CYP2B6rs2279343 Is Associated with Improved Survival of Pediatric Rhabdomyosarcoma Treated with Cyclophosphamide

Abstract

BackgroundRhabdomyosarcoma (RMS) is a small round blue cell malignant tumor, representing 7% of childhood malignancies, and over 50% of all soft tissue sarcomas. Cyclophosphamide (CPA) is a prodrug and is the mainstay of RMS treatment. CYP2B6 is a highly polymorphic drug metabolizing enzyme involved in CPA bioactivation. The influence of CYP2B6 single nucleotide polymorphisms (SNPs) on the survival of RMS is still unknown.MethodsWe genotyped CYP2B6SNPs rs2279343, rs3745274, and rs3211371 by restriction fragment polymorphism (RFLP) after PCR amplification in a cohort of 73 pediatric RMS patients treated with CPA-based first line treatment. We then analyzed the association between those genotypes and survival outcome of RMS.ResultsThe frequencies of CYP2B6 rs2279343, rs3745274, and rs3211371 were 63%, 45.2%, and 5.5%, respectively. There was no association between rs3745274, rs3211371 genotypes and survival outcomes of RMS. However, the carriers of at least one mutant allele CYP2B6rs2279343 had significantly longer event-free survival (p-value = 0.03).ConclusionOur results demonstrated that CYP2B6 rs2279343 may predict EFS in RMS patients and warrants future studies to clarify the pharmacogenetics of CPA in pediatrics. If validated, integration of genetic factors with clinical and molecular characteristics could be used for a composite algorithm to better stratify risk prior to treatment.

Genetic Polymorphism of GSTP-1 Affects Cyclophosphamide Treatment of Autoimmune Diseases

“…The allelic frequencies of Q172H and K262R were 11% and 33% respectively. Earlier studies found similar frequencies both for K262R and Q172H [4,[12][13][14]. Allelic frequencies of the investigated GST genes were quite diverse, both variant and wild type alleles were abundant in all three cases ( Table 2).…”

Genetic polymorphisms effect on cyclophosphamide’s tolerability and clinical efficacy in Egyptian patients with lupus nephritis

“…The effect of genetic polymorphisms on CYC’s efficacy when it is used in combination with other chemotherapeutic agents was studied in another 2 studies and the results were CYP2B6 GT and TT are related to diminished effect to CYC and fludarabine in individuals with Leukemia, Lymphocytic, Persistent, B-Cell when contrasted with CYP2B6 GG [33]. The other study [34] concluded that the increased overall survival was not related to genotypes GT and TT after treatment with CYC, dactinomycin, and vincristine in children compared with genotype GG. Table 4 summarizes all tolerability/ toxicity-related parameters, about 44.5% of GG genotype patients developed multiple infections versus 42 and 13.5% in GT and TT genotype patients respectively and there was not any statistically significant difference between the different genotypes.…”

Effects of Genetic Polymorphisms of CYP2B6 on the Pharmacokinetics of Bupropion and Hydroxybupropion in Healthy Chinese Subjects

“…The low hepatic expressions of c.516G>T and c.785A>G SNPs observed in BUP reflected variable activities. Meanwhile, SNPs at positions 516 and 785 on the CYP2B6 gene are essential in the metabolism of several drugs [ 33 , 34 ]. CYP2B6 T516T was definitely related to plasma concentration, supporting its effect on lower pharmacokinetic parameters of BUP [ 33 ].…”

“…Although high plasma BUP levels were observed in CYP2B6*9 participants at all time-points, they were all well-tolerated within the therapeutic window and had no adverse effects. The functional impacts of CYP2B6 A785G are associated with the enhanced catalytic activation of hydroxylation [ 34 ], exhibiting rapidly metabolic activity. CYP2B6 catalyzed the hydroxylation of a diverse number of xenobiotics, and the metabolic activity in hydroxylation relied on SNPs [ 35 ].…”