Pharmacogenomic studies of the anticancer and immunosuppressive thiopurines mercaptopurine and azathioprine.
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.
Hawwa
Ahmed F
AF
Clinical and Practice Research Group, School of Pharmacy, Medical Biology Centre, Queen's University Belfast, Belfast, UK.
Millership
Jeff S
JS
Collier
Paul S
PS
Vandenbroeck
Koen
K
McCarthy
Anthony
A
Dempsey
Sid
S
Cairns
Carole
C
Collins
John
J
Rodgers
Colin
C
McElnay
James C
JC
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
D000964:Antimetabolites, Antineoplastic; D006150:Guanine Nucleotides; D013873:Thionucleotides; C003964:6-thioguanylic acid; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine