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Glutathione S-transferase gene variations influence BU pharmacokinetics and outcome of hematopoietic SCT in pediatric patients.
MedLine Citation:
PMID:  23292236     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
BU is a key compound of conditioning regimens in children undergoing hematopoietic SCT (HSCT). Inter-individual differences in BU pharmacokinetics (PKs) might affect BU efficacy and toxicity. As BU is mainly metabolized by glutathione S-transferase (GST), we investigated the relationship between GSTA1, GSTM1 and GSTP1 genotypes with first-dose BU PKs, and the relationship with HSCT outcomes in 69 children receiving myeloablative conditioning regimen. GSTM1 null genotype correlated with higher BU exposure and lower clearance in patients older than 4 years (P0.04). In accordance with the suggested functional role, GSTA1*A2 haplotype was associated with lower drug levels and higher drug clearance (P0.03). Gene-dosage effect was also observed (P0.007). GSTA1 haplotypes were associated with HSCT outcomes. Patients with two copies of haplotype *A2 had better event free survival (P=0.03). In contrast, homozygous individuals for haplotypes *B and *B1 had higher occurrence of veno-occlusive disease (P=0.009). GSTM1 null individuals older than 4 years had more frequently graft versus host disease (P=0.03). In conclusion, we showed that GST gene variants influence BU PK and outcomes of HSCT in children. A model for the dosage adjustment with the inclusion of genetic and non-genetic factors should be evaluated in a future prospective validation cohort.Bone Marrow Transplantation advance online publication, 7 January 2013; doi:10.1038/bmt.2012.265.
Authors:
M Ansari; M A Rezgui; Y Théoret; C R S Uppugunduri; S Mezziani; M-F Vachon; C Desjean; J Rousseau; M Labuda; C Przybyla; M Duval; M Champagne; C Peters; H Bittencourt; M Krajinovic
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-07
Journal Detail:
Title:  Bone marrow transplantation     Volume:  -     ISSN:  1476-5365     ISO Abbreviation:  Bone Marrow Transplant.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-7     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8702459     Medline TA:  Bone Marrow Transplant     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
1] Department of Pediatrics, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada [2] CANSEARCH Research Laboratory, Department of Pediatrics, Faculty of Medicine, Geneva, Switzerland [3] Department of Pediatrics, Onco-Hematology Unit, Geneva University Hospital, Geneva University, Geneva, Switzerland.
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