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Synergistic reversal of multidrug-resistance phenotype in acute myeloid
leukemia cells by cyclosporin A and cremophor EL
DD Ross, PJ Wooten, Y Tong, B Cornblatt, C Levy, R Sridhara, EJ Lee and CA Schiffer
University of Maryland Cancer Center, Baltimore 21201.
Cremophor (Crem) EL, the vehicle for intravenous delivery of cyclosporin A
(CsA), has been reported to counteract multidrug resistance (MDR) in
P-glycoprotein (Pgp)-over-expressing cell lines. Because of this, we sought
to determine whether Crem functions independently as a modulator of MDR in
blast cells obtained from acute myelogenous leukemia (AML) patients, and
the nature of its interaction in combination with CsA in reversing an MDR
phenotype. In the phenotypically classical MDR AML cell lines HL-60/Vinc
(overexpresses Pgp) or HL-60/AR (does not overexpress Pgp), the dose
causing half- maximum enhancement (D50) of daunorubicin (DNR, 1
micrograms/mL, 3 hours) accumulation was achieved by the combination of CsA
and Crem (CsA/Crem) at 1.2 mumol/L CsA. In contrast, the D50 for Crem alone
was approached at an amount that would be needed to suspend 6.2 mumol/L CsA
for HL-60/Vinc, and 81 mumol/L CsA for HL-60/AR. The D50 concentrations for
CsA alone (dissolved in ethanol, which does not alter DNR accumulation)
were also higher than those for CsA/Crem, being 6.5 mumol/L for HL-60/Vinc,
and 3.1 mumol/L for HL-60/AR. The maximum absolute level of enhancement of
DNR accumulation (Emax) in each cell line was approximately equivalent for
CsA/Crem or CsA alone, and was equal to the 3 hr intracellular DNR
accumulation observed in parental, drug sensitive HL-60/W cells. For Crem
alone, HL-60/AR and HL-60/Vinc cells showed markedly different responses:
HL-60/Vinc cells attained intracellular DNR content comparable to HL-60/W,
whereas HL-60/AR cells achieved only approximately 35% of this level.
Multiple-drug effects were analyzed by calculation of the Combination Index
(Chou and Talalay, Adv Enzyme Regul 22:27, 1984), which indicated that CsA
and Crem are synergistic in causing enhancement of DNR accumulation in
these MDR HL-60 cell lines. In blasts from AML patients, 5 mumol/L CsA/Crem
or an equivalent amount of Crem alone each caused significant (P < .001)
enhancement of DNR accumulation (60 AML-patient marrow samples) or DNR
retention (51 AML-patient marrows). Similarly, CsA/Crem or Crem alone
caused significant (P < .01) enhancement of the cytotoxicity of DNR in
36 AML blast cell specimens. The degree of enhancement of
accumulation/retention or cytotoxicity by CsA/Crem was approximately
equivalent to that obtained with Crem alone. These studies indicate that
Crem can reverse an MDR phenotype in patient AML blast cells.(ABSTRACT
TRUNCATED AT 400 WORDS)
Volume 83,
Issue 5,
pp. 1337-1347,
03/01/1994
Copyright © 1994 by The American Society of Hematology
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