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Pharmacogenomic studies of the anticancer and immunosuppressive thiopurines mercaptopurine and azathioprine.
- Source :
-
British journal of clinical pharmacology [Br J Clin Pharmacol] 2008 Oct; Vol. 66 (4), pp. 517-28. Date of Electronic Publication: 2008 Jun 28. - Publication Year :
- 2008
-
Abstract
- 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).<br />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.<br />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.
- Subjects :
- Adolescent
Antimetabolites, Antineoplastic immunology
Antimetabolites, Antineoplastic metabolism
Azathioprine immunology
Azathioprine metabolism
Child
Child, Preschool
Female
Gene Frequency genetics
Genotype
Guanine Nucleotides genetics
Guanine Nucleotides metabolism
Humans
Inflammatory Bowel Diseases enzymology
Male
Mercaptopurine immunology
Mercaptopurine metabolism
Methyltransferases immunology
Methyltransferases metabolism
Pharmacogenetics methods
Polymorphism, Genetic genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma enzymology
Thionucleotides metabolism
Treatment Outcome
Antimetabolites, Antineoplastic therapeutic use
Azathioprine therapeutic use
Inflammatory Bowel Diseases drug therapy
Mercaptopurine therapeutic use
Methyltransferases therapeutic use
Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1365-2125
- Volume :
- 66
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- British journal of clinical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 18662289
- Full Text :
- https://doi.org/10.1111/j.1365-2125.2008.03248.x