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Blood, Vol. 93 No. 12 (June 15), 1999:
pp. 4086-4095
RAPID COMMUNICATION
Altered Multidrug Resistance Phenotype Caused by
Anthracycline Analogues and Cytosine Arabinoside in Myeloid
Leukemia
Xiu F. Hu,
Alison Slater,
Phillip Kantharidis,
Danny Rischin,
Surender Juneja,
Ralph Rossi,
Grace Lee,
John D. Parkin, and
John
R. Zalcberg
From Trescowthick Laboratory, Peter MacCallum Cancer Institute,
Melbourne, Australia; and the Division of Pathology, Austin & Repatriation Medical Centre, Melbourne, Australia.
The expression of P-glycoprotein (Pgp) is often increased in acute
myeloid leukemia (AML). However, little is known of the regulation of
Pgp expression by cytotoxics in AML. We examined whether Pgp expression
and function in leukemic blasts was altered after a short exposure to
cytotoxics. Blasts were isolated from 19 patients with AML (15 patients) or chronic myeloid leukemia in blastic transformation
(BT-CML, 4 patients). Pgp expression and function were
analyzed by flow cytometric analysis of MRK 16 binding and Rhodamine
123 retention, respectively. At equitoxic concentrations, ex vivo
exposure for 16 hours to the anthracyclines epirubicin (EPI),
daunomycin (DAU), idarubicin (IDA), or MX2 or the nucleoside analogue
cytosine arabinoside (AraC) differentially upregulated MDR1/Pgp
expression in Pgp-negative and Pgp-positive blast cells. In
Pgp-negative blasts, all four anthracyclines and AraC significantly
increased Pgp expression (P = .01) and Pgp function
(P = .03). In contrast, MX2, DAU, and AraC were the most potent in inducing Pgp expression and function in Pgp positive blasts
(P < .05). A good correlation between increased Pgp
expression and function was observed in Pgp-negative (r = .90, P = .0001) and Pgp-positive blasts (r = .77, P = .0002). This increase in Pgp expression and function was
inhibited by the addition of 1 µmol/L PSC 833 to blast cells at the
time of their exposure to these cytotoxics. In 1 patient with AML, an
increase in Pgp levels was observed in vivo at 4 and 16 hours after the
administration of standard chemotherapy with DAU/AraC. Upregulation of
Pgp expression was also demonstrated ex vivo in blasts harvested from
this patient before the commencement of treatment. In 3 other cases (1 patient with AML and 2 with BT-CML) in which blasts were Pgp negative at the time of initial clinical presentation, serial samples at 1 to 5 months after chemotherapy showed the presence of Pgp-positive blasts.
All 3 patients had refractory disease. Interestingly, in all 3 cases,
upregulation of Pgp by cytotoxics was demonstrated ex vivo in blasts
harvested at the time of presentation. These data suggest that
upregulation of the MDR1 gene may represent a normal response of
leukemic cells to cytotoxic stress and may contribute to clinical drug resistance.
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