title: Pharmacogenomic studies of the anticancer and immunosuppressive thiopurines mercaptopurine and azathioprine.
abstract: OBJECTIVE
  To examine the allelic variation of three enzymes involved in 6-mercaptopurine/azathioprine (6-MP/AZA) metabolism and evaluate the influence of these polymorphisms on toxicity, haematological parameters and metabolite levels in patients with acute lymphoblastic leukaemia (ALL) or inflammatory bowel disease (IBD).
  
  
  METHODS
  Clinical data and blood samples were collected from 19 ALL paediatric patients and 35 IBD patients who were receiving 6-MP/AZA therapy. All patients were screened for seven genetic polymorphisms in three enzymes involved in mercaptopurine metabolism [xanthine oxidase, inosine triphosphatase (C94-->A and IVS2+21A-->C) and thiopurine methyltransferase]. Erythrocyte and plasma metabolite concentrations were also determined. The associations between the various genotypes and myelotoxicity, haematological parameters and metabolite concentrations were determined.
  
  
  RESULTS
  Thiopurine methyltransferase variant alleles were associated with a preferential metabolism away from 6-methylmercaptopurine nucleotides (P = 0.008 in ALL patients, P = 0.038 in IBD patients) favouring 6-thioguanine nucleotides (6-TGNs) (P = 0.021 in ALL patients). Interestingly, carriers of inosine triphosphatase IVS2+21A-->C variants among ALL and IBD patients had significantly higher concentrations of the active cytotoxic metabolites, 6-TGNs (P = 0.008 in ALL patients, P = 0.047 in IBD patients). The study confirmed the association of thiopurine methyltransferase heterozygosity with leucopenia and neutropenia in ALL patients and reported a significant association between inosine triphosphatase IVS2+21A-->C variants with thrombocytopenia (P = 0.012). CONCLUSIONS; Pharmacogenetic polymorphisms in the 6-MP pathway may help identify patients at risk for associated toxicities and may serve as a guide for dose individualization.
authors.affiliation: Clinical and Practice Research Group, School of Pharmacy, Medical Biology Centre, Queen's University Belfast, Belfast, UK.
authors.forename: Ahmed F
authors.initials: AF
authors.lastname: Hawwa
authors.forename: Jeff S
authors.initials: JS
authors.lastname: Millership
authors.forename: Paul S
authors.initials: PS
authors.lastname: Collier
authors.forename: Koen
authors.initials: K
authors.lastname: Vandenbroeck
authors.forename: Anthony
authors.initials: A
authors.lastname: McCarthy
authors.forename: Sid
authors.initials: S
authors.lastname: Dempsey
authors.forename: Carole
authors.initials: C
authors.lastname: Cairns
authors.forename: John
authors.initials: J
authors.lastname: Collins
authors.forename: Colin
authors.initials: C
authors.lastname: Rodgers
authors.forename: James C
authors.initials: JC
authors.lastname: McElnay
mesh_terms: D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D001379:Azathioprine / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006150:Guanine Nucleotides / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D015122:Mercaptopurine / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D008780:Methyltransferases / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D010597:Pharmacogenetics / Q000379:methods; D011110:Polymorphism, Genetic / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology; D013873:Thionucleotides / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D006150:Guanine Nucleotides; D013873:Thionucleotides; C003964:6-thioguanylic acid; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine