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Inhibitory effect of 2-chlorodeoxyadenosine on granulocytic, erythroid, and
T-lymphocytic colony growth
AL Petzer, R Bilgeri, U Zilian, M Haun, FH Geisen, I Pragnell, H Braunsteiner and G Konwalinka
Department of Internal Medicine, University of Innsbruck, Austria.
Previous studies have shown that 2-chloro-2'-deoxyadenosine (CdA) is
markedly toxic to normal and malignant human lymphocytes in vitro and in
vivo. Recent clinical trials have shown that CdA is a very promising drug
for the treatment of lymphoid malignancies. The present investigations were
designed to test the effect of CdA on the in vitro clonal growth of both
myeloid progenitors and T-lymphocyte colony- forming cells (CFU-TL)
obtained from normal human bone marrow and peripheral blood. Cells were
exposed to CdA in doses up to 1280 nmol/L. To reduce indirect effects of
CdA mediated by accessory cells, monocyte- and T-lymphocyte-depleted bone
marrow cells were used for our investigations. The results show a marked
inhibition of myeloid progenitor and lymphocyte colony-forming cells in a
dose-dependent manner, correlating with maturation stage in that the
immature progenitor cells are more sensitive to this drug. Furthermore, our
studies suggest that a sequence of metabolic events previously described
for lymphocytes may be operative in myeloid progenitor cells because a
minimal exposure time of 48 hours is required to obtain a marked
inhibition. CdA toxicity was proposed to be linked with phosphorylation by
deoxycytidine-kinase (E.C. 2.7.1.74), the levels of which have been found
to be high in lymphocytes, but low in granulocytes. However, the marked
inhibition of myeloid progenitor cells shown in these studies suggests that
other factors such as modulation of the effect of CdA by the ambient levels
of other deoxynucleosides might influence the apparent sensitivity of
myeloid cells.
Volume 78,
Issue 10,
pp. 2583-2587,
11/15/1991
Copyright © 1991 by The American Society of Hematology
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