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Relationship Between Major Vault Protein/Lung Resistance Protein,
Multidrug Resistance-Associated Protein, P-Glycoprotein Expression,
and Drug Resistance in Childhood Leukemia
M.L. den Boer,
R. Pieters,
K.M. Kazemier,
M.M.A. Rottier,
C.M. Zwaan,
G.J.L. Kaspers,
G. Janka-Schaub,
G. Henze,
U. Creutzig,
R.J. Scheper, and
A.J.P. Veerman
From the Departments of Pediatric Hematology/Oncology and Pathology,
University Hospital Vrije Universiteit, Amsterdam, The Netherlands; the
COALL Study Group, Hamburg, Germany; the ALL-REZ BFM Group, Berlin,
Germany; and the AML-BFM Group, Münster, Germany.
Cellular drug resistance is related to a poor prognosis in childhood
leukemia, but little is known about the underlying mechanisms. We
studied the expression of P-glycoprotein (P-gp), multidrug resistance
(MDR)-associated protein (MRP), and major vault protein/lung resistance
protein (LRP) in 141 children with acute lymphoblastic leukemia (ALL)
and 27 with acute myeloid leukemia (AML) by flow cytometry. The
expression was compared between different types of leukemia and was
studied in relation with clinical risk indicators and in vitro
cytotoxicity of the MDR-related drugs daunorubicin (DNR), vincristine
(VCR), and etoposide (VP16) and the non-MDR-related drugs prednisolone
(PRD) and L-asparaginase (ASP). In ALL, P-gp, MRP, and LRP expression
did not differ between 112 initial and 29 unrelated relapse samples nor
between paired initial and relapse samples from 9 patients. In multiple
relapse samples, LRP expression was 1.6-fold higher compared with both
initial (P = .026) and first relapse samples (P = .050), which was not observed for P-gp and MRP. LRP expression was
weakly but significantly related to in vitro resistance to DNR
(Spearman's rank correlation coefficient 0.25, P = .016) but
not to VCR, VP16, PRD, and ASP. No significant correlations were found
between P-gp or MRP expression and in vitro drug resistance. Samples
with a marked expression of two or three resistance proteins did not
show increased resistance to the tested drugs compared with the
remaining samples. The expression of P-gp, MRP, and LRP was not higher
in initial ALL patients with prognostically unfavorable
immunophenotype, white blood cell count, or age. The expression of P-gp
and MRP in 20 initial AML samples did not differ or was even lower
compared with 112 initial ALL samples. However, LRP expression was
twofold higher in the AML samples (P < .001), which are more
resistant to a variety of drugs compared with ALL samples. In
conclusion, P-gp and MRP are unlikely to be involved in drug resistance
in childhood leukemia. LRP might contribute to drug resistance but only
in specific subsets of children with leukemia.
Blood, Vol. 91 No. 6 (March 15), 1998:
pp. 2092-2098
© 1998 by The American Society of Hematology.
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