title: Vincristine pharmacokinetics pathway and neurotoxicity during early phases of treatment in pediatric acute lymphoblastic leukemia.
abstract: Vincristine is an important component of acute lymphoblastic leukemia (ALL) treatment protocols that can cause neurotoxicity. Patients treated with LAL/SHOP protocols often suffer from vincristine-related neurotoxicity in early phases of treatment. Recently, a genome-wide association study connected a SNP in CEP72, involved in vincristine pharmacodynamics, with neurotoxicity during later phases of therapy, which was not replicated during induction phase. These results, together with previous studies indicating that polymorphisms in pharmacokinetic genes are associated with drug toxicity, suggest that changes in the activity or levels of vincristine transporters or metabolizers could work as predictors of vincristine-related neurotoxicity in early phases of treatment in pediatric ALL.
  
  
  
  We analyzed 150 SNPs in eight key genes involved in vincristine pharmacokinetics and in 13 miRNAs that regulate them. We studied their correlation with neurotoxicity during induction phase in 152 ALL patients treated with LAL/SHOP protocols.
  
  
  
  The strongest associations with neurotoxicity were observed for two SNPs in ABCC2. The genotypes rs3740066 GG and rs12826 GG were associated with increased neurotoxicity.
  
  
  
  Polymorphisms in ABCC2 could be novel markers for vincristine-related neurotoxicity in pediatric ALL in early phases.
authors.affiliation: Department of Genetics, Physical Anthropology & Animal Physiology, Faculty of Medicine & Odontology, University of the Basque Country (UPV/EHU), Leioa, Spain.
authors.forename: Elixabet
authors.initials: E
authors.lastname: Lopez-Lopez
authors.affiliation: Department of Genetics, Physical Anthropology & Animal Physiology, Faculty of Medicine & Odontology, University of the Basque Country (UPV/EHU), Leioa, Spain.
authors.forename: Angela
authors.initials: A
authors.lastname: Gutierrez-Camino
authors.affiliation: Unit of Pediatric Hematology/Oncology, University Hospital Cruces, Bilbao, Spain.
authors.forename: Itziar
authors.initials: I
authors.lastname: Astigarraga
authors.affiliation: Unit of Pediatric Hematology/Oncology, University Hospital Cruces, Bilbao, Spain.
authors.forename: Aurora
authors.initials: A
authors.lastname: Navajas
authors.affiliation: Unit of Pediatric Hematology/Oncology, University Hospital Cruces, Bilbao, Spain.
authors.forename: Aizpea
authors.initials: A
authors.lastname: Echebarria-Barona
authors.affiliation: Service of Pediatric Oncohematology, University Hospital La Paz, Madrid, Spain.
authors.forename: Purificacion
authors.initials: P
authors.lastname: Garcia-Miguel
authors.affiliation: Unit of Pediatric Oncohematology, University Hospital Donostia, San Sebastian, Spain.
authors.forename: Nagore
authors.initials: N
authors.lastname: Garcia de Andoin
authors.affiliation: Department of Anatomic Pathology, University Hospital Donostia, Donostia, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Lobo
authors.affiliation: Department of Pathology, University Hospital of Araba, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Guerra-Merino
authors.affiliation: Department of Genetics, Physical Anthropology & Animal Physiology, Faculty of Medicine & Odontology, University of the Basque Country (UPV/EHU), Leioa, Spain.
authors.forename: Idoia
authors.initials: I
authors.lastname: Martin-Guerrero
authors.affiliation: Department of Genetics, Physical Anthropology & Animal Physiology, Faculty of Medicine & Odontology, University of the Basque Country (UPV/EHU), Leioa, Spain.|BioCruces Health Research Institute, Barakaldo, Spain.
authors.forename: Africa
authors.initials: A
authors.lastname: Garcia-Orad
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism*; D020258:Neurotoxicity Syndromes / Q000209:etiology; D000071185:Pharmacogenomic Testing; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D012189:Retrospective Studies; D014750:Vincristine / Q000009:adverse effects* / Q000493:pharmacokinetics*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000972:Antineoplastic Agents, Phytogenic; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014750:Vincristine; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; C542475:CEP72 protein, human; C421109:multidrug resistance-associated protein 1
keywords: acute lymphoblastic leukemia; neurotoxicity; pharmacokinetics; polymorphism; vincristine