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Defective transport is a common mechanism of acquired methotrexate
resistance in acute lymphocytic leukemia and is associated with decreased
reduced folate carrier expression
R Gorlick, E Goker, T Trippett, P Steinherz, Y Elisseyeff, M Mazumdar, WF Flintoff and JR Bertino
Program of Molecular Pharmacology and Therapeutics, Memorial Sloan-
Kettering Cancer Center, New York 10021, USA.
Methotrexate (MTX) transport was examined in 27 patients with untreated
acute lymphocytic leukemia (ALL) and 31 patients with relapsed ALL using a
previously described fluorescent MTX analog (PT430) displacement assay
(Blood 80:1158, 1992). Only 13% of untreated patients were considered to
have impaired MTX transport, whereas more than 70% of relapsed patients had
evidence of impaired MTX transport. To further characterize the basis for
this defect, Northern analyses for the reduced folate carrier (RFC) were
performed on the RNA available from the leukemic blasts of 24 patients in
whom MTX transport had been measured. Six of nine samples with impaired MTX
transport had decreased RFC expression (one had no detectable RFC
expression), while three had no decrease in RFC expression. None of 15
samples with normal MTX transport had decreased RFC expression. A
reverse-transcriptase polymerase chain reaction (RT-PCR) assay was
developed to quantitate RFC mRNA expression more accurately. Decreased RFC
expression was demonstrated in six of the nine samples with impaired MTX
transport, confirming the results obtained by Northern blot. These data
indicate decreased RFC expression associated with impaired MTX transport is
observed in relapsed ALL following treatment with MTX-containing therapy.
Volume 89,
Issue 3,
pp. 1013-1018,
02/01/1997
Copyright © 1997 by The American Society of Hematology
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