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首页> 外文期刊>Pharmacogenetics and genomics >Relations between polymorphisms in drug-metabolising enzymes and toxicity of chemotherapy with cyclophosphamide, thiotepa and carboplatin.
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Relations between polymorphisms in drug-metabolising enzymes and toxicity of chemotherapy with cyclophosphamide, thiotepa and carboplatin.

机译：药物代谢酶中的多态性与环磷酰胺，噻替帕和卡铂化疗的毒性之间的关系。

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PURPOSE: High-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin (CTC) has been developed as a possible curative treatment modality in several solid tumours. However, a large interindividual variability in toxicity is encountered in high-dose chemotherapy. A priori identification of patients at risk for toxicity could be an attractive prospect. Genotyping of genes encoding drug-metabolising enzymes might provide such a tool. EXPERIMENTAL DESIGN: We assessed 16 selected polymorphisms in nine genes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1) of putative relevance in CTC metabolism using polymerase chain reaction and DNA sequencing in 113 patients who were treated with high-dose chemotherapy regimens based on CTC. RESULTS: Patients heterozygous for the ALDH3A1*2 allele (allelic frequency 21.2%) had an increased risk of haemorrhagic cystitis when compared with patients with wild-type alleles [5/38 vs. 1/70; odds ratio (OR): 11.95, 95% confidence interval (CI): 1.18-120.56; P=0.04]. Furthermore, patients heterozygous for the ALDH1A1*2 allele (allelic frequency 5.8%) had an increased risk of liver toxicity when compared with patients with wild-type alleles (6/13 vs. 19/99; OR: 5.13, 95% CI: 1.30-20.30; P=0.02). No other relations reached significance. CONCLUSION: Patients heterozygous for the ALDH3A1*2 and ALDH1A1*2 allele have an increased risk of haemorrhagic cystitis and liver toxicity, respectively, compared with patients with wild-type alleles when treated with a high-dose chemotherapy combination of CTC. Pharmacogenetic approaches can identify patients who are at risk of experiencing toxic side effects in high-dose chemotherapy.
机译：目的：已开发出使用环磷酰胺，噻替帕和卡铂（CTC）的大剂量化学疗法作为几种实体瘤的可能治疗方法。但是，在大剂量化疗中会遇到很大的个体间毒性差异。事先确定有毒性风险的患者可能是一个有吸引力的前景。编码药物代谢酶的基因的基因分型可能提供了这种工具。实验设计：我们使用聚合酶链反应和DNA测序技术对113例接受治疗的患者进行了9种基因（CYP2B6，CYP2C9，CYP2C19，CYP3A4，CYP3A5，GSTA1，GSTP1，ALDH1A1和ALDH3A1）在CTC代谢中相关性的评估，评估了16种选择的多态性。基于CTC的大剂量化疗方案。结果：与野生型等位基因患者相比，ALDH3A1 * 2等位基因杂合子（等位基因频率为21.2％）出血性膀胱炎的风险增加[5/38 vs. 1/70;比值比（OR）：11.95，95％置信区间（CI）：1.18-120.56; P = 0.04]。此外，与野生型等位基因患者相比，ALDH1A1 * 2等位基因（等位基因频率为5.8％）杂合的患者具有更高的肝毒性风险（6/13 vs. 19/99; OR：5.13，95％CI： 1.30-20.30; P ＝ 0.02）。没有其他关系达到意义。结论：与野生型等位基因患者一起接受大剂量CTC化疗后，ALDH3A1 * 2和ALDH1A1 * 2等位基因杂合的患者分别具有更高的出血性膀胱炎和肝毒性风险。药物遗传学方法可以识别在大剂量化疗中有发生毒副作用的风险的患者。

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