胃癌细胞色素氧化酶CYP3A4基因多态性与含紫杉醇方案化疗敏感性的研究

目的 探讨胃癌细胞色素氧化酶CYP3A4基因多态性与含紫杉醇方案化疗敏感性的关系。方法 采用变性高效液相色谱技术（DHPLC）和基因测序技术检测53例晚期胃癌患者外周血中CYP3A4基因的突变情况，观察并评价含紫杉醇化疗方案的疗效与CYP3A4基因多态性的关系。结果 DHPLC检测显示，53例胃癌患者中CYP3A4基因单峰者（野生型）32例，双峰者（突变型）21例；测序结果显示，CYP3A4基因第10号外显子第27位C缺失突变。野生型组有效率（RR）为40.6％，疾病控制率（DCR）为84.4％；突变型组RR为33.3％，DCR为85.7％，两组RR和DCR的差异均无统计学意义（P＞0.05）。53例胃癌患者的中位无进展生存时间（PFS）为6.5个月（95％CI：3.576～9.424个月），中位总生存时间（OS）为11.0个月（95％CI：6.955～15.045个月）。CYP3A4野生型与突变型患者中位PFS（7.0个月vs.7.0个月）和OS（10.0个月 vs.14.0个月）的差异均无统计学意义（P＞0.05）。使用含铂方案患者CYP3A4基因野生型和突变型中位PFS的差异无统计学意义（P＞0.05），使用非含铂方案中位PFS的差异有统计学意义（P=0.024），含铂与非含铂方案中位OS的差异均无统计学意义（P＞0.05）。采用3药联合与两药联合方案患者的中位PFS和OS均与CYP3A4基因多态性无关。野生型与突变型患者不良反应均较轻，以1～2级为主，常见不良反应包括食欲减退、恶心呕吐和白细胞减少。结论 CYP3A4基因第10号外显子第27位C缺失突变，CYP3A4基因突变型晚期胃癌患者使用含紫杉醇方案有延长OS的趋势。

Trial of the correlation between cytochrome oxidase CYP3A4 with the susceptibility of paclitaxel-based reg- imen for advanced gastric cancer

Objective To inveatigate the relationship between susceptibility of paclitaxel-based regimen and gene polymor- phisms of cytochrome oxidase CYP3A4 for advanced gastric cancer. Methods Peripheral venous blood samples of 53 advanced gastric cancer patients were enrolled to test the mutation of CYP3A4 gene by denaturing high performance liquid chromatography （DHPLC） and DNA sequencing. The relation between the efficacy of paclitaxel-based regimen and CYP3A4 gene polymorphisms was further ana- lyzed. Results DHPLC indicated that among the 53 patients, 21 cases showed bimodal type （mutation） and 32 cases were of unimod- al type （wild-type）. Sequencing results showed that the deletion mutation was found at the 27th basic group of C in exon 10 of CYP3A4 gene. The response rate （RR） and disease control rate （DCR） of wild-type group were 40. 6% and 84. 4%, while in mutation group they were 33.3% and 85.7%, with no significance between the two groups（ P〉0.05 ）. The median progression-free survival （PFS） was 6. 5 months （ 95% CI ： 3. 576-9. 424 months）, and the median overall survival （OS） was 11.0 months （ 95% CI ： 6. 955-15.045 months） of the 53 patients. The median PFS and OS in wild-type group had no differences compared with those in mutation group （7.0 months vs. 7. 0 months, P〉0. 05; 10. 0 months vs. 14.0 months, P〉0. 05）. Between wild-type and mutation groups, the median PFS of patients applied with oxaliplatin containing regimen and the median OS in patients applied with/without oxaliplatin had no significant differences （P〉0. 05）, while the median PFS in patients received non-oxaliplatin regimen had statistical differences （P= 0. 024）. The median PFS and OS in patients reveiving 3-drug or 2-drug regimen had no correlation with CYP3A4 gene polymorphisms. The adverse effect in the two groups were mild, mainly in grade 1-2. The common adverse effects were anorexia, nausea/vomiting and leukopenia. Conclusion Deletion mutation was located in the 2Th basic group of C in exon 10 of CYP3A4 gene. Paclitaxel-based regimen has a trend to prolong the OS of advanced gastric cancer with mutation type.