A possible role for methotrexate in the treatment of childhood acute myeloid leukaemia, in particular for acute monocytic leukaemia

M. G. Rots; R. Pieters; G. Jansen; G. J.L. Kaspers; C. H. Van Zantwijk; P. Noordhuis; D. A. Voorn; E. R. Van Wering; U. Creutzig; A. J.P. Veerman; G. J. Peters

doi:10.1016/S0959-8049(00)00433-0

A possible role for methotrexate in the treatment of childhood acute myeloid leukaemia, in particular for acute monocytic leukaemia

M. G. Rots, R. Pieters, G. Jansen, G. J.L. Kaspers, C. H. Van Zantwijk, P. Noordhuis, D. A. Voorn, E. R. Van Wering, U. Creutzig, A. J.P. Veerman, G. J. Peters

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Acute myeloid leukaemia (AML) is thought to be methotrexate (MTX)-resistant. However, a small study suggested that acute monocytic leukemia (AML-M5) is sensitive to MTX. We measured MTX accumulation/polyglutamylation in 20 AML-nonM5, 37 AML-M5 and 83 common/preB-acute lymphoblastic leukaemia (c/preB-ALL) samples. Membrane transport was determined in 11 childhood AMLs (including 3 AML-M5) and in 25 c/preB-ALL samples. MTX sensitivity was determined in 23 AML-nonM5, 15 AML-M5 and 63 common/preB-ALL samples using the thymidylate synthase (TS) inhibition assay. MTX transport was higher in AML samples compared with c/preB-ALL precluding a transport defect in AML. Accumulation of long-chain polyglutamates MTX-Glu_4-6 was 3-fold lower for AML-nonM5 compared with c/preB-ALL cells (median 268 versus 889 pmol MTX-Glu_4-6/10⁹ cells; P ≤ 0.001); for AML-M5 samples, median accumulation of MTX-Glu_4-6 was 0 pmol/10⁹ cells (P ≤ 0.001). After short-term MTX exposure, AML-nonM5 was 6-fold more resistant to MTX compared with c/preB-ALL cells (2.16 versus 0.39 μM; P < 0.001), while AML-M5 was 2-fold more resistant (P = 0.02). In both AML-nonM5 and AML-M5 cells, MTX resistance was circumvented by continuous MTX exposure (median TSI₅₀ values: 0.052 and 0.041 μM, respectively) compared with a c/preB-ALL value of 0.066 μM. In conclusion, AML-M5 is relatively sensitive to MTX compared with other AML-subtypes even though polyglutamylation of MTX is poor. Using continuous exposure, AML-nonM5 and AML-M5 cells were at least as sensitive to MTX as c/preB-ALL cells. This report suggests that MTX might be an overlooked drug in the treatment of childhood AML.

Originele taal-2	Engels
Pagina's (van-tot)	492-498
Aantal pagina's	7
Tijdschrift	European Journal of Cancer
Volume	37
Nummer van het tijdschrift	4
DOI's	https://doi.org/10.1016/S0959-8049(00)00433-0
Status	Gepubliceerd - 2001
Extern gepubliceerd	Ja

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10.1016/S0959-8049(00)00433-0

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Rots, M. G., Pieters, R., Jansen, G., Kaspers, G. J. L., Van Zantwijk, C. H., Noordhuis, P., Voorn, D. A., Van Wering, E. R., Creutzig, U., Veerman, A. J. P., & Peters, G. J. (2001). A possible role for methotrexate in the treatment of childhood acute myeloid leukaemia, in particular for acute monocytic leukaemia. European Journal of Cancer, 37(4), 492-498. https://doi.org/10.1016/S0959-8049(00)00433-0

@article{f0cfa67be9844cada8f1dd66cf594674,

title = "A possible role for methotrexate in the treatment of childhood acute myeloid leukaemia, in particular for acute monocytic leukaemia",

abstract = "Acute myeloid leukaemia (AML) is thought to be methotrexate (MTX)-resistant. However, a small study suggested that acute monocytic leukemia (AML-M5) is sensitive to MTX. We measured MTX accumulation/polyglutamylation in 20 AML-nonM5, 37 AML-M5 and 83 common/preB-acute lymphoblastic leukaemia (c/preB-ALL) samples. Membrane transport was determined in 11 childhood AMLs (including 3 AML-M5) and in 25 c/preB-ALL samples. MTX sensitivity was determined in 23 AML-nonM5, 15 AML-M5 and 63 common/preB-ALL samples using the thymidylate synthase (TS) inhibition assay. MTX transport was higher in AML samples compared with c/preB-ALL precluding a transport defect in AML. Accumulation of long-chain polyglutamates MTX-Glu4-6 was 3-fold lower for AML-nonM5 compared with c/preB-ALL cells (median 268 versus 889 pmol MTX-Glu4-6/109 cells; P ≤ 0.001); for AML-M5 samples, median accumulation of MTX-Glu4-6 was 0 pmol/109 cells (P ≤ 0.001). After short-term MTX exposure, AML-nonM5 was 6-fold more resistant to MTX compared with c/preB-ALL cells (2.16 versus 0.39 μM; P < 0.001), while AML-M5 was 2-fold more resistant (P = 0.02). In both AML-nonM5 and AML-M5 cells, MTX resistance was circumvented by continuous MTX exposure (median TSI50 values: 0.052 and 0.041 μM, respectively) compared with a c/preB-ALL value of 0.066 μM. In conclusion, AML-M5 is relatively sensitive to MTX compared with other AML-subtypes even though polyglutamylation of MTX is poor. Using continuous exposure, AML-nonM5 and AML-M5 cells were at least as sensitive to MTX as c/preB-ALL cells. This report suggests that MTX might be an overlooked drug in the treatment of childhood AML.",

keywords = "Acute monocytic leukaemia, Childhood acute myeloid leukaemia, Methotrexate, Polyglutamylation, Reduced folate carrier",

author = "Rots, {M. G.} and R. Pieters and G. Jansen and Kaspers, {G. J.L.} and {Van Zantwijk}, {C. H.} and P. Noordhuis and Voorn, {D. A.} and {Van Wering}, {E. R.} and U. Creutzig and Veerman, {A. J.P.} and Peters, {G. J.}",

note = "Funding Information: The authors thank Professor Dr H. Gadner and Professor Dr O.A. Haas (St Anna Kinderspital, Vienna, Austria), Professor Dr W.-D. Ludwig (Rudolf Virchow Medical Center, Berlin, Germany), Dr G.J. Schuurhuis (Department of Hematology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands) and the Dutch Childhood Leukemia Study Group (The Hague, The Netherlands) for providing the AML-M5 samples. Finally, Dr R.G. Gorlick and Dr J.R. Bertino are acknowledged for re-analysing the samples and for helpful discussions during the preparation of this manuscript. This work was supported by the Dutch Cancer Society (grant VU 94-679).",

year = "2001",

doi = "10.1016/S0959-8049(00)00433-0",

language = "English",

volume = "37",

pages = "492--498",

journal = "European Journal of Cancer",

issn = "0959-8049",

publisher = "Elsevier Ltd.",

number = "4",

}

Rots, MG, Pieters, R, Jansen, G, Kaspers, GJL, Van Zantwijk, CH, Noordhuis, P, Voorn, DA, Van Wering, ER, Creutzig, U, Veerman, AJP & Peters, GJ 2001, 'A possible role for methotrexate in the treatment of childhood acute myeloid leukaemia, in particular for acute monocytic leukaemia', European Journal of Cancer, vol. 37, nr. 4, blz. 492-498. https://doi.org/10.1016/S0959-8049(00)00433-0

TY - JOUR

T1 - A possible role for methotrexate in the treatment of childhood acute myeloid leukaemia, in particular for acute monocytic leukaemia

AU - Rots, M. G.

AU - Pieters, R.

AU - Jansen, G.

AU - Kaspers, G. J.L.

AU - Van Zantwijk, C. H.

AU - Noordhuis, P.

AU - Voorn, D. A.

AU - Van Wering, E. R.

AU - Creutzig, U.

AU - Veerman, A. J.P.

AU - Peters, G. J.

N1 - Funding Information: The authors thank Professor Dr H. Gadner and Professor Dr O.A. Haas (St Anna Kinderspital, Vienna, Austria), Professor Dr W.-D. Ludwig (Rudolf Virchow Medical Center, Berlin, Germany), Dr G.J. Schuurhuis (Department of Hematology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands) and the Dutch Childhood Leukemia Study Group (The Hague, The Netherlands) for providing the AML-M5 samples. Finally, Dr R.G. Gorlick and Dr J.R. Bertino are acknowledged for re-analysing the samples and for helpful discussions during the preparation of this manuscript. This work was supported by the Dutch Cancer Society (grant VU 94-679).

PY - 2001

Y1 - 2001

N2 - Acute myeloid leukaemia (AML) is thought to be methotrexate (MTX)-resistant. However, a small study suggested that acute monocytic leukemia (AML-M5) is sensitive to MTX. We measured MTX accumulation/polyglutamylation in 20 AML-nonM5, 37 AML-M5 and 83 common/preB-acute lymphoblastic leukaemia (c/preB-ALL) samples. Membrane transport was determined in 11 childhood AMLs (including 3 AML-M5) and in 25 c/preB-ALL samples. MTX sensitivity was determined in 23 AML-nonM5, 15 AML-M5 and 63 common/preB-ALL samples using the thymidylate synthase (TS) inhibition assay. MTX transport was higher in AML samples compared with c/preB-ALL precluding a transport defect in AML. Accumulation of long-chain polyglutamates MTX-Glu4-6 was 3-fold lower for AML-nonM5 compared with c/preB-ALL cells (median 268 versus 889 pmol MTX-Glu4-6/109 cells; P ≤ 0.001); for AML-M5 samples, median accumulation of MTX-Glu4-6 was 0 pmol/109 cells (P ≤ 0.001). After short-term MTX exposure, AML-nonM5 was 6-fold more resistant to MTX compared with c/preB-ALL cells (2.16 versus 0.39 μM; P < 0.001), while AML-M5 was 2-fold more resistant (P = 0.02). In both AML-nonM5 and AML-M5 cells, MTX resistance was circumvented by continuous MTX exposure (median TSI50 values: 0.052 and 0.041 μM, respectively) compared with a c/preB-ALL value of 0.066 μM. In conclusion, AML-M5 is relatively sensitive to MTX compared with other AML-subtypes even though polyglutamylation of MTX is poor. Using continuous exposure, AML-nonM5 and AML-M5 cells were at least as sensitive to MTX as c/preB-ALL cells. This report suggests that MTX might be an overlooked drug in the treatment of childhood AML.

AB - Acute myeloid leukaemia (AML) is thought to be methotrexate (MTX)-resistant. However, a small study suggested that acute monocytic leukemia (AML-M5) is sensitive to MTX. We measured MTX accumulation/polyglutamylation in 20 AML-nonM5, 37 AML-M5 and 83 common/preB-acute lymphoblastic leukaemia (c/preB-ALL) samples. Membrane transport was determined in 11 childhood AMLs (including 3 AML-M5) and in 25 c/preB-ALL samples. MTX sensitivity was determined in 23 AML-nonM5, 15 AML-M5 and 63 common/preB-ALL samples using the thymidylate synthase (TS) inhibition assay. MTX transport was higher in AML samples compared with c/preB-ALL precluding a transport defect in AML. Accumulation of long-chain polyglutamates MTX-Glu4-6 was 3-fold lower for AML-nonM5 compared with c/preB-ALL cells (median 268 versus 889 pmol MTX-Glu4-6/109 cells; P ≤ 0.001); for AML-M5 samples, median accumulation of MTX-Glu4-6 was 0 pmol/109 cells (P ≤ 0.001). After short-term MTX exposure, AML-nonM5 was 6-fold more resistant to MTX compared with c/preB-ALL cells (2.16 versus 0.39 μM; P < 0.001), while AML-M5 was 2-fold more resistant (P = 0.02). In both AML-nonM5 and AML-M5 cells, MTX resistance was circumvented by continuous MTX exposure (median TSI50 values: 0.052 and 0.041 μM, respectively) compared with a c/preB-ALL value of 0.066 μM. In conclusion, AML-M5 is relatively sensitive to MTX compared with other AML-subtypes even though polyglutamylation of MTX is poor. Using continuous exposure, AML-nonM5 and AML-M5 cells were at least as sensitive to MTX as c/preB-ALL cells. This report suggests that MTX might be an overlooked drug in the treatment of childhood AML.

KW - Acute monocytic leukaemia

KW - Childhood acute myeloid leukaemia

KW - Methotrexate

KW - Polyglutamylation

KW - Reduced folate carrier

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U2 - 10.1016/S0959-8049(00)00433-0

DO - 10.1016/S0959-8049(00)00433-0

M3 - Article

C2 - 11267859

AN - SCOPUS:0035088009

SN - 0959-8049

VL - 37

SP - 492

EP - 498

JO - European Journal of Cancer

JF - European Journal of Cancer

IS - 4

ER -

A possible role for methotrexate in the treatment of childhood acute myeloid leukaemia, in particular for acute monocytic leukaemia

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