Effects of thymidine and hydroxyurea on the metabolism and cytotoxicity of
1-B-D arabinofuranosylcytosine in highly resistant human leukemia cells
K Bhalla, P Swerdlow and S Grant
Division of Hematology/Oncology, Medical University of South Carolina,
Charleston 29425.
We have examined the effect of the ribonucleotide reductase inhibitors
thymidine (dThd) and hydroxyurea (HU) on the metabolism and cytotoxicity of
high concentrations (10 to 100 mumol/L) of cytosine arabinoside (Ara-C) in
a deoxycytidine kinase-deficient, highly Ara-C- resistant human
promyelocytic leukemic cell subline (HL-60/Ara-C). Administration of dThd
or HU (0.5 to 3 mmol/L) in conjunction with high concentrations of Ara-C
either sequentially or simultaneously lead to enhanced (and in some cases a
supra-additive) inhibition of HL-60/Ara-C suspension culture growth and
soft agar colony formation. In addition, exposure of cells to 0.5 mmol/L
dThd or HU for 48 hours significantly increased the percentage of
HL-60/Ara-C in S-phase. In contrast to previous studies involving low-dose
Ara-C administration, we were unable to detect dThd- or HU-mediated
increments in Ara-CTP formation in HL-60/Ara-C cells treated with high-dose
Ara-C despite reductions in intracellular dCTP pools as great as 65%.
However, dThd or HU did increase Ara-C incorporation into newly synthesized
DNA. These studies show that administration of dThd or HU in conjunction
with high concentrations of Ara-C results in an enhanced antiproliferative
effect of Ara-C against Ara-C-resistant leukemic cells deficient in
deoxycytidine kinase.
Volume 78,
Issue 11,
pp. 2937-2944,
12/01/1991
Copyright © 1991 by The American Society of Hematology
