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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
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).
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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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