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Elevated dihydrofolate reductase and impaired methotrexate transport as
elements in methotrexate resistance in childhood acute lymphoblastic
leukemia
LH Matherly, JW Taub, Y Ravindranath, SA Proefke, SC Wong, P Gimotty, S Buck, JE Wright and A Rosowsky
Developmental Therapeutics Program, Michigan Cancer Foundation, Detroit
48201.
A retrospective study of clinical resistance to methotrexate (MTX) was
performed on 29 archival specimens of frozen lymphoblasts obtained from
children with acute lymphoblastic leukemia (ALL), including 19 at initial
presentation and 10 at first relapse. Blasts were assayed for dihydrofolate
reductase and MTX transport by flow cytometry using the fluorescent
methotrexate analog, PT430 (Rosowsky et al, J Biol Chem 257:14162, 1982).
In contrast to tissue culture cells, patient blasts were often
heterogeneous for dihydrofolate reductase content. Of the 19 specimens at
initial diagnosis, 7 exhibited dual blast populations, characterized by
threefold to 10-fold differences in relative dihydrofolate reductase; the
dihydrofolate reductase-overproducing populations comprised 12% to 68% of
the total blasts for these specimens. Remission duration intervals for
patients exhibiting dual blast populations were notably shorter than for
patients expressing a single blast population with lower dihydrofolate
reductase ( < or = 9 months v > or = 15 months, respectively), a
difference that was statistically significant (P = .045). There was no
apparent correlation between expression of increased dihydrofolate
reductase at diagnosis and known patient and disease prognostic features
(immunophenotype, age, sex, and white blood count). For the relapsed
patients, 4 of 10 exhibited dual lymphoblast populations with elevated
dihydrofolate reductase. The majority of the patient lymphoblast specimens
were entirely competent for MTX transport and, likewise, expressed
immunoreactive reduced folate carriers by indirect immunofluorescence
staining with specific antiserum to the transporter. Three patients (2 at
relapse and 1 at diagnosis) exhibited heterogeneous expression of imparied
MTX transport (14% to 73% of blasts). In only 1 of these patients did the
majority of the lymphoblasts (73%) show impaired MTX transport and for this
specimen, immunoreactive carrier proteins were virtually undetectable.
These results suggest that heterogeneous expression of elevated
dihydrofolate reductase and impaired MTX transport are important modes of
resistance in childhood ALL patients undergoing chemotherapy with MTX and
that these parameters may serve as predictive indices of clinical response
to MTX.
Volume 85,
Issue 2,
pp. 500-509,
01/15/1995
Copyright © 1995 by The American Society of Hematology
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