INTRACELLULAR RETENTION OF CYTOSINE-ARABINOSIDE TRIPHOSPHATE IN BLASTCELLS FROM CHILDREN WITH ACUTE MYELOGENOUS AND LYMPHOBLASTIC-LEUKEMIA

The importance of the cellular pharmacokinetics of cytarabine triphosp hate (ara-CTP) with regard to therapeutic efficacy is well established . In vitro and in vivo monitoring of pharmacokinetic parameters of leu kemic blast cells were initiated in order to contribute to the pharmac ological basis of optimal ara-C treatment strategies. Peripheral or bo ne marrow blast cells from 66 leukemic patients 51 acute myelogenous l eukemia (ALL), 15 acute lymphoblastic leukemia (AML) were separated an d 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 fo r induction treatment, the ara-CTP concentration in circulating blast cells was monitored in vivo. The in vitro values observed in this assa y corresponded to the cellular levels monitored in vivo. The ara-CTP r etention differed clearly among the individual groups, as classified b y immunphenotype 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 A ML (P<0.05) as well as T-ALL (P<0.05) was significant. There was a ten dency toward lower ara-CTP retention in relapsed as compared with newl y diagnosed ALL, but the difference was not significant. The maximal a ccumulation of ara-CTP (after 1 hour incubation) was comparable in AML , T-ALL, non-T-ALL, and blast cells from children in relapse. The obse rved similarity of cellular accumulation in all groups and the signifi cantly more rapid decrease in T-ALL and AML provide the pharmacokineti c rationale supporting the prolonged infusion duration for ara-C in th ese subgroups as an alternative to the intensification by high-dose ar a-C schedules with short-term infusion. (C) 1996 Wiley-Liss. Inc.