TY - JOUR
T1 - Methotrexate resistance in relapsed childhood acute lymphoblastic leukaemia
AU - Rots, Marianne G.
AU - Pieters, Rob
AU - Peters, Godefridus J.
AU - Noordhuis, Paul
AU - Van Zantwijk, Christina H.
AU - Henze, Günter
AU - Janka-Schaub, Gritta E.
AU - Veerman, Anjo J.P.
AU - Jansen, Gerrit
PY - 2000
Y1 - 2000
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 ≤ 0.01). [3H]-MTX membrane transport did not differ between eight rALL and 25 precursor-B ALL samples. Incubation for 24 h with 1 μM [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 ≤ 0.01). [3H]-MTX membrane transport did not differ between eight rALL and 25 precursor-B ALL samples. Incubation for 24 h with 1 μM [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 - Antifolates
KW - Drug resistance
KW - Polyglutamylation
KW - Reduced folate carrier
UR - http://www.scopus.com/inward/record.url?scp=0034051298&partnerID=8YFLogxK
U2 - 10.1046/j.1365-2141.2000.02071.x
DO - 10.1046/j.1365-2141.2000.02071.x
M3 - Article
C2 - 10886214
AN - SCOPUS:0034051298
SN - 0007-1048
VL - 109
SP - 629
EP - 634
JO - British Journal of Haematology
JF - British Journal of Haematology
IS - 3
ER -