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[Intracellular retention of cytarabine-triphosphate (Ara-CTP) in blasts of children with acute lymphoblastic leukemia. Correlation with clinical course parameters].

AbstractBACKGROUND:
Cellular uptake and intracellular phosphorylation to the nucleotide cytosine arabinoside-triphosphate (Ara-CTP) is the precondition for the cytostatic effect of cytarabine. The pharmacokinetics of Ara-CTP in leukemic cells was reported to be of clinical importance in adult nonlymphoblastic leukemia. Therefore, the role of intracellular Ara-CTP formation and retention was investigated in blast cells from children with acute lymphoblastic leukemia (ALL).
PATIENTS AND METHODS:
At the time of diagnosis, peripheral or bone marrow blast cells from 41 children with ALL and 13 with relapsed ALL were incubated in Ara-C containing medium (1 hour, 1 or 3 micrograms/ml) followed by reincubation in Ara-C free medium (3 h). Intracellular Ara CTP formation and Ara-CTP retention were determined.
MAIN RESULTS:
Ara-CTP formation did not show marked differences between the different immunological subtypes. Ara-CTP retention, however, was significantly lower in T-ALL (37 +/- 15%, n = 8) compared to non-T-ALL (67 +/- 25%, n = 33; p < 0.003). Ara-CTP retention was also significantly different in children with and without persistence of peripheral blast cells after one week of prednison treatment (71 +/- 30%, n = 9 and 53 +/- 19%, n = 21; p = 0.031) as well as in children with and without complete bone marrow remission on day 15 of the ALL-BFM treatment protocol (66 +/- 17%, n = 19 and 43 +/- 18%, n = 11; p = 0.018). Ara-CTP retention was inversely correlated with the risk groups defined by the ALL-BFM treatment protocols (standard 79 +/- 29, intermediate 59 +/- 25, high risk 47 +/- 21%). A trend towards lower Ara-CTP retention was observed in relapsed leukemias (relapsed non-T-ALL 51 +/- 17%, p = 0.061). The difference in the probability of event free survival (following risk group adapted treatment according to ALL-BFM trials) between children with high (> or = 72%; 0.92 +/- 0.08) and low (< 72%: 0.58 +/- 0.15) Ara-CTP retention up to now did not reach statistical significance (p = 0.12).
CONCLUSIONS:
The more rapid decrease of cellular Ara-CTP in T-cell leukemia and children at higher clinical risk groups provide a pharmacokinetic rationale for prolonged infusion duration as an alternative to the intensification by dose escalation alone.
AuthorsM Schiller, B Hohenlöchter, P Schulze-Westhoff, M Zimmermann, J Ritter, H Jürgens, J Boos
JournalKlinische Padiatrie (Klin Padiatr) 1996 Jul-Aug Vol. 208 Issue 4 Pg. 151-9 ISSN: 0300-8630 [Print] Germany
Vernacular TitleIntrazelluläre Retention von Cytarabin-Triphosphat (Ara-CTP) in Blasten von Kindern mit akuter lymphoblastischer Leukämie. Korrelation zu klinischen Verlaufsparametern.
PMID8926681 (Publication Type: English Abstract, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cytarabine
  • Arabinofuranosylcytosine Triphosphate
Topics
  • Adolescent
  • Adult
  • Arabinofuranosylcytosine Triphosphate (pharmacokinetics)
  • Blast Crisis (blood, drug therapy, mortality)
  • Bone Marrow (drug effects, metabolism)
  • Child
  • Child, Preschool
  • Cytarabine (administration & dosage, pharmacokinetics)
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Humans
  • Infant
  • Leukemia, Myeloid, Acute (blood, drug therapy, mortality)
  • Male
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (blood, drug therapy, mortality)
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma (blood, drug therapy, mortality)
  • Prognosis
  • Remission Induction

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