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GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study
Busulfan (BU) dose adjustment following therapeutic drug monitoring contributes to better outcome of hematopoietic stem cell transplantation (HSCT). Further improvement could be achieved through genotype-guided BU dose adjustments. To investigate this aspect, polymorphism within glutathione S transf...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710889/ https://www.ncbi.nlm.nih.gov/pubmed/29207608 http://dx.doi.org/10.18632/oncotarget.20310 |
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author | Ansari, Marc Curtis, Patricia Huezo-Diaz Uppugunduri, Chakradhara Rao S. Rezgui, Mohammed Aziz Nava, Tiago Mlakar, Vid Lesne, Laurence Théoret, Yves Chalandon, Yves Dupuis, Lee L. Schechter, Tao Bartelink, Imke H. Boelens, Jaap J. Bredius, Robbert Dalle, Jean-Hugues Azarnoush, Saba Sedlacek, Petr Lewis, Victor Champagne, Martin Peters, Christina Bittencourt, Henrique Krajinovic, Maja |
author_facet | Ansari, Marc Curtis, Patricia Huezo-Diaz Uppugunduri, Chakradhara Rao S. Rezgui, Mohammed Aziz Nava, Tiago Mlakar, Vid Lesne, Laurence Théoret, Yves Chalandon, Yves Dupuis, Lee L. Schechter, Tao Bartelink, Imke H. Boelens, Jaap J. Bredius, Robbert Dalle, Jean-Hugues Azarnoush, Saba Sedlacek, Petr Lewis, Victor Champagne, Martin Peters, Christina Bittencourt, Henrique Krajinovic, Maja |
author_sort | Ansari, Marc |
collection | PubMed |
description | Busulfan (BU) dose adjustment following therapeutic drug monitoring contributes to better outcome of hematopoietic stem cell transplantation (HSCT). Further improvement could be achieved through genotype-guided BU dose adjustments. To investigate this aspect, polymorphism within glutathione S transferase genes were assessed. Particularly, promoter haplotypes of the glutathione S transferase A1 (GSTA1) were evaluated in vitro, with reporter gene assays and clinically, in a pediatric multi-center study (N =138) through association with BU pharmacokinetics (PK) and clinical outcomes. Promoter activity significantly differed between the GSTA1 haplotypes (p<0.001) supporting their importance in capturing PK variability. Four GSTA1 diplotype groups that significantly correlated with clearance (p=0.009) were distinguished. Diplotypes underlying fast and slow metabolizing capacity showed higher and lower BU clearance (ml/min/kg), respectively. GSTA1 diplotypes with slow metabolizing capacity were associated with higher incidence of sinusoidal obstruction syndrome, acute graft versus host disease and combined treatment-related toxicity (p<0.0005). Among other GST genes investigated, GSTP1 313GG correlated with acute graft versus host disease grade 1-4 (p=0.01) and GSTM1 non-null genotype was associated with hemorrhagic cystitis (p=0.003). This study further strengthens the hypothesis that GST diplotypes/genotypes could be incorporated into already existing population pharmacokinetic models for improving first BU dose prediction and HSCT outcomes. (N(o) Clinicaltrials.gov identifier: NCT01257854. Registered 8 December 2010, retrospectively registered). |
format | Online Article Text |
id | pubmed-5710889 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-57108892017-12-04 GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study Ansari, Marc Curtis, Patricia Huezo-Diaz Uppugunduri, Chakradhara Rao S. Rezgui, Mohammed Aziz Nava, Tiago Mlakar, Vid Lesne, Laurence Théoret, Yves Chalandon, Yves Dupuis, Lee L. Schechter, Tao Bartelink, Imke H. Boelens, Jaap J. Bredius, Robbert Dalle, Jean-Hugues Azarnoush, Saba Sedlacek, Petr Lewis, Victor Champagne, Martin Peters, Christina Bittencourt, Henrique Krajinovic, Maja Oncotarget Research Paper Busulfan (BU) dose adjustment following therapeutic drug monitoring contributes to better outcome of hematopoietic stem cell transplantation (HSCT). Further improvement could be achieved through genotype-guided BU dose adjustments. To investigate this aspect, polymorphism within glutathione S transferase genes were assessed. Particularly, promoter haplotypes of the glutathione S transferase A1 (GSTA1) were evaluated in vitro, with reporter gene assays and clinically, in a pediatric multi-center study (N =138) through association with BU pharmacokinetics (PK) and clinical outcomes. Promoter activity significantly differed between the GSTA1 haplotypes (p<0.001) supporting their importance in capturing PK variability. Four GSTA1 diplotype groups that significantly correlated with clearance (p=0.009) were distinguished. Diplotypes underlying fast and slow metabolizing capacity showed higher and lower BU clearance (ml/min/kg), respectively. GSTA1 diplotypes with slow metabolizing capacity were associated with higher incidence of sinusoidal obstruction syndrome, acute graft versus host disease and combined treatment-related toxicity (p<0.0005). Among other GST genes investigated, GSTP1 313GG correlated with acute graft versus host disease grade 1-4 (p=0.01) and GSTM1 non-null genotype was associated with hemorrhagic cystitis (p=0.003). This study further strengthens the hypothesis that GST diplotypes/genotypes could be incorporated into already existing population pharmacokinetic models for improving first BU dose prediction and HSCT outcomes. (N(o) Clinicaltrials.gov identifier: NCT01257854. Registered 8 December 2010, retrospectively registered). Impact Journals LLC 2017-08-27 /pmc/articles/PMC5710889/ /pubmed/29207608 http://dx.doi.org/10.18632/oncotarget.20310 Text en Copyright: © 2017 Ansari et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Ansari, Marc Curtis, Patricia Huezo-Diaz Uppugunduri, Chakradhara Rao S. Rezgui, Mohammed Aziz Nava, Tiago Mlakar, Vid Lesne, Laurence Théoret, Yves Chalandon, Yves Dupuis, Lee L. Schechter, Tao Bartelink, Imke H. Boelens, Jaap J. Bredius, Robbert Dalle, Jean-Hugues Azarnoush, Saba Sedlacek, Petr Lewis, Victor Champagne, Martin Peters, Christina Bittencourt, Henrique Krajinovic, Maja GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study |
title | GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study |
title_full | GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study |
title_fullStr | GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study |
title_full_unstemmed | GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study |
title_short | GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study |
title_sort | gsta1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710889/ https://www.ncbi.nlm.nih.gov/pubmed/29207608 http://dx.doi.org/10.18632/oncotarget.20310 |
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