Modulation of ara-CTP levels by fludarabine and hydroxyurea in leukemic cells.
The rate of ara-cytosine triphosphate (ara-CTP) accumulation and its retention has been correlated with 1-beta-D-arabinofuranosylcytosine (ara-C)-mediated toxicity and clinical outcome in childhood and adult leukemia. We tested to what extent preincubation with the ribonucleotide reductase inhibitors fludarabine (F-ara-A) and hydroxyurea (HU) enhanced ara-CTP levels in two human myeloid (HL-60, CMK) and two lymphoblastic leukemia cell lines (MOLT-4, BLIN-1) and also in blasts from 28 children with acute leukemia (AML: 14, ALL: 14). Incubation experiments carried out with cell lines showed F-ara-A and HU to be equipotent in increasing ara-CTP levels. The highest increase was observed in HL-60 cells whereas preincubation had no modulatory effect in MOLT-4 cells. Accordingly, modulation of intracellular ara-CTP levels differed between the subtypes of childhood acute leukemia: whereas in T-ALL (five) preincubation with F-ara-A and HU had no effect on intracellular ara-C metabolism, increased ara-CTP levels were seen in some cases of pre-B-ALL (seven). In myelogenous blasts (12) clinically relevant enhancement of ara-C toxification was regularly obtained with both, F-ara-A (1.9-fold) and HU (1.5-fold). In conclusion, our data suggest that combinations of ara-C and ribonucleotide reductase inhibitors are apt to increase ara-CTP levels depending on the individual cell type and its sensitivity towards ara-C modulators.
Department of Pediatric Oncology, University of Münster, Germany.
M
M
Ahlmann
C
C
Lanvers
K
K
Lümkemann
C
C
Rössig
A
A
Freund
M
M
Baumann
J
J
Boos
D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D007938:Leukemia / Q000378:metabolism*; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001085:Arabinofuranosylcytosine Triphosphate; D014740:Vidarabine; C024352:fludarabine; D006918:Hydroxyurea