Pharmacogenetic Studies of Paclitaxel in the Treatment of Ovarian Cancer
Pharmacogenetic Studies of Paclitaxel in the Treatment of Ovarian Cancer
复制标题
DOI：
10.1111/j.1742-7843.2008.00351.x
复制
发表时间：
2009-02-01
影响因子：
3.1
通讯作者：
Peterson, Curt
中科院分区：
文献类型：
--
作者：
Green, Henrik;Soderkvist, Peter;Peterson, Curt
本研究的目的是评价CYP 2C 8、ABCB 1和CYP 3A 4基因序列变异和CYP 3A 4表型对卵巢癌患者紫杉醇药代动力学和毒性的作用。38例患者接受紫杉醇和卡铂治疗。采用焦磷酸测序法检测CYP 2C 8 *1B、*1C、*2、*3、*4、*5、*6、*7、*8和P404 A基因型、ABCB 1 G2677 T/A和C3435 T基因型以及CYP 3A 4 *1B基因型。以奎宁为探针，在体内进行CYP 3A 4的表型分析。对患者进行了毒性监测，23例患者接受了更广泛的神经毒性评价。ABCB 1基因2677位G/A杂合子患者的紫杉醇清除率显著高于大多数其他ABCB 1变体。当根据ABCB 1 G2677 T/A基因型分层时，发现CYP 2C 8 *3杂合子患者的紫杉醇清除率较低。此外，体内CYP 3A 4酶活性影响每例患者的主要代谢途径，但不影响紫杉醇的总清除率。紫杉醇暴露与神经毒性程度相关。我们的研究结果表明，紫杉醇药代动力学的个体间变异性可以通过ABCB 1和CYP 2C 8基因型预测，并为个体化化疗提供有用的信息。
The purpose of this study was to evaluate the role of sequence variants in the CYP2C8, ABCB1 and CYP3A4 genes and the CYP3A4 phenotype for the pharmacokinetics and toxicity of paclitaxel in ovarian cancer patients. Thirty-eight patients were treated with paclitaxel and carboplatin. The genotypes of CYP2C8*1B, *1C, *2, *3, *4, *5, *6, *7, *8 and P404A, ABCB1 G2677T/A and C3435T, as well as CYP3A4*1B, were determined by pyrosequencing. Phenotyping of CYP3A4 was performed in vivo with quinine as a probe. The patients were monitored for toxicity and 23 patients underwent a more extensive neurotoxicity evaluation. Patients heterozygous for G/A in position 2677 in ABCB1 had a significantly higher clearance of paclitaxel than most other ABCB1 variants. A lower clearance of paclitaxel was found for patients heterozygous for CYP2C8*3 when stratified according to the ABCB1 G2677T/A genotype. In addition, the CYP3A4 enzyme activity in vivo affected which metabolic pathway was dominant in each patient, but not the total clearance of paclitaxel. The exposure to paclitaxel correlated to the degree of neurotoxicity. Our findings suggest that interindividual variability in paclitaxel pharmacokinetics might be predicted by ABCB1 and CYP2C8 genotypes and provide useful information for individualized chemotherapy.