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Defective transport as a mechanism of acquired resistance to methotrexate
in patients with acute lymphocytic leukemia
T Trippett, S Schlemmer, Y Elisseyeff, E Goker, M Wachter, P Steinherz, C Tan, E Berman, JE Wright and A Rosowsky
Program of Molecular Pharmacology and Therapeutics, Memorial Sloan-
Kettering Cancer Center, New York, NY 10021.
Although the mechanisms of resistance to methotrexate (MTX) are known in
experimental tumors made resistant to this drug, little information is
available regarding acquired resistance to MTX in patients. A competitive
displacement assay using the fluorescent lysine analogue of MTX,
N-(4-amino-4-deoxy-N10-methylpteroyl)-N epsilon-(4'-fluorescein-
thiocarbamyl)-L-lysine (PT430), was developed as a sensitive method of
detection of transport resistance to MTX in cell lines, as well as in blast
cells from patients with leukemia. Rapid uptake of PT430 at high
concentrations (20 mumol/L) in leukemic blasts resulted in achievement of
steady-state levels within 2 hours. Subsequent incubation with the folate
antagonists, MTX and trimetrexate (TMTX), which differ in the mode of
carrier transport, produced characteristic patterns of PT430 displacement.
Flow cytometric analysis of the mean fluorescence intensity in the human
CCRF-CEM T-cell lymphoblastic leukemia cell line and its MTX-resistant
subline clearly identified the presence of transport deficiency in the
resistant subline. Analysis of blasts from 17 patients with leukemia, nine
with no prior chemotherapy and eight previously treated with chemotherapy,
found evidence of MTX transport resistance in two of the four patients who
were treated with MTX and considered to be clinically resistant to the
drug. The finding that blast cells of some patients with leukemia
considered clinically resistant to MTX is due to decreased MTX transport
has important implications for clinical use of this drug and for new drug
development.
Volume 80,
Issue 5,
pp. 1158-1162,
09/01/1992
Copyright © 1992 by The American Society of Hematology
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