title: Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia.
abstract: 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.
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: M A H
authors.initials: MA
authors.lastname: den Hoed
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Lopez-Lopez
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: M L
authors.initials: ML
authors.lastname: te Winkel
authors.affiliation: Department of Oncology/Hematology, University of Groningen, University Medical Center Groningen-Beatrix Children's Hospital, Groningen, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: Tissing
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: J D E
authors.initials: JD
authors.lastname: de Rooij
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Gutierrez-Camino
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Garcia-Orad
authors.affiliation: Department of Clinical Chemistry, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: den Boer
authors.affiliation: 1] Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands [2] Department of Pediatric Oncology/Hematology, Princess Maxima Center, Utrecht, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Pieters
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: S M F
authors.initials: SM
authors.lastname: Pluijm
authors.affiliation: Department of Clinical Chemistry, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: de Jonge
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: M M
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
mesh_terms: D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000627:therapeutic use*; D052016:Mucositis / Q000139:chemically induced* / Q000235:genetics*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics; D011446:Prospective Studies
chemical_list: D000964:Antimetabolites, Antineoplastic; D005492:Folic Acid; D008727:Methotrexate; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C073492:ABCC4 protein, human