CYP3A4基因多态性与晚期胃癌患者接受紫杉醇/奥沙利铂多线化疗、化疗周期数及不良反应的相关性
| 作者: |
1杨建伟,
1苏颖,
1陈增,
1蒙燕,
1高炜,
1林锦源
1 福建省肿瘤医院腹部肿瘤内科，福州 350014 |
| 通讯: |
杨建伟
Email: swzcq62@163.com |
| DOI: | 10.3978/j.issn.2095-6959.2014.01.003 |
| 基金: | 福建省自然科学基金；福建省医学创新项目, 2009J01120；2009-CXB-27 |
摘要
目的：应用变性高效液相色谱技术(denaturing-performance liquid chromatography，DHPLC)高通量的实验平台，探讨晚期胃癌患者细胞色素P450代谢酶CYP3A4基因的多态性与患者接受多线化疗、化疗周期数及不良反应的相关性。方法：福建省肿瘤医院住院的接受含紫杉醇和/或奥沙利铂联合姑息化疗晚期胃癌患者外周血53份，进行全血DNA分离、提取，经PCR，DHPLC分析筛查以及DNA测序鉴定基因型，观察并评价患者接受多线化疗、化疗周期数及不良反应与CYP3A4多态性的相关性。结果：53例进展期胃癌患者CYP3A4经DHPLC筛查，单峰者(野生型)32例，双峰者(突变型)21例。测序结果显示双峰者CYP3A4第10号外显子上27位C的缺失突变。单峰组接受一线治疗15例，二线治疗10例，二线以上治疗8例，其中3例为三线以上治疗；平均化疗周期数为8.2周期，中位总生存时间为13.0个月(95%CI：7.092~18.908个月)。双峰组接受一线治疗10例，二线治疗8例，二线以上治疗3例，平均化疗8.7周期，中位总生存时间为14.0个月(95%CI：7.555~20.445个月)。两组中位总生存时间比较差异无统计学意义(P=0.326)。野生型组较突变型组不良反应发生率低，在3~4级毒副作用方面较为明显，结论：CYP3A4突变型者第10号外显子上第27位C缺失；该基因多态性与化疗不良反应相关，尚不能作为疗效的预测指标。
关键词：
DHPLC；CYP3A4；基因多态性；晚期胃癌
Correlation between gene polymorphisms of CYP3A4 and multi-line chemotherapy, cycles of chemotherapy or adverse reactions in gastric cancer patients received therapy of paclitaxel and/or oxaliplatin combination regimens
CorrespondingAuthor: YANG Jianwei Email: swzcq62@163.com
DOI: 10.3978/j.issn.2095-6959.2014.01.003
Abstract
Objective: To investigate correlation between gene polymorphisms of drug-metabolizing enzyme CYP3A4 and multi-line chemotherapy, cycles of chemotherapy, or adverse reactions in gastric cancer patients received therapy of paclitaxel and/or oxaliplatin combination regimens. Methods: Patients with advanced gastric cancer who received palliative chemotherapy of paclitaxel and/or oxaliplatin combination regimens were from Fujian Province Tumor Hospital. Peripheral venous blood was collected before the chemotherapy. DNA was extracted and amplified by PCR. Denaturing high performance liquid chromatography (DHPLC) technology was performed to detect gene polymorphisms. The multi-line chemotherapy, cycles of chemotherapy, and adverse reactions in patients with different CYP3A4 gene polymorphisms were evaluated. Results: The genotype of CYP3A4 in 53 patients was screened by DHPLC, of which 21 cases were bimodal (mutation) and 32 were unimodal (wild-type). Sequencing results showed that in the bimodal CYP3A4, the 27th basic group of C in Exon 10 of the CYP3A4 gene was the absence of mutation. In the unimodal CYP3A4 group, 15 cases received first-line therapy, 10 received second-line therapy, 8 received therapy beyond second-line drug, and 3 received therapy beyond third-line drugs. The average chemotherapy cycle was 8.2 and the median overall survival was 13.0 months (95% CI: 7.092-18.908 months). In the bimodal CYP3A4 group, 10 cases received first-line therapy, 8 received second-line therapy, and 3 received therapy beyond second-line drug. The average chemotherapy cycle was 8.7 and the median overall survival was 14.0 months (95% CI: 7.555-20.445 months). There was no statistical difference in the median overall survival between the unimodal CYP3A4 group and the bimodal CYP3A4 group (P=0.326). For the adverse reactions, wild type displayed lower incidence than the mutant type, especially at the 3-4 grade side effects, including nausea, vomiting, fatigue, leukopenia, drug-induced hepatitis, etc. Conclusion: The 27th basic group of C in Exon 10 of the CYP3A4 gene is missing. The CYP3A4 gene polymorphism is associated with adverse reactions of chemotherapy, but it can not be used as a predictor for efficacy of chemotherapy.