Open AccessGenetic polymorphism of CYP3A4 is associated with poor response to ifosfamide treatment in children with solid embryonic tumors
Author(s) -
Luz María Torres Espindola,
Manuel de Jesús Castillejos Lόpez,
Armando De Uña Flores,
Liliana Rivera Espinosa,
Julio Granados,
Juan Luis Chávez Pacheco,
Martín Pérez García,
Ma Teresa Ramos Cervantes,
Carolina Bekker-Méndez,
Susana Hernández Doño,
Daniela Ruíz-Gómez
Publication year - 2019
Publication title -
archives of medical science/archives of medical science (online)
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 46
eISSN - 1896-9151
pISSN - 1734-1922
DOI - 10.5114/aoms.2019.86648
Subject(s) - ifosfamide , genotype , medicine , single nucleotide polymorphism , genotyping , cyp3a4 , cyp2d6 , taqman , gastroenterology , pharmacology , genetics , gene , biology , chemotherapy , polymerase chain reaction , cytochrome p450 , metabolism , etoposide
The CYP450 complex participates in the metabolism of ifosfamide, an antineoplastic drug used to treat solid tumors. 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, Q25 0.9–Q75 4.6) compared with patients with genotype TT + CT (median = 2.8 µmol/l, Q25 1.9–Q75 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, (Q25 0.7–Q75 2.7), while patients with the CC + TC genotype had higher levels of ifosfamide (median = 2.0 µmol/l, Q25 1.0–Q75 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.