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Enhancement of daunorubicin accumulation, retention, and cytotoxicity by
verapamil or cyclosporin A in blast cells from patients with previously
untreated acute myeloid leukemia
DD Ross, PJ Wooten, R Sridhara, JV Ordonez, EJ Lee and CA Schiffer
University of Maryland Cancer Center, Baltimore, MD 21201.
This work was designed to discern the frequency of expression of classical
multidrug resistance (MDR) in acute myeloid leukemia (AML) at the time of
diagnosis, using Western blotting for P-glycoprotein (Pgp) and functional
assays for an MDR phenotype (enhancement of daunorubicin [DNR]
accumulation/retention and cytotoxicity by the known MDR modulators
verapamil, cyclosporin A, and progesterone). Blast cells were studied from
49 newly diagnosed AML patients who were subsequently treated with the "3
and 7" combination of cytosine arabinoside (ara-C) and DNR. DNR
accumulation (1 microgram/mL, 3 hours) and retention (16 hours) were
determined by flow cytometry. Cyclosporin A (CsA, 5 mumol/L) or verapamil
(6.6 mumol/L) each caused significant enhancement of DNR accumulation and
retention in these blast cell samples (P < .001, Wilcoxon's test).
Verapamil or CsA caused greater than 20% enhancement of DNR accumulation or
retention in over 25% or 50% of these patients, respectively; however,
there was no correlation with the presence or degree of enhancement and
response to treatment. Progesterone (10 mumol/L) caused no significant
enhancement of DNR accumulation or retention. The effects of the MDR
modulators on the cytotoxicity of DNR was also determined in blast cells
from 40 of the patients, using a flow cytometric assay. CsA alone was
cytotoxic (caused an approximate 20% decrease in cell survival compared
with control, P < .001); CsA or verapamil caused enhancement of 1
mumol/L DNR cytotoxicity (P < .001). Greater than 40% enhancement of
cell kill by CsA or verapamil was observed in over 75% of patients studied.
There was no difference in the degree of enhancement of cytotoxicity
between patients clinically sensitive or resistant to treatment.
Progesterone caused no enhancement in DNR cytotoxicity. In contrast to the
functional assays, highly sensitive immunoblots using the C219 antibody to
Pgp showed evidence of low level expression of Pgp in blast cells from only
3 of these patients: 1 was chemotherapy resistant, 2 were sensitive. Thus,
although the functional assays suggest a high frequency of expression of a
classic MDR phenotype in AML patients at the time of diagnosis, with
enhancement by CsA obtained at a clinically relevant concentration (5
mumol/L), the frequency of Pgp expression detectable by C219 Western blots
was low in these patients. This could be interpreted either that the method
used was not sufficiently sensitive to detect Pgp in all of the blast cell
specimens that actually overexpressed mdr1, or that the
accumulation/efflux-based MDR phenotype observed is not always mediated by
Pgp in these previously untreated patients.
Volume 82,
Issue 4,
pp. 1288-1299,
08/15/1993
Copyright © 1993 by The American Society of Hematology
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