title: Polymorphisms of the vincristine pathway and response to treatment in children with childhood acute lymphoblastic leukemia.
abstract: BACKGROUND
  Vincristine (VCR) is a standard component in the treatment of childhood acute lymphoblastic leukemia (ALL). VCR cytotoxicity is primarily due to its ability to disrupt the formation of microtubules of the mitotic spindle.
  
  
  METHODS
  Seventeen polymorphisms in regulatory and coding regions of genes controlling VCR targets (TUBB1, MAP4, ACTG1 and CAPG) or potentially influencing VCR levels (ABCB1 and CYP3A5) were investigated for an association with peripheral neuropathy and outcome in childhood ALL patients.
  
  
  RESULTS
  High-grade neurotoxicity was more frequent in carriers of the A allele of synonymous (Ala310) G to A (rs1135989) variation in the ACTG1 gene. Substitution (rs4728709) in the promoter of the ABCB1 gene had a protective effect against lower grade neurotoxicity and C to A variation (rs3770102) located 17 nucleotides upstream from the transcription start site had a protective effect against high-grade neurotoxicity. Patients with the ABCB1 3435TT genotype had lower event-free survival; the association with event-free survival was not supported by the analysis in the replication patient set.
  
  
  CONCLUSIONS
  The polymorphisms in the ACTG1, CAPG and ABCB1 genes may modulate VCR-related neurotoxicity, whereas the risk of relapse seems not to be affected by the genes of the VCR pathway.
authors.affiliation: Research Center, CHU Sainte-Justine, 3175 Chemin de la Côte-Ste-Catherine, Montréal, H3T 1C5, Québec, Canada.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ceppi
authors.forename: Chloé
authors.initials: C
authors.lastname: Langlois-Pelletier
authors.forename: Vincent
authors.initials: V
authors.lastname: Gagné
authors.forename: Julie
authors.initials: J
authors.lastname: Rousseau
authors.forename: Claire
authors.initials: C
authors.lastname: Ciolino
authors.forename: Samanta
authors.initials: S
authors.lastname: De Lorenzo
authors.forename: Kojok M
authors.initials: KM
authors.lastname: Kevin
authors.forename: Diana
authors.initials: D
authors.lastname: Cijov
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Silverman
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Daniel
authors.initials: D
authors.lastname: Sinnett
authors.forename: Caroline
authors.initials: C
authors.lastname: Laverdière
authors.forename: Maja
authors.initials: M
authors.lastname: Krajinovic
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000199:Actins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D014750:Vincristine / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: C513055:ABCB1 protein, human; C000594243:ACTG1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000199:Actins; D008840:Microfilament Proteins; D009687:Nuclear Proteins; C066575:CAPG protein, human; D014750:Vincristine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A
keywords: childhood leukemia; peripheral neurotoxicity; pharmacogenetics; polymorphisms; treatment outcome; vincristine
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