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Blood, Vol. 94 No. 9 (November 1), 1999:
pp. 3121-3128
Circumvention of Methotrexate Resistance in Childhood Leukemia
Subtypes by Rationally Designed Antifolates
Marianne G. Rots,
Rob Pieters,
Godefridus J. Peters,
Christina H. van Zantwijk,
Rob Mauritz,
Paul Noordhuis,
James C. Willey,
Karel Hählen,
Ursula Creutzig,
Gritta Janka-Schaub,
Gertjan J.L. Kaspers,
Anjo J.P. Veerman, and
Gerrit Jansen
From the Departments of Pediatric Hematology/Oncology and Medical
Oncology, University Hospital Vrije Universiteit, Amsterdam; the
Department of Pediatric Hematology/Oncology, Sophia Children's
Hospital, Erasmus University, Rotterdam, The Netherlands; the
Department of Medicine, Medical College of Ohio, Toledo, OH; and the
AML-Berlin-Frankfurt-Münster Study Group and the COALL Study
Group, Hamburg, Germany.
Cellular methotrexate (MTX) resistance may cause treatment failure
in childhood common/preB-acute lymphoblastic leukemia (c/preB-ALL), T-lineage ALL (T-ALL), and acute myeloid leukemia (AML). The ex vivo
potency of several antifolates (MTX, trimetrexate [TMQ], GW1843U89,
multitargeted antifolate [MTA], Raltitrexed, and ZD9331) was studied
via in situ inhibition of thymidylate synthase (TS). After short-term
exposure, relapsed c/preB-ALL (rALL, n = 21), T-ALL (n = 22), and
AML (n = 22) were 3-fold, 10-fold, and 6-fold less sensitive to MTX
(P  .01) compared with initial c/preB-ALL (n = 43). This
difference in resistance was not observed for TMQ. Also for GW1843U89
and MTA, no resistance was observed in rALL and AML compared with
c/preB-ALL. T-ALL compared with c/preB-ALL tended to be less resistant
to GW1843U89 (3-fold) and MTA (6-fold) than to MTX (10-fold) (P
= .06). Raltitrexed was more active against c/preB-ALL compared with
the other subtypes. After 21 hours continuous incubation, T-ALL and AML
samples were equally sensitive as c/preB-ALL to MTX, but rALL was
3-fold resistant to MTX compared with initial c/preB-ALL
(P = .003). The resistance of rALL was circumvented by TMQ (1-fold; P = .03) and GW1843U89 (1.4-fold; P
= .004). Novel antifolates, except MTA, displayed a more potent TS
inhibition than MTX during continuous exposure. These results suggest
that MTX resistance in AML and T-ALL can be circumvented by continuous exposure, and that novel antifolates should be explored further for
MTX-resistant T-ALL, rALL, and AML cells.
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