Boos J, Hohenlöchter B, Schulze-Westhoff P, Schiller M, Zimmermann M, Creutzig U, Ritter J, Jurgens H
Department of Pediatric Hematology & Oncology, University of Münster, Germany.
Med Pediatr Oncol. 1996 Jun;26(6):397-404. doi: 10.1002/(SICI)1096-911X(199606)26:6<397::AID-MPO5>3.0.CO;2-C.
The importance of the cellular pharmacokinetics of cytarabine triphosphate (ara-CTP) with regard to therapeutic efficacy is well established. In vitro and in vivo monitoring of pharmacokinetic parameters of leukemic blast cells were initiated in order to contribute to the pharmacological basis of optimal ara-C treatment strategies. Peripheral or bone marrow blast cells from 66 leukemic patients [51 acute myelogenous leukemia (ALL), 15 acute lymphoblastic leukemia (AML) were separated and incubated with ara-C for 1 hour and in ara-C-free medium for another 3 hours, and the intracellular formation and retention of ara-CTP was measured. In eight children who received continuous ara-C infusion for induction treatment, the ara-CTP concentration in circulating blast cells was monitored in vivo. The in vitro values observed in this assay corresponded to the cellular levels monitored in vivo. The ara-CTP retention differed clearly among the individual groups, as classified by immunophenotype at the time of the initial diagnosis: non-T-ALL 67+/-25% (x+/-SD, n=33), T-ALL 37+/-15% (n=8), and AML 34+/-18% (n=14). The difference in ara-CTP retention between non-T-All and AML (P<0.05) as well as T-ALL (P<0.05) was significant. There was a tendency toward lower ara-CTP retention in relapsed as compared with newly diagnosed ALL, but the difference was not significant. The maximal accumulation of ara-CTP (after 1 hour incubation) was comparable in AML, T-ALL, non-T-ALL, and blast cells from children in relapse. The observed similarity of cellular accumulation in all groups and the significantly more rapid decrease in T-ALL and AML provide the pharmacokinetic rationale supporting the prolonged infusion duration for ara-C in these subgroups as an alternative to the intensification by high-dose ara-C schedules with short-term infusion.
三磷酸阿糖胞苷（ara - CTP）的细胞药代动力学对治疗效果的重要性已得到充分证实。为了为优化阿糖胞苷治疗策略提供药理学依据，开展了白血病原始细胞药代动力学参数的体外和体内监测。分离了66例白血病患者[51例急性髓系白血病（ALL），15例急性淋巴细胞白血病（AML）]的外周血或骨髓原始细胞，与阿糖胞苷孵育1小时，然后在无阿糖胞苷的培养基中再孵育3小时，并测定细胞内ara - CTP的形成和保留情况。在8例接受持续阿糖胞苷输注诱导治疗的儿童中，对循环原始细胞中的ara - CTP浓度进行了体内监测。该试验中观察到的体外值与体内监测的细胞水平相对应。根据初始诊断时的免疫表型分类，各亚组之间的ara - CTP保留情况明显不同：非T - ALL为67±25%（x±SD，n = 33），T - ALL为37±15%（n = 8），AML为34±18%（n = 14）。非T - ALL与AML（P<0.05）以及与T - ALL（P<0.05）之间的ara - CTP保留差异具有统计学意义。与新诊断的ALL相比，复发ALL的ara - CTP保留有降低趋势，但差异不显著。AML、T - ALL、非T - ALL以及复发儿童的原始细胞中ara - CTP的最大积累量（孵育1小时后）相当。所有组中观察到的细胞积累相似性以及T - ALL和AML中明显更快的下降，为这些亚组中阿糖胞苷延长输注时间提供药代动力学依据，作为短期输注高剂量阿糖胞苷强化方案的替代方案。
