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Genetic polymorphism of CYP3A4 is associated with poor response to ifosfamide treatment in children with solid embryonic tumors
INTRODUCTION: The CYP450 complex participates in the metabolism of ifosfamide, an antineoplastic drug used to treat solid tumors. CYP450 genes contain several single nucleotide polymorphisms (SNPs) that confer different activity towards the enzyme. The aim of our study was to analyze gene frequencie...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Termedia Publishing House
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8641500/ https://www.ncbi.nlm.nih.gov/pubmed/34900058 http://dx.doi.org/10.5114/aoms.2019.86648 |
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author | Espindola, Luz María Torres López, Manuel De JesÚs Castillejos Flores, Armando De Uña Espinosa, Liliana Rivera Granados, Julio Pacheco, Juan Luis Chávez García, Martín Pérez Cervantes, Ma Teresa Ramos Méndez, Vilma Carolina Bekker Doño, Susana Hernández Ruíz Gómez, Daniela |
author_facet | Espindola, Luz María Torres López, Manuel De JesÚs Castillejos Flores, Armando De Uña Espinosa, Liliana Rivera Granados, Julio Pacheco, Juan Luis Chávez García, Martín Pérez Cervantes, Ma Teresa Ramos Méndez, Vilma Carolina Bekker Doño, Susana Hernández Ruíz Gómez, Daniela |
author_sort | Espindola, Luz María Torres |
collection | PubMed |
description | INTRODUCTION: The CYP450 complex participates in the metabolism of ifosfamide, an antineoplastic drug used to treat solid tumors. CYP450 genes contain several single nucleotide polymorphisms (SNPs) that confer different activity towards the enzyme. The aim of our study was to analyze gene frequencies of allelic variants and their association with ifosfamide blood levels and patient prognosis. MATERIAL AND METHODS: 148 DNA samples from children were analyzed. Genotyping was performed by real-time PCR with TaqMan probes and ifosfamide levels were determined in dried blood drop by UPLCMS/MS. RESULTS: Ifosfamide levels increased according to the genotype, and patients with the variant rs1799853 in CYP2C9 genotype CC had lower levels of ifosfamide (median = 1.8 μmol/l, Q(25) 0.9–Q(75) 4.6) compared with patients with genotype TT + CT (median = 2.8 μmol/l, Q(25) 1.9–Q(75) 5.1), p < 0.001. In the case of the rs2740574 variant in the CYP3A4 gene, patients with normal genotype (TT) presented median = 1.4 μmol/l, (Q(25) 0.7–Q(75) 2.7), while patients with the CC + TC genotype had higher levels of ifosfamide (median = 2.0 μmol/l, Q(25) 1.0–Q(75) 4.3), p = 0.024. In addition, patients with CC + CT genotype of this variant had a higher risk of non-response to treatment compared to patients with TT genotype (RR = 1.3, 95% CI: 1.07–1.59, p = 0.03). CONCLUSIONS: Polymorphisms in CYP2C9 and CYP3A4 genes are associated with high levels of ifosfamide. In addition, the polymorphism rs2740574 in CYP3A4 was associated with a worse therapeutic response. |
format | Online Article Text |
id | pubmed-8641500 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Termedia Publishing House |
record_format | MEDLINE/PubMed |
spelling | pubmed-86415002021-12-09 Genetic polymorphism of CYP3A4 is associated with poor response to ifosfamide treatment in children with solid embryonic tumors Espindola, Luz María Torres López, Manuel De JesÚs Castillejos Flores, Armando De Uña Espinosa, Liliana Rivera Granados, Julio Pacheco, Juan Luis Chávez García, Martín Pérez Cervantes, Ma Teresa Ramos Méndez, Vilma Carolina Bekker Doño, Susana Hernández Ruíz Gómez, Daniela Arch Med Sci Basic Research INTRODUCTION: The CYP450 complex participates in the metabolism of ifosfamide, an antineoplastic drug used to treat solid tumors. CYP450 genes contain several single nucleotide polymorphisms (SNPs) that confer different activity towards the enzyme. The aim of our study was to analyze gene frequencies of allelic variants and their association with ifosfamide blood levels and patient prognosis. MATERIAL AND METHODS: 148 DNA samples from children were analyzed. Genotyping was performed by real-time PCR with TaqMan probes and ifosfamide levels were determined in dried blood drop by UPLCMS/MS. RESULTS: Ifosfamide levels increased according to the genotype, and patients with the variant rs1799853 in CYP2C9 genotype CC had lower levels of ifosfamide (median = 1.8 μmol/l, Q(25) 0.9–Q(75) 4.6) compared with patients with genotype TT + CT (median = 2.8 μmol/l, Q(25) 1.9–Q(75) 5.1), p < 0.001. In the case of the rs2740574 variant in the CYP3A4 gene, patients with normal genotype (TT) presented median = 1.4 μmol/l, (Q(25) 0.7–Q(75) 2.7), while patients with the CC + TC genotype had higher levels of ifosfamide (median = 2.0 μmol/l, Q(25) 1.0–Q(75) 4.3), p = 0.024. In addition, patients with CC + CT genotype of this variant had a higher risk of non-response to treatment compared to patients with TT genotype (RR = 1.3, 95% CI: 1.07–1.59, p = 0.03). CONCLUSIONS: Polymorphisms in CYP2C9 and CYP3A4 genes are associated with high levels of ifosfamide. In addition, the polymorphism rs2740574 in CYP3A4 was associated with a worse therapeutic response. Termedia Publishing House 2019-07-17 /pmc/articles/PMC8641500/ /pubmed/34900058 http://dx.doi.org/10.5114/aoms.2019.86648 Text en Copyright: © 2019 Termedia & Banach https://creativecommons.org/licenses/by-nc-sa/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license. |
spellingShingle | Basic Research Espindola, Luz María Torres López, Manuel De JesÚs Castillejos Flores, Armando De Uña Espinosa, Liliana Rivera Granados, Julio Pacheco, Juan Luis Chávez García, Martín Pérez Cervantes, Ma Teresa Ramos Méndez, Vilma Carolina Bekker Doño, Susana Hernández Ruíz Gómez, Daniela Genetic polymorphism of CYP3A4 is associated with poor response to ifosfamide treatment in children with solid embryonic tumors |
title | Genetic polymorphism of CYP3A4 is associated with poor response to ifosfamide treatment in children with solid embryonic tumors |
title_full | Genetic polymorphism of CYP3A4 is associated with poor response to ifosfamide treatment in children with solid embryonic tumors |
title_fullStr | Genetic polymorphism of CYP3A4 is associated with poor response to ifosfamide treatment in children with solid embryonic tumors |
title_full_unstemmed | Genetic polymorphism of CYP3A4 is associated with poor response to ifosfamide treatment in children with solid embryonic tumors |
title_short | Genetic polymorphism of CYP3A4 is associated with poor response to ifosfamide treatment in children with solid embryonic tumors |
title_sort | genetic polymorphism of cyp3a4 is associated with poor response to ifosfamide treatment in children with solid embryonic tumors |
topic | Basic Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8641500/ https://www.ncbi.nlm.nih.gov/pubmed/34900058 http://dx.doi.org/10.5114/aoms.2019.86648 |
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