Blood, Vol. 94 No. 7 (October 1), 1999:
pp. 2414-2423
Triggering Noncycling Hematopoietic Progenitors and Leukemic Blasts to
Proliferate Increases Anthracycline Retention and Toxicity by
Downregulating Multidrug Resistance
Mariëlle E.P. Smeets,
Reinier A.P. Raymakers,
Gerty Vierwinden,
Arie H.M. Pennings,
Hans Wessels, and
Theo de Witte
From the Division of Hematology, University Hospital Nijmegen,
Nijmegen, The Netherlands.
Expression of the multidrug resistance (MDR) mechanisms
P-glycoprotein (Pgp) and MDR-related protein (MRP) decrease cellular retention and consequently cytotoxicity of anthracyclines. MDR is
expressed on normal human hematopoietic progenitors and leukemic blasts. Normal CD34+ progenitors showed rhodamine efflux
in 20% to 30% of the cells, which could be blocked by verapamil.
These cells appeared noncycling, in contrast to the proliferating
rhodamine bright (RhoB) cells. We postulated that MDR expression can be
downregulated by proliferation induction. Triggering rhodamine dull
(RhoD) CD34+ cells to proliferate indeed resulted in a
higher rhodamine retention and significantly decreased efflux
modulation by verapamil (P = .04). Also in acute myeloid
leukemia (AML), the proliferation rate (percentage S/G2+M
and Iododeoxyuridine labelings index) was significantly less in the
RhoD blasts (P 
.008) and proliferation induction of RhoD
blasts resulted in increased rhodamine retention. Anthracycline
cytotoxicity was less for RhoD than RhoB cells in both normal
progenitors and leukemic blasts. Proliferation induction of the RhoD
cells resulted in increased anthracycline sensitivity. We conclude that
noncycling progenitors, both normal and leukemic, have a relatively
high MDR expression. Triggering these cells into proliferation
downregulates MDR expression. These findings can be exploited to
overcome MDR in the treatment of AML patients.
