Relations between polymorphisms in drug-metabolising enzymes and toxicity of chemotherapy with cyclophosphamide, thiotepa and carboplatin
Relations between polymorphisms in drug-metabolising enzymes and toxicity of chemotherapy with cyclophosphamide, thiotepa and carboplatin
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DOI：
10.1097/fpc.0b013e328313aaa4
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发表时间：
2008-11-01
影响因子：
2.6
通讯作者：
Hultema, Alwin D. R.
中科院分区：
文献类型：
--
作者：
Ekhart, Corine;Rodenhuis, Sjoerd;Hultema, Alwin D. R.
目的环磷酰胺、塞替派和卡铂（CTC）联合大剂量化疗已被开发为几种实体瘤的可能治愈性治疗方式。然而，在大剂量化疗中遇到了大的个体间毒性变异。先验识别患者的毒性风险可能是一个有吸引力的前景。药物代谢酶基因分型可能提供这样一个工具。实验设计我们评估了9个基因中16个选择的多态性（CYP2B6，CYP2C9，CYP2C19，CYP3A4，CYP3A5，GSTA1，GSTP1，在113例接受高剂量化疗的患者中，使用聚合酶链反应和DNA测序，发现ALDH 1A 1和ALDH 3A 1在CTC代谢中具有假定的相关性。结果ALDH 3A 1 *2等位基因杂合子患者中，（等位基因频率21.2%）与野生型等位基因患者相比，出血性膀胱炎风险增加[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，ALDH 1A 1 *2等位基因杂合子患者（等位基因频率5.8%）与野生型等位基因患者相比，肝毒性风险增加（6/13 vs. 19/99; OR：5.13，95%CI：1.30-20.30; P=0.02）。结论ALDH 3A 1 *2和ALDH 1A 1 *2等位基因杂合子患者在接受大剂量CTC联合化疗时，与携带野生型等位基因的患者相比，出血性膀胱炎和肝毒性的风险分别增加。药物遗传学方法可以识别在高剂量化疗中有毒副作用风险的患者。药理遗传学和遗传学18：1009-1015（C）2008年沃尔特斯·克鲁沃健康垂直酒吧Lippincott威廉姆斯&威尔金斯。
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 ALDH1Al*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% Cl: 1.30-20.30; P=0.02). No other relations reached significance.Conclusion Patients heterozygous for the ALDH3A1*2 and ALDH1Al*2 allele have an increased risk of haernorrhagic 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. Pharmacogenetics and Genornics 18:1009-1015 (C) 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.