二氢嘧啶脱氢酶基因IVS14+1多态性联合氟尿嘧啶血药浓度检测在预测及减少结直肠癌氟尿嘧啶为基础化疗不良反应中的作用  

IVS14+1 G>A genotype in the dihydropyrimidine dehydrogenase gene:a predictive marker with fluorouracil pharmacokinetic in reducing adverse reactions of fluorouracil-based chemotherapy in patients with local advanced and metastatic colorectal cancer

作　　者：蔡讯[1] 方珏敏[2] 薛鹏[1] 宋卫峰[1] 胡炯[1] 顾鸿莉[1] 杨海燕[1] 王理伟[1] 

机构地区：[1]上海交通大学附属第一人民医院肿瘤科,上海200080 [2]同济大学附属第十人民医院肿瘤科,上海200072

出　　处：《中国癌症杂志》2013年第2期130-136,共7页China Oncology

摘　　要：背景与目的:由于个体差异,5-FU按常规给药可能发生严重不良反应,二氢嘧啶脱氢酶基因(dihydropyrimidine dehydrogenase,DPD)是5-FU代谢关键酶,DPD单核甘酸多态性(single nucleotidepolymorphisms,SNPs)的差异是影响其活性的主要原因,而IVS14+1据报道约占DPD SNPs的一半以上,国内有关IVS14+1预测5-FU不良反应的报道很少。本研究回顾性分析80例局部进展或转移性结直肠癌患者DPD IVS14+1多态性与不良反应之间的关系,明确其在预测和减少不良反应中的作用。方法:80例不可切除局部进展或转移性结直肠癌患者在化疗前采血应用HRM曲线分析进行DPD SNPs的检测,于每个周期5-FU持续滴注开始后12 h应用HPLC检测5-FU血药浓度(4～6 Am),分别取各周期血药浓度的平均值,通过逐步回归分析筛选与5-FU血药浓度的相关因素,在大于有效预测值下限的患者中回顾性分析DPD IVS14+1 SNPs与不良反应之间的关系。结果:在5-FU平均血药浓度大于有效预测值的下限26.83 mg/L的56例患者中,DPD IVS14+1突变型患者骨髓抑制、手足综合征和腹泻(尤其是Ⅲ、Ⅳ度)的发生率显著高于野生型患者(13/56 vs 43/56,P分别为0.04、0.03和0.04),而在mPFS和mOS中差异无统计学意义[mPFS:(7.50±0.44)个月vs(8.50±0.40)个月,P=0.69;mOS:(21.00±1.12)个月vs(20.00±1.16)个月,P=0.72]。结论:局部进展或转移性结直肠癌患者在接受5-FU为基础的方案化疗前DPD IVS14+1发生突变及化疗后5-FU浓度升高,下次化疗前应进行5-FU剂量调整,其中杂合型应根据5-FU血药浓度适当减量以减轻不良反应,而纯合型则应避免应用5-FU类药物。Background and purpose： Serious adverse reactions may happen in the routine administration of fluorouracil （5-FU） due to individual differences, DPD is the rate-limiting enzyme in the catabolism of 5-FU, single nucleotide polymorphisms （SNPs） in DPD gene is the main reason affecting the activity of DPD, while IVS14＋1 G〉A accounted for about 50% of the total mutation, reports such as IVS14＋1 G〉A forecasting 5-FU associated adverse reactions was rare, so we retrospectively investigated the relationship between IVS 14＋1 G〉A genotype in the dihydropyrimidine dehydrogenase （DPD） gene and 5-FU associated adverse reactions in 80 patients with locally advanced or metastatic colorectal cancer, in order to confirm the role of DPD IVS14＋1 G〉A genotype in predictingand reducing adverse reactions of 5-FU-based chemotherapy. Methods： Eighty patients with unresectable locally advanced or metastatic colorectal cancer were enrolled. Single nucleotide polymorphisms for DPD gene were analyzed before chemotherapy by high-resolution melting （HRM） analysis, and the plasma concentration of 5-FU was detected by high performance liquid chromatography （HPLC） after continuous infusion of 5-FU over 12 h in each cycle. The factors related to plasma concentration of 5-FU were screened by stepwise regression. The relationship between DPD IVS 14＋1 genotype and adverse reactions was retrospectively analyzed in 56 patients whose plasma concentrations were greater than predicted lower limit. Results： Of the 56 patients whose plasma concentration were greater than 26.83 rag/L, the predicted lower limit, the incidence of bone marrow suppression, hand-foot syndrome and diarrhea for DPD IVS14＋1 mutant patients were both higher than those DPD IVSI4＋1 wide type ones （P=0.04, P=-0.03 and P=0.04）, while there were no difference in median progression free survival （mPFS） and median OS （mOS） （mPFS： 7.50±0.44 months vs 8.50±0.40 months, P=0.69; mOS： 21.00±1.12 months vs 20.00±1.16 months,

关 键 词：肠肿瘤 血药浓度 氟尿嘧啶 药物监测 化疗反应 

分 类 号：R735.35[医药卫生—肿瘤]