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Hydroxyurea increases fetal hemoglobin in cultured erythroid cells derived
from normal individuals and patients with sickle cell anemia or
beta-thalassemia
E Fibach, KP Burke, AN Schechter, CT Noguchi and GP Rodgers
Department of Hematology, Hadassah University Hospital, Jerusalem, Israel.
Hydroxyurea (HU), an inhibitor of DNA synthesis, has been shown to increase
fetal hemoglobin (HbF) levels in patients with sickle cell anemia and in
some patients with beta-thalassemia. However, until now there have not been
good in vitro model systems that simulate this effect for study of the
molecular and cellular mechanism(s) involved in perturbing the normal
ontogeny of the globin genes. We analyzed the cellular effects of HU using
a two-phase liquid culture procedure (Fibach et al: Blood 73:100, 1989) in
which human peripheral blood- derived progenitor cells undergo
proliferation and differentiation. HU was found to have multiple effects on
these cultured cells: (1) an increase in the proportion of HbF produced;
(2) a decrease in cell number due to inhibition of cell proliferation; (3)
an increase in hemoglobin content per cell (mean corpuscular hemoglobin
[MCH]); and (4) an increase in cell size (mean corpuscular volume). The
extent of these effects was related to the HU dose and time of addition.
When added to cell cultures from normal individuals, 4 days following their
exposure to erythropoietin (EPO), 100 mumol/L HU caused a 1.3- to 3.5- fold
increase in the proportion of HbF, from 0.4% to 5.2% (mean 1.6) in
untreated to 1.5% to 8.2% (mean 3.1) in HU-treated cultures and a 45% +/-
10% increase in MCH but only a 25% +/- 7% decrease in cell number on day
13. Cultures of cells derived from five patients with sickle cell anemia
have shown a twofold to fivefold increase in the percentage of Hb F
following addition of HU while four patients with beta- thalassemia showed
a 1.3- to 6.2-fold increase. We believe that this primary cell culture
procedure should prove useful in studying the cellular and molecular
mechanisms of pharmacologic induction of HbF and might provide a valuable
predictive assay system for evaluation of the response of individual
patients with hemoglobinopathies to HU and similar agents.
Volume 81,
Issue 6,
pp. 1630-1635,
03/15/1993
Copyright © 1993 by The American Society of Hematology
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