{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T03:23:45Z","timestamp":1773458625044,"version":"3.50.1"},"reference-count":38,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2001,12,24]],"date-time":"2001-12-24T00:00:00Z","timestamp":1009152000000},"content-version":"vor","delay-in-days":571,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Br J Haematol"],"published-print":{"date-parts":[[2000,6]]},"abstract":"<jats:p>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 <jats:italic>ex vivo<\/jats:italic> MTX resistance in precursor\u2010B ALL at relapse (rALL) and determined possible defects in MTX membrane transport and polyglutamylation. Using the <jats:italic>in situ<\/jats:italic> thymidylate synthase inhibition assay, 21 rALL samples were threefold more MTX resistant than 63 initial precursor\u2010B ALL samples, both after short\u2010term and after continuous MTX exposure (<jats:italic>P<\/jats:italic>\u2003\u2264\u20030\u00b701). [<jats:sup>3<\/jats:sup>H]\u2010MTX membrane transport did not differ between eight rALL and 25 precursor\u2010B ALL samples. Incubation for 24\u2003h with 1\u2003\u00b5<jats:sc>m<\/jats:sc>[<jats:sup>3<\/jats:sup>H]\u2010MTX resulted in a trend towards a lower accumulation of MTX in 20 relapsed than in 83 initial samples of precursor\u2010B ALL samples (906 vs. 1364\u2003pmol\/10<jats:sup>9<\/jats:sup> cells; <jats:italic>P<\/jats:italic>\u2003=\u20030\u00b707). Accumulation of long\u2010chain MTX polyglutamates (MTX\u2010Glu<jats:sub>4\u22126<\/jats:sub>) did not differ between relapsed and newly diagnosed samples (746 and 889\u2003pmol\/10<jats:sup>9<\/jats:sup> cells; <jats:italic>P<\/jats:italic>\u2003=\u20030\u00b71). Activities of the enzymes involved in polyglutamylation (folylpolyglutamate synthetase and folylpolyglutamate hydrolase) did not differ between rALL and untreated c\/pre\u2010B\u2010ALL. This study demonstrates that leukaemic cells of children with relapsed precursor\u2010B ALL are relatively MTX resistant, but that this MTX resistance is not associated with major impairments in MTX uptake or polyglutamylation.<\/jats:p>","DOI":"10.1046\/j.1365-2141.2000.02071.x","type":"journal-article","created":{"date-parts":[[2003,3,11]],"date-time":"2003-03-11T06:24:24Z","timestamp":1047363864000},"page":"629-634","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Methotrexate resistance in relapsed childhood acute lymphoblastic leukaemia"],"prefix":"10.1111","volume":"109","author":[{"given":"Marianne G.","family":"Rots","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rob","family":"Pieters","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Godefridus J.","family":"Peters","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Noordhuis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina H.","family":"Van Zantwijk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G\u00fcnter","family":"Henze","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gritta E.","family":"Janka\u2010Schaub","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anjo J. 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