PDF(Pubmed)
Abstract：
UNASSIGNED: Imatinib mesylate (IM) is a reliable first line treatment for chronic myeloid leukaemia (CML). Nevertheless, despite promising results, a considerable proportion of patients develop resistance to the drug. Cytochrome P450 (CYP) enzymes play a crucial role in IM metabolism. Thus, point mutations in CYP genes may modify IM enzyme activity resulting in insufficient treatment response. This investigation was aimed to identify the functional impact of CYP3A5*3, CYP3A4*18 and CYP2B6*6 polymorphisms on the IM response in patients with CML in Azerbaijan.
UNASSIGNED: Genotyping of CYP3A5*3, CYP3A4*18 and CYP2B6*6 was performed in 153 patients (102 IM non-responders and 51 IM responders) with CML by the PCR-restriction fragment length polymorphism (RFLP) assays. The odds ratios (ORs) with 95 per cent confidence intervals (CIs) were applied to assess the association between allelic variants and IM therapy outcome. The results were validated by sequencing.
UNASSIGNED: The frequency of the CYP3A4*18 allele was considerably lower in the responder\'s group (97.1 vs. 100%; P=0.036). For CYP3A5*3, the allelic frequency was slightly higher among the IM responders (100 vs. 99.02%) with no significant difference. Although patients heterozygous (TC) for CYP2B6*6 demonstrated a higher risk of acquiring resistance (OR 1.04; 95% CI: 0.492-2.218), differences were not significant (P=0.909). In addition, the homozygous genotype (TT) demonstrated a lower risk of unresponsiveness (OR 0.72; 95% CI: 0.283-1.836), but associations were not significant (P=0.491).
UNASSIGNED: Our results demonstrated that CYP3A4*18 was significantly associated with IM treatment response in patients with CML in Azerbaijan, whereas rather common CYP3A5*3 was identified to have no such association.
UNASSIGNED: Genotyping of CYP3A5*3, CYP3A4*18 and CYP2B6*6 was performed in 153 patients (102 IM non-responders and 51 IM responders) with CML by the PCR-restriction fragment length polymorphism (RFLP) assays. The odds ratios (ORs) with 95 per cent confidence intervals (CIs) were applied to assess the association between allelic variants and IM therapy outcome. The results were validated by sequencing.
UNASSIGNED: The frequency of the CYP3A4*18 allele was considerably lower in the responder\'s group (97.1 vs. 100%; P=0.036). For CYP3A5*3, the allelic frequency was slightly higher among the IM responders (100 vs. 99.02%) with no significant difference. Although patients heterozygous (TC) for CYP2B6*6 demonstrated a higher risk of acquiring resistance (OR 1.04; 95% CI: 0.492-2.218), differences were not significant (P=0.909). In addition, the homozygous genotype (TT) demonstrated a lower risk of unresponsiveness (OR 0.72; 95% CI: 0.283-1.836), but associations were not significant (P=0.491).
UNASSIGNED: Our results demonstrated that CYP3A4*18 was significantly associated with IM treatment response in patients with CML in Azerbaijan, whereas rather common CYP3A5*3 was identified to have no such association.
摘要：
■甲磺酸伊马替尼（IM）是慢性髓性白血病（CML）的可靠一线治疗方法。然而，尽管有希望的结果，相当比例的患者对药物产生抗药性。细胞色素P450（CYP）酶在IM代谢中起着至关重要的作用。因此，CYP基因的点突变可能会改变IM酶的活性，导致治疗反应不足。这项研究旨在确定CYP3A5*3，CYP3A4*18和CYP2B6*6多态性对阿塞拜疆CML患者IM反应的功能影响。
■通过PCR限制性片段长度多态性（RFLP）测定，对153例CML患者（102例IM无应答者和51例IM应答者）进行了CYP3A5*3，CYP3A4*18和CYP2B6*6的基因分型。应用比值比（ORs）和95%置信区间（CIs）来评估等位基因变异与IM治疗结果之间的关联。通过测序验证结果。
■在应答者组中，CYP3A4*18等位基因的频率大大降低（97.1与100%;P=0.036)。对于CYP3A5*3，IM应答者的等位基因频率略高（100vs.99.02%)无显著差异。尽管CYP2B6*6的杂合（TC）患者表现出更高的获得抵抗的风险（OR1.04;95％CI：0.492-2.218），差异无统计学意义(P=0.909)。此外,纯合基因型（TT）表现出较低的无反应风险（OR0.72;95％CI：0.283-1.836），但相关性不显著(P=0.491)。
■我们的结果表明，CYP3A4*18与阿塞拜疆CML患者的IM治疗反应显着相关，而相当常见的CYP3A5*3被鉴定为没有这种关联。
■通过PCR限制性片段长度多态性（RFLP）测定，对153例CML患者（102例IM无应答者和51例IM应答者）进行了CYP3A5*3，CYP3A4*18和CYP2B6*6的基因分型。应用比值比（ORs）和95%置信区间（CIs）来评估等位基因变异与IM治疗结果之间的关联。通过测序验证结果。
■在应答者组中，CYP3A4*18等位基因的频率大大降低（97.1与100%;P=0.036)。对于CYP3A5*3，IM应答者的等位基因频率略高（100vs.99.02%)无显著差异。尽管CYP2B6*6的杂合（TC）患者表现出更高的获得抵抗的风险（OR1.04;95％CI：0.492-2.218），差异无统计学意义(P=0.909)。此外,纯合基因型（TT）表现出较低的无反应风险（OR0.72;95％CI：0.283-1.836），但相关性不显著(P=0.491)。
■我们的结果表明，CYP3A4*18与阿塞拜疆CML患者的IM治疗反应显着相关，而相当常见的CYP3A5*3被鉴定为没有这种关联。
