2'-Deoxycytidine protects normal human bone marrow progenitor cells in
vitro against the cytotoxicity of 3'-azido-3'-deoxythymidine with
preservation of antiretroviral activity
K Bhalla, M Birkhofer, GR Li, S Grant, W MacLaughlin, J Cole, G Graham and DJ Volsky
Department of Medicine, Columbia University College of Physicians and
Surgeons, New York, NY.
Bone marrow cytotoxicity of 3'-azido-3'-deoxythymidine (AZT), an anti-
human immunodeficiency virus (anti-HIV) drug, has been attributed to
deoxyribonucleotide pool perturbations that might result in impaired DNA
synthesis in normal bone marrow elements. We examined, in vitro, the effect
of high, but clinically achievable and nontoxic, concentrations of
2'-deoxycytidine (dCyd) (greater than or equal to 100 mumol/L) on high-dose
AZT mediated growth inhibition and intracellular biochemical perturbations
in normal bone marrow progenitor cells. Colony formation by bone marrow
progenitor cells in semisolid medium was significantly protected by dCyd
against the inhibitory effects of co-administered, high concentrations of
AZT (10 mumol/L). Also, dCyd significantly corrected AZT mediated depletion
of intracellular thymidine triphosphate (dTTP) and dCyd triphosphate (dCTP)
levels in normal bone marrow mononuclear cells (BMMC). Moreover, dCyd
reduced the intracellular accumulation of AZT triphosphate (AZT-TP) and its
DNA incorporation in BMMC. In contrast, co-administration of dCyd (100
mumol/L to 1 mmol/L) did not reverse AZT (10 mumol/L) mediated suppression
of HIV infectivity in HUT-102 cells in culture, although a partial
reduction in intracellular AZT-TP pools and its DNA incorporation as well
as a correction of AZT mediated depletion of dTTP and dCTP pools was
observed in these cells. These studies suggest that dCyd at high
concentrations might ameliorate the bone marrow cytotoxicity of high-dose
AZT without impairing its anti-HIV effect.
Volume 74,
Issue 6,
pp. 1923-1928,
11/01/1989
Copyright © 1989 by The American Society of Hematology
