Sensitivity to 5-azacytidine of blast progenitors in acute myeloblastic
leukemia
C Wang and EA McCulloch
In a previous study, we showed that the blast stem cells of acute
myeloblastic leukemia (AML) were more sensitive to cytosine arabinoside
(ara-C) when growing in suspension culture than during colony formation in
methylcellulose. We suggested that the difference might be explained by
considering the cellular mechanisms responsible for growth in suspension
and colony formation. In the former, the clonogenic cells increase in
number (self-renewal); in the latter, most of the divisions are terminal.
The increased sensitivity to ara-C in suspension might then be attributed
to its ability to inhibit self-renewal to a greater degree than cell
division generally. A test of this hypothesis would be to compare the
survival curves in suspension and in methylcellulose using a drug that
spared or stimulated self-renewal. Such an agent is 5- azacytidine (5-aza)
and has the additional advantage that its analogue, 6-azacytidine (6-aza)
has no effect on self renewal. The data supported the hypothesis, since
clonogenic AML blasts were much less sensitive to 5-aza in suspension than
in methylcellulose. The effect of 6-aza, while qualitatively similar, was
much less marked. Controls showed that the difference in survival curves
could not be explained on a kinetic basis or by the secretion of growth
factors by 5-aza-treated cells. We suggest that a comparison of the effects
of drugs in suspension and in methylcellulose may be useful in preclinical
screening of putative anti- AML compounds.
Volume 69,
Issue 2,
pp. 553-559,
02/01/1987
Copyright © 1987 by The American Society of Hematology
