Methotrexate resistance in relapsed childhood acute lymphoblastic leukaemia

M G Rots, R Pieters, G J Peters, P Noordhuis, C H Van Zantwijk, G Henze, G E Janka-Schaub, A J Veerman, G Jansen

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Treatment failure in childhood acute lymphoblastic leukaemia (ALL) might be associated with methotrexate (MTX) resistance. Little is known about MTX resistance in relapsed ALL. In this study, we determined ex vivo MTX resistance in precursor-B ALL at relapse (rALL) and determined possible defects in MTX membrane transport and polyglutamylation. Using the in situ thymidylate synthase inhibition assay, 21 rALL samples were threefold more MTX resistant than 63 initial precursor-B ALL samples, both after short-term and after continuous MTX exposure (P < or = 0.01). [3H]-MTX membrane transport did not differ between eight rALL and 25 precursor-B ALL samples. Incubation for 24 h with 1 microM [3H]-MTX resulted in a trend towards a lower accumulation of MTX in 20 relapsed than in 83 initial samples of precursor-B ALL samples (906 vs. 1364 pmol/109 cells; P = 0.07). Accumulation of long-chain MTX polyglutamates (MTX-Glu4-6) did not differ between relapsed and newly diagnosed samples (746 and 889 pmol/109 cells; P = 0.1). Activities of the enzymes involved in polyglutamylation (folylpolyglutamate synthetase and folylpolyglutamate hydrolase) did not differ between rALL and untreated c/pre-B-ALL. This study demonstrates that leukaemic cells of children with relapsed precursor-B ALL are relatively MTX resistant, but that this MTX resistance is not associated with major impairments in MTX uptake or polyglutamylation.

Original languageEnglish
Pages (from-to)629-34
Number of pages6
JournalBritish Journal of Haematology
Volume109
Issue number3
Publication statusPublished - Jun 2000

Cite this

Rots, M. G., Pieters, R., Peters, G. J., Noordhuis, P., Van Zantwijk, C. H., Henze, G., ... Jansen, G. (2000). Methotrexate resistance in relapsed childhood acute lymphoblastic leukaemia. British Journal of Haematology, 109(3), 629-34.
Rots, M G ; Pieters, R ; Peters, G J ; Noordhuis, P ; Van Zantwijk, C H ; Henze, G ; Janka-Schaub, G E ; Veerman, A J ; Jansen, G. / Methotrexate resistance in relapsed childhood acute lymphoblastic leukaemia. In: British Journal of Haematology. 2000 ; Vol. 109, No. 3. pp. 629-34.
@article{cfd0824f7e9a4e5f960b6a4aa67851cd,
title = "Methotrexate resistance in relapsed childhood acute lymphoblastic leukaemia",
abstract = "Treatment failure in childhood acute lymphoblastic leukaemia (ALL) might be associated with methotrexate (MTX) resistance. Little is known about MTX resistance in relapsed ALL. In this study, we determined ex vivo MTX resistance in precursor-B ALL at relapse (rALL) and determined possible defects in MTX membrane transport and polyglutamylation. Using the in situ thymidylate synthase inhibition assay, 21 rALL samples were threefold more MTX resistant than 63 initial precursor-B ALL samples, both after short-term and after continuous MTX exposure (P < or = 0.01). [3H]-MTX membrane transport did not differ between eight rALL and 25 precursor-B ALL samples. Incubation for 24 h with 1 microM [3H]-MTX resulted in a trend towards a lower accumulation of MTX in 20 relapsed than in 83 initial samples of precursor-B ALL samples (906 vs. 1364 pmol/109 cells; P = 0.07). Accumulation of long-chain MTX polyglutamates (MTX-Glu4-6) did not differ between relapsed and newly diagnosed samples (746 and 889 pmol/109 cells; P = 0.1). Activities of the enzymes involved in polyglutamylation (folylpolyglutamate synthetase and folylpolyglutamate hydrolase) did not differ between rALL and untreated c/pre-B-ALL. This study demonstrates that leukaemic cells of children with relapsed precursor-B ALL are relatively MTX resistant, but that this MTX resistance is not associated with major impairments in MTX uptake or polyglutamylation.",
keywords = "B-Lymphocytes/drug effects, Biological Transport, Cell Membrane/metabolism, Drug Resistance, Neoplasm, Humans, Methotrexate/pharmacology, Neoplastic Stem Cells/drug effects, Peptide Synthases/metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Recurrence, Thymidylate Synthase/metabolism, Tumor Cells, Cultured, gamma-Glutamyl Hydrolase/metabolism",
author = "Rots, {M G} and R Pieters and Peters, {G J} and P Noordhuis and {Van Zantwijk}, {C H} and G Henze and Janka-Schaub, {G E} and Veerman, {A J} and G Jansen",
year = "2000",
month = "6",
language = "English",
volume = "109",
pages = "629--34",
journal = "British Journal of Haematology",
issn = "0007-1048",
publisher = "Wiley-Blackwell",
number = "3",

}

Rots, MG, Pieters, R, Peters, GJ, Noordhuis, P, Van Zantwijk, CH, Henze, G, Janka-Schaub, GE, Veerman, AJ & Jansen, G 2000, 'Methotrexate resistance in relapsed childhood acute lymphoblastic leukaemia' British Journal of Haematology, vol. 109, no. 3, pp. 629-34.

Methotrexate resistance in relapsed childhood acute lymphoblastic leukaemia. / Rots, M G; Pieters, R; Peters, G J; Noordhuis, P; Van Zantwijk, C H; Henze, G; Janka-Schaub, G E; Veerman, A J; Jansen, G.

In: British Journal of Haematology, Vol. 109, No. 3, 06.2000, p. 629-34.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Methotrexate resistance in relapsed childhood acute lymphoblastic leukaemia

AU - Rots, M G

AU - Pieters, R

AU - Peters, G J

AU - Noordhuis, P

AU - Van Zantwijk, C H

AU - Henze, G

AU - Janka-Schaub, G E

AU - Veerman, A J

AU - Jansen, G

PY - 2000/6

Y1 - 2000/6

N2 - Treatment failure in childhood acute lymphoblastic leukaemia (ALL) might be associated with methotrexate (MTX) resistance. Little is known about MTX resistance in relapsed ALL. In this study, we determined ex vivo MTX resistance in precursor-B ALL at relapse (rALL) and determined possible defects in MTX membrane transport and polyglutamylation. Using the in situ thymidylate synthase inhibition assay, 21 rALL samples were threefold more MTX resistant than 63 initial precursor-B ALL samples, both after short-term and after continuous MTX exposure (P < or = 0.01). [3H]-MTX membrane transport did not differ between eight rALL and 25 precursor-B ALL samples. Incubation for 24 h with 1 microM [3H]-MTX resulted in a trend towards a lower accumulation of MTX in 20 relapsed than in 83 initial samples of precursor-B ALL samples (906 vs. 1364 pmol/109 cells; P = 0.07). Accumulation of long-chain MTX polyglutamates (MTX-Glu4-6) did not differ between relapsed and newly diagnosed samples (746 and 889 pmol/109 cells; P = 0.1). Activities of the enzymes involved in polyglutamylation (folylpolyglutamate synthetase and folylpolyglutamate hydrolase) did not differ between rALL and untreated c/pre-B-ALL. This study demonstrates that leukaemic cells of children with relapsed precursor-B ALL are relatively MTX resistant, but that this MTX resistance is not associated with major impairments in MTX uptake or polyglutamylation.

AB - Treatment failure in childhood acute lymphoblastic leukaemia (ALL) might be associated with methotrexate (MTX) resistance. Little is known about MTX resistance in relapsed ALL. In this study, we determined ex vivo MTX resistance in precursor-B ALL at relapse (rALL) and determined possible defects in MTX membrane transport and polyglutamylation. Using the in situ thymidylate synthase inhibition assay, 21 rALL samples were threefold more MTX resistant than 63 initial precursor-B ALL samples, both after short-term and after continuous MTX exposure (P < or = 0.01). [3H]-MTX membrane transport did not differ between eight rALL and 25 precursor-B ALL samples. Incubation for 24 h with 1 microM [3H]-MTX resulted in a trend towards a lower accumulation of MTX in 20 relapsed than in 83 initial samples of precursor-B ALL samples (906 vs. 1364 pmol/109 cells; P = 0.07). Accumulation of long-chain MTX polyglutamates (MTX-Glu4-6) did not differ between relapsed and newly diagnosed samples (746 and 889 pmol/109 cells; P = 0.1). Activities of the enzymes involved in polyglutamylation (folylpolyglutamate synthetase and folylpolyglutamate hydrolase) did not differ between rALL and untreated c/pre-B-ALL. This study demonstrates that leukaemic cells of children with relapsed precursor-B ALL are relatively MTX resistant, but that this MTX resistance is not associated with major impairments in MTX uptake or polyglutamylation.

KW - B-Lymphocytes/drug effects

KW - Biological Transport

KW - Cell Membrane/metabolism

KW - Drug Resistance, Neoplasm

KW - Humans

KW - Methotrexate/pharmacology

KW - Neoplastic Stem Cells/drug effects

KW - Peptide Synthases/metabolism

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma

KW - Recurrence

KW - Thymidylate Synthase/metabolism

KW - Tumor Cells, Cultured

KW - gamma-Glutamyl Hydrolase/metabolism

M3 - Article

VL - 109

SP - 629

EP - 634

JO - British Journal of Haematology

JF - British Journal of Haematology

SN - 0007-1048

IS - 3

ER -

Rots MG, Pieters R, Peters GJ, Noordhuis P, Van Zantwijk CH, Henze G et al. Methotrexate resistance in relapsed childhood acute lymphoblastic leukaemia. British Journal of Haematology. 2000 Jun;109(3):629-34.