Genetic polymorphism of CYP3A4 is associated with poor response to ifosfamide treatment in children with solid embryonic tumors

Luz María Torres Espindola, Manuel De JesÚs Castillejos López, Armando De Uña Flores, Liliana Rivera Espinosa, Julio Granados, Juan Luis Chávez Pacheco, Martín Pérez García, Ma Teresa Ramos Cervantes, Vilma Carolina Bekker Méndez, Susana Hernández Doño, Daniela Ruíz Gómez
2019 Archives of Medical Science  
A b s t r a c t Introduction: 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
more » ... ng 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.
doi:10.5114/aoms.2019.86648 fatcat:6pqzqgbpsrbkhfsflk4s3ditva