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

Abstract

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 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.

The rs776746 variant of CYP3A5 is associated with intravenous midazolam plasma levels and higher clearance in critically ill Mexican paediatric patients

“…The functional significance of the rs2740574 variant in CYP3A4 suggests that CYP3A4*1B does not affect the metabolism and elimination of CYP3A4 substrates, [13][14][15][16][17][18] but the rs2740574 variant has been found to be associated with high levels of ifosfamide and a worse therapeutic response in children with solid embryonal tumours. 19 Regarding the role of this variant in the pharmacokinetic parameters of midazolam, a clear association between the parameters and the variant in CYP3A4 has also not been found, 18,20,21 and similar results were observed in this cohort of critically ill patients.…”

“…Studies in the literature have shown that wide variation in the expression and activity of CYP3A isoforms in humans, which is reflected in large inter‐individual differences in the metabolism and clearance of CYP3A substrates such as midazolam. The functional significance of the rs2740574 variant in CYP3A4 suggests that CYP3A4*1B does not affect the metabolism and elimination of CYP3A4 substrates, 13‐18 but the rs2740574 variant has been found to be associated with high levels of ifosfamide and a worse therapeutic response in children with solid embryonal tumours 19 …”

Interplay of Vitamin D and CYP3A4 Polymorphisms in Endocrine Disorders and Cancer

“…A prostate cancer prevention trial revealed that finasteride, an anticancer drug, showed altered concentrations due to the CYP3A4*1G polymorphism [ 74 ]. A recent study on ifosfamide treatment in children with solid embryonic tumors identified associations of drug treatment among CYP polymorph individuals, and found that detrimental therapeutic failure was associated with the rs2740574 polymorphism in CYP3A4 [ 108 ]. As CYP3A4 is not merely involved in vitamin D metabolism, its involvement in other aspects (including drug metabolism) needs to be meticulously examined to improve pharmacotherapy.…”

Sex and Age Influence on Association of CYP450 Polymorphism with Midazolam Levels in Critically Ill Children

“…Although it has been proposed that sex differences in the activity of CYP3A4 exist [ 14 , 15 ], current evidence supporting this is limited, non-existent [ 16 ], or contradictory [ 17 ]. In previous studies of our group, the allelic variants of the CYP450 genes (nine probes in the CYP2B6, CYP2C9, CYP3A4, and CYP3A5 genes) have been analyzed, and an association of toxicity and response to treatment was reported in patients with solid tumors with the allelic CYP3A4 and CYP3A5 variants [ 18 , 19 ], so it was decided to explore them in a cohort of critically ill pediatric patients. Due to the reasons stated before, the aim of the present study was to determine the sex and age influence on association of CYP450 polymorphism with midazolam levels in critically ill children.…”