Pharmacogenomic studies of the anticancer and immunosuppressive thiopurines mercaptopurine and azathioprine.

Ahmed F. Hawwa, Jeff S. Millership, Paul S. Collier, Koen Vandenbroeck, Anthony McCarthy, Sid Dempsey, Carole Cairns, John Collins, Colin Rodgers, James C. McElnay

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79 Citations (Scopus)

Abstract

AIMS
To examine the allelic variation of three enzymes involved in 6-mercaptopurine/azathioprine (6-MP/AZA) metabolism and evaluate the in?uence of these polymorphisms on toxicity, haematological parameters and metabolite levels in patients with acute lymphoblastic leukaemia (ALL) or in?ammatory 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 signi?cantly higher concentrations of the active cytotoxic metabolites, 6-TGNs (P = 0.008 in ALL patients,P = 0.047 in IBD patients). The study con?rmed the association of thiopurine methyltransferase heterozygosity with leucopenia and neutropenia in ALL patients and reported a signi?cant 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.
Original languageEnglish
Pages (from-to)517-528
Number of pages12
JournalBritish Journal of Clinical Pharmacology
Volume66
Issue number4
Early online date28 Jun 2008
DOIs
Publication statusPublished - Oct 2008

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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    Hawwa, A. F., Millership, J. S., Collier, P. S., Vandenbroeck, K., McCarthy, A., Dempsey, S., Cairns, C., Collins, J., Rodgers, C., & McElnay, J. C. (2008). Pharmacogenomic studies of the anticancer and immunosuppressive thiopurines mercaptopurine and azathioprine. British Journal of Clinical Pharmacology, 66(4), 517-528. https://doi.org/10.1111/j.1365-2125.2008.03248.x