Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity
Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity
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DOI：
10.1038/tpj.2010.13
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发表时间：
2011-04-01
影响因子：
2.8
通讯作者：
Rodriguez-Antona, C.
中科院分区：
文献类型：
--
作者：
Leskelae, S.;Jara, C.;Rodriguez-Antona, C.
神经毒性是抗癌药物紫杉醇最相关的剂量限制性毒性之一。它表现出未知分子基础的显著个体间变异性，代表了改善紫杉醇治疗的主要挑战之一。紫杉醇清除和代谢的广泛变异性导致我们研究紫杉醇消除途径中的多态性与神经毒性之间的关联。我们在118名接受紫杉醇治疗的西班牙癌症患者中选择了编码紫杉醇代谢酶（CYP 2C 8、CYP 3A 4和CYP 3A 5）和转运蛋白（有机阴离子转运多肽（OATP）1B 1、OATP 1B 3和P-糖蛋白）的基因中的13种相关多态性，并对其进行基因分型。在调整年龄和治疗方案后，CYP 2C 8单体型C和CYP 3A 5 *3与保护作用相关（风险比（HR））（每个等位基因）= 0.55; 95%置信区间（CI）= 0.34-0.89; P = 0.014，HR（每个等位基因）= 0.51; 95% CI = 0.30-0.86; P = 0.012）和CYP 2C 8 *3风险增加（HR（每个等位基因）= 1.72; 95% CI = 1.05-2.82; P = 0.032）。在每种情况下，导致紫杉醇代谢增加的等位基因与神经毒性增加相关，表明代谢和羟基化紫杉醇代谢物的重要作用。我们估计在三种多态性中携带的每个紫杉醇代谢增加等位基因的HR为HR = 1.64（95%CI = 1.26-2.14; P =0.0003）。P-糖蛋白的结果是不确定的，没有观察到与其他研究基因的关联。在治疗选择中纳入这种遗传数据有助于减少神经毒性事件，从而使紫杉醇药物治疗个体化。这些结果需要在独立系列中进行验证。药物基因组学杂志（2011）11，121-129; doi：10.1038/tpj.2010.13; 2010年3月9日在线发表
Neurotoxicity is one of the most relevant dose-limiting toxicities of the anticancer drug paclitaxel. It exhibits substantial interindividual variability of unknown molecular basis, and represents one of the major challenges for the improvement of paclitaxel therapy. The extensive variability in paclitaxel clearance and metabolism lead us to investigate the association between polymorphisms in paclitaxel elimination pathway and neurotoxicity. We selected 13 relevant polymorphisms in genes encoding paclitaxel metabolizing enzymes (CYP2C8, CYP3A4 and CYP3A5) and transporters (organic anion transporting polypeptide (OATP) 1B1, OATP1B3 and P-glycoprotein) and genotyped them in 118 Spanish cancer patients treated with paclitaxel. After adjusting for age and treatment schedule, CYP2C8 Haplotype C and CYP3A5*3 were associated with protection (hazard ratio (HR) (per allele) = 0.55; 95% confidence interval (CI) = 0.34-0.89; P = 0.014 and HR (per allele) = 0.51; 95% CI = 0.30-0.86; and P = 0.012, respectively) and CYP2C8*3 with increased risk (HR (per allele) = 1.72; 95% CI = 1.05-2.82; and P = 0.032). In each case, the allele causing increased paclitaxel metabolism was associated with increased neurotoxicity, suggesting an important role for metabolism and hydroxylated paclitaxel metabolites. We estimated the HR per paclitaxel-metabolism increasing allele carried across the three polymorphisms to be HR = 1.64 (95% CI = 1.26-2.14; P =0.0003). The results for P-glycoprotein were inconclusive, and no associations were observed for the other genes studied. The incorporation of this genetic data in treatment selection could help to reduce neurotoxicity events, thereby individualizing paclitaxel pharmacotherapy. These results warrant validation in independent series. The Pharmacogenomics Journal (2011) 11, 121-129; doi:10.1038/tpj.2010.13; published online 9 March 2010