Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia

Methotrexate (MTX) is an effective and toxic chemotherapeutic drug in the treatment of pediatric acute lymphoblastic leukemia(ALL). In this prospective study, we aimed to identify metabolic and genetic determinants of MTX toxicity. One hundred and thirty-four Dutch pediatric ALL patients were treate...

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Autores: den Hoed, M. A., López López, Elixabet, Te Winkel, M. L., Tissing, W., de Rooij, J. D., Gutiérrez Camino, Ángela, García-Orad Carles, África, den Boer, E., Pieters, R., Pluijm, S. M., de Jonge, R., van den Heuvel-Eibrink, Marry M.
Formato: artículo
Fecha de publicación:2014
País:España
Recursos:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/66694
Acesso em linha:http://hdl.handle.net/10810/66694
Access Level:acceso abierto
Palavra-chave:childhood acute lymphoblastic leukemia (ALL)
methotrexate toxicity
single nucleotide polymorphisms
pharmacogenetics
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spelling Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemiaden Hoed, M. A.López López, ElixabetTe Winkel, M. L.Tissing, W.de Rooij, J. D.Gutiérrez Camino, ÁngelaGarcía-Orad Carles, Áfricaden Boer, E.Pieters, R.Pluijm, S. M.de Jonge, R.van den Heuvel-Eibrink, Marry M.childhood acute lymphoblastic leukemia (ALL)methotrexate toxicitysingle nucleotide polymorphismspharmacogeneticsMethotrexate (MTX) is an effective and toxic chemotherapeutic drug in the treatment of pediatric acute lymphoblastic leukemia(ALL). In this prospective study, we aimed to identify metabolic and genetic determinants of MTX toxicity. One hundred and thirty-four Dutch pediatric ALL patients were treated with four high infusions MTX (HD-MTX: 5 g m(-2)) every other week according to the DCOG-ALL-10 protocol. Mucositis (National Cancer Institute grade ⩾ 3) was the most frequent occurring toxicity during the HD-MTX phase (20%) and occurred especially after the first MTX course. Mucositis was not associated with plasma MTX, plasma folate or plasma homocysteine levels. Patients with mucositis had higher erythrocyte folate levels at the start of protocol M than patients without mucositis (median 1.4 vs 1.2 μmol l(-1), P<0.008), this could reflect an increased MTX uptake in mucosal cells of patients with mucositis. From 17 single-nucleotide polymorphisms in the MTX pathway, only patients with the wild-type variant of rs7317112 SNP in the ABCC4 gene had more mucositis (AA (39%) vs AG/GG (15%), P=0.016). We found no evidence that erythrocyte folate levels mediate in the association between the rs7317112 and mucositis.This study was financially supported by Stichting Kinderen Kankervrij (KiKa errant, nr. 67) and an Erasmus MC translational grant (to EdB).Springer Nature202420242014info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/66694reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoIngléshttps://www.nature.com/articles/tpj201463info:eu-repo/semantics/openAccess© 2014, Macmillan Publishers Limitedoai:addi.ehu.eus:10810/666942026-06-18T09:23:17Z
dc.title.none.fl_str_mv Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia
title Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia
spellingShingle Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia
den Hoed, M. A.
childhood acute lymphoblastic leukemia (ALL)
methotrexate toxicity
single nucleotide polymorphisms
pharmacogenetics
title_short Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia
title_full Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia
title_fullStr Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia
title_full_unstemmed Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia
title_sort Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia
dc.creator.none.fl_str_mv den Hoed, M. A.
López López, Elixabet
Te Winkel, M. L.
Tissing, W.
de Rooij, J. D.
Gutiérrez Camino, Ángela
García-Orad Carles, África
den Boer, E.
Pieters, R.
Pluijm, S. M.
de Jonge, R.
van den Heuvel-Eibrink, Marry M.
author den Hoed, M. A.
author_facet den Hoed, M. A.
López López, Elixabet
Te Winkel, M. L.
Tissing, W.
de Rooij, J. D.
Gutiérrez Camino, Ángela
García-Orad Carles, África
den Boer, E.
Pieters, R.
Pluijm, S. M.
de Jonge, R.
van den Heuvel-Eibrink, Marry M.
author_role author
author2 López López, Elixabet
Te Winkel, M. L.
Tissing, W.
de Rooij, J. D.
Gutiérrez Camino, Ángela
García-Orad Carles, África
den Boer, E.
Pieters, R.
Pluijm, S. M.
de Jonge, R.
van den Heuvel-Eibrink, Marry M.
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv childhood acute lymphoblastic leukemia (ALL)
methotrexate toxicity
single nucleotide polymorphisms
pharmacogenetics
topic childhood acute lymphoblastic leukemia (ALL)
methotrexate toxicity
single nucleotide polymorphisms
pharmacogenetics
description Methotrexate (MTX) is an effective and toxic chemotherapeutic drug in the treatment of pediatric acute lymphoblastic leukemia(ALL). In this prospective study, we aimed to identify metabolic and genetic determinants of MTX toxicity. One hundred and thirty-four Dutch pediatric ALL patients were treated with four high infusions MTX (HD-MTX: 5 g m(-2)) every other week according to the DCOG-ALL-10 protocol. Mucositis (National Cancer Institute grade ⩾ 3) was the most frequent occurring toxicity during the HD-MTX phase (20%) and occurred especially after the first MTX course. Mucositis was not associated with plasma MTX, plasma folate or plasma homocysteine levels. Patients with mucositis had higher erythrocyte folate levels at the start of protocol M than patients without mucositis (median 1.4 vs 1.2 μmol l(-1), P<0.008), this could reflect an increased MTX uptake in mucosal cells of patients with mucositis. From 17 single-nucleotide polymorphisms in the MTX pathway, only patients with the wild-type variant of rs7317112 SNP in the ABCC4 gene had more mucositis (AA (39%) vs AG/GG (15%), P=0.016). We found no evidence that erythrocyte folate levels mediate in the association between the rs7317112 and mucositis.
publishDate 2014
dc.date.none.fl_str_mv 2014
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10810/66694
url http://hdl.handle.net/10810/66694
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://www.nature.com/articles/tpj201463
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
© 2014, Macmillan Publishers Limited
eu_rights_str_mv openAccess
rights_invalid_str_mv © 2014, Macmillan Publishers Limited
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv reponame:Addi. Archivo Digital para la Docencia y la Investigación
instname:Universidad del País Vasco
instname_str Universidad del País Vasco
reponame_str Addi. Archivo Digital para la Docencia y la Investigación
collection Addi. Archivo Digital para la Docencia y la Investigación
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301603

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