CAJ | 학술논문

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 nucleotide polymorphisms,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.
배경여목적:유우개체차이,5-FU안상규급약가능발생엄중불량반응,이경밀정탈경매기인(dihydropyrimidine dehydrogenase,DPD)시5-FU대사관건매,DPD단핵감산다태성(single nucleotide polymorphisms,SNPs)적차이시영향기활성적주요원인,이IVS14+1거보도약점DPD SNPs적일반이상,국내유관IVS14+1예측5-FU불량반응적보도흔소.본연구회고성분석80례국부진전혹전이성결직장암환자DPD IVS14+1다태성여불량반응지간적관계,명학기재예측화감소불량반응중적작용.방법:80례불가절제국부진전혹전이성결직장암환자재화료전채혈응용HRM곡선분석진행DPD SNPs적검측,우매개주기5-FU지속적주개시후12 h응용HPLC검측5-FU혈약농도(4~6 Am),분별취각주기혈약농도적평균치,통과축보회귀분석사선여5-FU혈약농도적상관인소,재대우유효예측치하한적환자중회고성분석DPD IVS14+1 SNPs여불량반응지간적관계.결과:재5-FU평균혈약농도대우유효예측치적하한26.83 mg/L적56례환자중,DPD IVS14+1돌변형환자골수억제、수족종합정화복사(우기시Ⅲ、Ⅳ도)적발생솔현저고우야생형환자(13/56 vs 43/56,P분별위0.04、0.03화0.04),이재mPFS화mOS중차이무통계학의의[mPFS:(7.50±0.44)개월vs (8.50±0.40)개월,P=0.69;mOS:(21.00±1.12)개월vs (20.00±1.16)개월,P=0.72].결론:국부진전혹전이성결직장암환자재접수5-FU위기출적방안화료전DPD IVS14+1발생돌변급화료후5-FU농도승고,하차화료전응진행5-FU제량조정,기중잡합형응근거5-FU혈약농도괄당감량이감경불량반응,이순합형칙응피면응용5-FU류약물.
@@@@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 IVS14+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 predicting and 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 IVS14+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 mg/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 IVS14+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, P=0.72). Conclusion:The patients with DPD IVS14+1 G>A mutation and higher 5-FU plasma concentration need to adjust 5-FU dosage in next chemotherapy:for patients with DPD heterozygous mutation, 5-FU dose should be appropriately reduced according to last plasma concentration to reduce adverse reactions, while the homozygous ones should avoid application of 5-FU and its derivatives.