients with acute lymphoblastic leukemia (ALL). The intracellular peak concentration of ara-CTP in circulating blast cells averaged 432.2 +/- 14.5 microM and 544.3 +/- 330 microM in patients with ANLL and ALL, respectively. The elimination kinetics of ara-CTP was monoexponential with t1/2,el of 3.30 +/- 0.8 h and 6.9 +/- 2.8 h in patients with ANLL and ALL. DNA synthetic capacity (DSC) of the blast cells was inhibited to between 24 and 64% of control after the first dose of ara-C and it declined further to between 1 and 32% after four doses of ara-C. The AUC of ara-CTP in leukemic cells ranged from 1,073 to 14,751 microMh and it was not related to the AUC of ara-C in plasma. The pharmacodynamic parameters of ara-CTP in circulating blast cells were more homogeneous in patients with ANLL than in patients with ALL. Four of six patients (67%) with ANLL and six of 14 patients (43%) with ALL achieved either complete remission or partial remission with high dose ara-C. We conclude that treatment of pediatric patients with leukemia in relapse with high dose ara-C is tolerable and moderately successful. Inhibition of DSC is positively correlated with the probability of having zero nadir peripheral blast cells. In turn there is a trend for a zero nadir peripheral blast cell count to be related to achievement of a response to therapy. This latter result is consistent with the results of larger studies in adults with leukemia.
对20例急性白血病患儿的血浆中1-β-D-阿拉伯呋喃糖基胞嘧啶（ara-C）及其活性代谢产物1-β-D-阿拉伯呋喃糖基胞嘧啶-5-三磷酸（ara-CTP）在循环和骨髓原始细胞中的药效学参数进行了研究。ara-C（3 g/m²）每12小时静脉滴注3小时，共8剂。首剂ara-C后，血浆中ara-C的峰值浓度范围为0.02至5.6微摩尔/升。首剂ara-C后，血浆中ara-C的浓度-时间曲线下面积（AUC）范围为302至20298微摩尔·小时。3例急性非淋巴细胞白血病（ANLL）患者血浆中ara-C的消除半衰期（t1/2,el）为2.4±1.5小时，9例急性淋巴细胞白血病（ALL）患者为4.78±4.1小时。ANLL和ALL患者循环原始细胞中ara-CTP的细胞内峰值浓度分别平均为432.2±14.5微摩尔/升和544.3±330微摩尔/升。ara-CTP的消除动力学呈单指数，ANLL和ALL患者的t1/2,el分别为3.30±0.8小时和6.9±2.8小时。首剂ara-C后，原始细胞的DNA合成能力（DSC）被抑制至对照的24%至64%，四剂ara-C后进一步降至1%至32%。白血病细胞中ara-CTP的AUC范围为1073至14751微摩尔·小时，与血浆中ara-C的AUC无关。ANLL患者循环原始细胞中ara-CTP的药效学参数比ALL患者更均匀。6例ANLL患者中有4例（67%）和14例ALL患者中有6例（43%）使用高剂量ara-C实现了完全缓解或部分缓解。我们得出结论，高剂量ara-C治疗复发的儿童白血病患者是可耐受的且取得了一定成功。DSC的抑制与外周原始细胞最低点为零的可能性呈正相关。反过来，外周原始细胞最低点计数为零的趋势与治疗反应的实现有关。后一结果与成人白血病的更大规模研究结果一致。
