passage-195
abstract
Pharmacogenomic studies of the anticancer and immunosuppressive thiopurines mercaptopurine and azathioprine.  AIMS: 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.
entity-195-0
DISEASE
acute lymphoblastic leukaemia
entity-195-1
DISEASE
ALL
entity-195-2
DISEASE
inflammatory bowel disease
entity-195-3
DISEASE
IBD
entity-195-4
DISEASE
ALL
entity-195-5
DISEASE
IBD
entity-195-6
ADVERSE
myelotoxicity
entity-195-7
DISEASE
ALL
entity-195-8
DISEASE
IBD
entity-195-9
DISEASE
ALL
entity-195-10
DISEASE
ALL
entity-195-11
DISEASE
IBD
entity-195-12
DISEASE
ALL
entity-195-13
DISEASE
IBD
entity-195-14
ADVERSE
leucopenia
entity-195-15
ADVERSE
neutropenia
entity-195-16
DISEASE
ALL
entity-195-17
ADVERSE
thrombocytopenia