黄欣昊,柳千帆,宋春灼,朱海涛
HUANG Xinhao,LIU Qianfan,SONG Chunzhuo,ZHU Haitao

• 1:贵州医科大学临床医学院
• 2:贵州医科大学附院肝胆外科
• 3:贵州医科大学
• 4:贵州医科大学附院临床研究中心

摘要(Abstract)：

目的:探讨吉西他滨(GEM)与厄洛替尼(ERL)联合应用对胰腺癌PANC-1细胞的抑制作用。方法:选用人胰腺癌细胞PANC-1的对数生长期细胞,采用CCK-8法检测GEM、或ERL分别对PANC-1细胞的细胞毒性,并计算各自的半数抑制浓度(IC_(50));根据两种药物对PANC-1细胞的IC_(50)值进行不同比例组合,观察两种药物联合应用时对PANC-1细胞抑制情况,采用Chou-Talalay法分析药物合用的效应;将PANC-1细胞设置为无干预组(对照组)、GEM组、ERL组、GEM联合ERL组(联合组),观察PANC-1细胞克隆形成情况。结果:GEM对PANC-1细胞的IC_(50)为80 nmol/L,ERL对PANC-1细胞的IC_(50)为12 nmol/L;ERL∶GEM的浓度比5∶1时,药物联合作用对PANC-1细胞的抑制率接近50%,高于浓度比1∶1和10∶1,且差异均有统计学意义(P<0.05);GEM合用ERL的Chou-Talalay联合指数(CI)为0.4,合用效果为协同作用;与对照组比较,GEM组、ERL组及联合组的PANC-1细胞克隆形成数均明显下降(P<0.05),且联合组的克隆形成数分别低于GEM组或ERL组(P<0.05)。结论:GEM和ERL联合使用具有协同作用,既降低了两种药物单独使用时的剂量,又提高了对胰腺癌PANC-1细胞增殖的抑制效果。
Objective: The aim of this study was to investigate the drug effects of the gemcitabine(GEM) combined with erlotinib(ERL) on the proliferation of pancreatic cancer cells.Methods:All the experiments were conducted with logarithmic growth phase cells of the PANC-1.The cytotoxicity test of GEM and ERL on PANC-1 cells was detected by CCK-8 method,and the inhibition concentration of half(IC_(50)) was calculated.According to the different proportion of IC_(50) values of the two drugs on panc-1 cells,the inhibition of the two drugs combination on panc-1 cells was observed and the effect of it was analyzed by Chou-Talalay method.PANC-1 cells were set as non-intervention group(control group) and GEM group,ERL group,GEM combined with ERL group(combined group),and the formation of PANC-1 cell clones was observed.Results:The IC_(50) of GEM to panc-1 cells was 80 nmol/L,and the IC_(50) of ERL to panc-1 cells was 12 nmol/L.When the concentration ratio of ERL:GEM was 5 ∶1,the inhibition rate on panc-1 cells by drug combination was nearly 50%,which was higher than the concentration ratio 1:1 and 10:1,and the difference was statistically significant(P<0.05).GEM combined ERL chou-talalay index(CI) was 0.4,and the combined effect was synergistic.Compared with the control group,the number of cell clones of PANC-1 cells in GEM group,ERL group and combination group was significantly decreased(P<0.05),and the number of clone formation in the combined group was significantly lower than that in the GEM group and the ERL group(P<0.05).Conclusion:The combination of GEM and ERL has a synergistic effect,and can reduce the dosage of the drug to achieve and enhance the inhibition effect of panc-1 cell proliferation in pancreatic cancer.

关键词(KeyWords)： 吉西他滨;厄洛替尼;胰腺肿瘤;药物协同作用;细胞增殖;联合治疗
gemcitabine;erlotinib;pancreatic neoplasms;synergistic effect;cell proliferation;combination therapy

Abstract:

Keywords:

基金项目(Foundation): 贵州省科技计划项目[黔科合平台人才(2018)5779-31]

作者(Author): 黄欣昊,柳千帆,宋春灼,朱海涛
HUANG Xinhao,LIU Qianfan,SONG Chunzhuo,ZHU Haitao

DOI: 10.19367/j.cnki.1000-2707.2019.08.007

参考文献(References)：

• [1] 郑荣寿,孙可欣,魏文强,等.2015年中国恶性肿瘤流行情况分析[J].中华肿瘤杂志,2019,4(1):19-28.
• [2] VINCENT A,HERMAN J,SCHULICK R,et al.Pancreatic cancer[J].The Lancet,2011,378(9791):607-627.
• [3] SIEGEL R L,MILLER K D,JEMAL A.Cancer statistics,2018[J].CA Cancer,2018,68(1):7-30.
• [4] JORG K,MURRAY K,MINOTI A,et al.Pancreatic cancer[J].Nature Reviews,2016,2:16022.
• [5] OETTLE H,LEHMANN T.Gemcitabine-resistant pancreatic cancer:a second-line option[J].The Lancet,2016,387(10018):507-514.
• [6] HIDALGO M.Pancreatic cancer[J].The New England Journal of Medicine,2010,362:1605-1621.
• [7] ALEKSANDRA A,ALICE D,MARCO F.Pancreatic Ductal Adenocarcinoma:Current and Evolving Therapies [J].International Journal of Molecular Sciences,2017,18(7):1338-1379.
• [8] MAY TUN S,LEI Z.Current Standards of Chemotherapy for Pancreatic Cancer [J].Clinical Therapeutics,2017,39(11):2125-2134.
• [9] TADROS S,SHUKLA S K,KING R J,et al.De novo lipid synthesis facilitates gemcitabine resistance through endoplasmic reticulum stress in pancreatic cancer[J].Cancer Res,2017,77(20):5503-5519.
• [10] MIYABAYASHI K,IJICHI H,MOHRI D,et al.Erlotinib prolongs survival in pancreatic cancer by blocking gemcitabine-induced MAPK signals[J].Cancer Res,2013,73(7):2221-2254.
• [11] MOORE M J,GOLDSTEIN D,HAMM J,et al.Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer:a phase III trial of the National Cancer Institute of Canada Clinical Trials GroupJournal of clinical oncology [J].The Official Journal Of the American Society of Clinical Oncology,2007,25(15):1960-1965.
• [12] 王士群,朱宇珍,郑学宝.Chou-Talalay在抗肿瘤联合用药中的研究应用概况[J].中国现代应用药学,2013,30(4):449-453.
• [13] CHOU T C.Drug combination studies and their synergy quantification using the Chou-Talalay method[J].Cancer Res,2010,70(2):440-446.
• [14] RYAN D P,HONG T S,BARDEESY N.Pancreatic adenocarcinoma[J].N Engl J Med,2014,371(11):1039-1049.
• [15] MARIANNE SINN M B,TORSTEN L,KLAUS G,et al.CONKO-005 adjuvant chemotherapy with gemcitabine plus erlotinib versus gemcitabine alone in patients after R0 resection of pancreatic cancer a multicenter randomized phase III trial[J].Journal of Clinical Oncology,2017,35(29):3330-3340.
• [16] DE SOUSA CAVALCANTE L,MONTEIRO G.Gemcitabine:metabolism and molecular mechanisms of action,sensitivity and chemoresistance in pancreatic cancer[J].European Journal Pharmacology,2014,741:8-16.
• [17] KULKE M H,BLASZKOWSKY L S,RYAN D P,et al.Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancerJournal of clinical oncology [J].The Official Journal Of The American Society of Clinical Oncology,2007,25(30):4787-4792.
• [18] MANOJ AMRUTKAR,IVAR P GLADHAUG.Pancreatic cancer chemoresistance to gemcitabine[J].Cancers,2017,9(11):157-179.
• [19] DCUNHA SANTOS G,DHANI N,DONG T,et al.Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer:National cancer institute of canada clinical trials group study pa3[J].Cancer,2010,116(24):5599-5607.
• [20] NATAL C,KRISTOPHER K F,MALCOLM M.Assessing the role of the EGF receptor in the development and progression of pancreatic cancer[J].Gastrointestinal Cancer:Targets and Therapy,2014,4:23-27.
• [21] CHRISTINE M A,BARBARA M.GRUNER K T,et al.EGF receptor is required[J].Cancer Cell,2012,22(3):304-317.
• [22] CHEN L,ZHOU D,LIU Z,et al.Combination of gemcitabine and erlotinib inhibits recurrent pancreatic cancer growth in mice via the JAK-STAT pathway[J].Oncol Rep,2018,39(3):1081-1089.
• [23] CAROLINA TORRES A L,MARIA J A,ROGELIO JESUS P M,et al.Interplay between gemcitabine and erlotinib over pancreatic adenocarcinoma cells [J].Pancreas,2016,45(2):269-280.

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