外周血中DPD mRNA和TS mRNA表达对含卡培他滨方案治疗进展期胃癌的疗效预测
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摘要
目的:探讨进展期胃癌(advanced gastric carcinoma,AGC)患者外周血中二氢嘧啶脱氢酶(dihydropyrimidine dehydrogenase,DPD)和胸苷酸合成酶(thymidylate synthase,TS)的表达,及其与含卡培他滨的方案疗效的关系。方法:选择经影像学及病理学诊断为AGC患者60例,化疗前抽取外周血,使用反转录PCR法检测患者外周血中DPD mRNA和TS mRNA的表达水平;给予含卡培他滨片(首辅)的方案化疗:卡培他滨片(1 000 mg·m~(-2)·d~(-1),分2次口服,d1～d14)+奥沙利铂130 mg·m~(-2),静脉滴注2 h,d1,21 d为1个周期;分析DPD mRNA和TS mRNA表达水平与患者临床病理特征及化疗疗效的关系。结果:60例AGC患者DPD mRNA和TS mRNA的相对表达量分别为2.702±1.993和0.717±0.360。AGC患者外周血中DPD mRNA及TS mRNA表达与患者Lauren分型明显相关(DPD:χ~2=4.571,P=0.033;TS:χ~2=8.124,P=0.004)。TS mRNA表达量亦与是否有远处转移明显相关(χ~2=7.716,P=0.007)。DPD mRNA及TS mRNA表达越高,患者接受含卡培他滨方案的疗效越差(DPD:r=-0.565,P<0.01;TS:r=-0.571,P<0.01)。DPD mRNA及TS mRNA联合高表达组接受含卡培他滨方案的疗效最差(P<0.05)。结论:AGC患者外周血清中DPD mRNA及TS mRNA呈高表达,与其部分恶性临床特征及含卡培他滨方案疗效不良相关。
Objective:To investigate the correlation between the therapeutic effect of chemotherapy scheme including Capecitabine on patients with advanced gastric cancer(AGC)and expression level of both dihydropyrimidine dehydrogenase(DPD)and thymidylate synthase(TS).Methods:A total of 60AGC patients were recruited.Both mRNA expression level of DPD and TS in peripheral blood were detected by reverse transcription-polymerase chain reaction before receiving chemotherapy.Then all patients were treated with Capecitabine-based regimen:Capecitabine(1 000 mg·m~(-2)·d~(-1),orally twice a day on days 1-14)+oxaliplatin(130 mg·m~(-2),intravenously on day1),repeating every twenty-one day.The association between therapeutic effect and DPD and TS expression level were analyzed by Spearman correlation.Results:The relative mRNA expression level of DPD and TS in all AGC patients were2.702±1.993 and 0.717±0.360,respectively.The Lauren classification was significantly associated with both DPD(χ~2=4.571,P=0.033)and TS(χ~2=8.124,P=0.004)expression level.Whether distant metastasis happening or not was significantly associated with TS expression level(χ~2=7.716,P=0.007).The therapeutic effect was negatively correlated with both DPD(r=-0.565,P<0.01)and TS(r=-0.571,P<0.01)expression level.Combined results analysis showed both DPD mRNA and TS mRNA high expression patients exhibited the worst therapeutic effect(P<0.05).Conclusion:In AGC patients,higher mRNA expression level of DPD and TS were associated with some malignant clinical features and poor efficacy of chemotherapy with capecitabine tablets.
Objective:To investigate the correlation between the therapeutic effect of chemotherapy scheme including Capecitabine on patients with advanced gastric cancer(AGC)and expression level of both dihydropyrimidine dehydrogenase(DPD)and thymidylate synthase(TS).Methods:A total of 60AGC patients were recruited.Both mRNA expression level of DPD and TS in peripheral blood were detected by reverse transcription-polymerase chain reaction before receiving chemotherapy.Then all patients were treated with Capecitabine-based regimen:Capecitabine(1 000 mg·m~(-2)·d~(-1),orally twice a day on days 1-14)+oxaliplatin(130 mg·m~(-2),intravenously on day1),repeating every twenty-one day.The association between therapeutic effect and DPD and TS expression level were analyzed by Spearman correlation.Results:The relative mRNA expression level of DPD and TS in all AGC patients were2.702±1.993 and 0.717±0.360,respectively.The Lauren classification was significantly associated with both DPD(χ~2=4.571,P=0.033)and TS(χ~2=8.124,P=0.004)expression level.Whether distant metastasis happening or not was significantly associated with TS expression level(χ~2=7.716,P=0.007).The therapeutic effect was negatively correlated with both DPD(r=-0.565,P<0.01)and TS(r=-0.571,P<0.01)expression level.Combined results analysis showed both DPD mRNA and TS mRNA high expression patients exhibited the worst therapeutic effect(P<0.05).Conclusion:In AGC patients,higher mRNA expression level of DPD and TS were associated with some malignant clinical features and poor efficacy of chemotherapy with capecitabine tablets.
引文
[1]陈万青,李贺,孙可欣,等.2014年中国恶性肿瘤发病和死亡分析[J].中华肿瘤杂志,2018,40(1):5-13.
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[10]迪丽拜尔·吾守,艾克白尔江·艾尼瓦尔,木合塔尔·吾布力卡斯木,等.胸苷酸合成酶和二氢嘧啶脱氢酶的表达与乳腺癌临床病理特征及预后的相关性[J].江苏大学学报(医学版),2018,28(5):414-417,422.
[11]Rogoza-Mateja W,Domagala P,Kaczmarczyk M,et al.Immunohistochemical analysis of thymidylate synthase expression in gastric carcinoma:correlation with clinicopathological parameters and survival[J].Histol Histopathol,2017,32(2):193-201.
[12]Okuda K,Tatematsu T,Yano M,et al.The relationship between the expression of thymidylate synthase,dihydropyrimidine dehydrogenase,orotate phosphoribosyltransferase,excision repair crosscomplementation group 1 and classⅢβ-tubulin,and the therapeutic effect of S-1 or carboplatin plus paclitaxel in non-small-cell lung cancer[J].Mol Clin Oncol,2018,9(1):21-29.
[13]张静,周子娇.替吉奥治疗胃癌的临床疗效与外周血内DPD mRNA和TS mRNA表达水平的相关性[J].胃肠病学和肝病学杂志,2016,25(11):1248-1252.
[14]Lauren P.The two histological main types of gastric carcinomas:diffuse and so called intestinal-type carcinoma:an attempt at a histo-clinical classification[J].Acta Pathol Microbiol Scand,1965,64:31-49.
[15]曹文君,李敏,李慧娟.肠型胃癌和弥漫型胃癌的临床特点及预后研究[J].中国全科医学,2017,20(13):1587-1591.
[16]艾晓晴,贾喜花,王晓博,等.DPD和p53蛋白在结肠癌中的表达及预后分析[J].中国热带医学,2015,15(11):1379-1382.
[17]Yu KH,Wang WX,Ding YM,et al.Polymorphism of thymidylate synthase gene associated with its protein expression in human colon cancer[J].World J Gastroenterol,2008,14(4):617-621.
[18]Ishikawa Y,Kubota T,Otani Y,et al.Dihydropyrimidine dehydrogenase and messenger RNA levels in gastric cancer:possible predictor for sensitivity to 5-fluorouracil[J].Jpn J Cancer Res,2010,91(1):105-112.
[19]Hisamitsu K,Tsujitani SK,Fukuda K,et al.Expression of dihydropyrimidine dehydrogenase in cancer cells but not in stromal cells predicts the efficacy of fluorouracil treatment in patients with gastric carcinoma[J].Anticancer Res,2004,24(4):2495-2501.
[20]Chazal M,Etienne MC,Renée N,et al.Link between dihydropyrimidine dehydrogenase activity in peripheral blood mononuclear cells and liver[J].Clin Cancer Res,1996,2(3):507-510.
[21]陶国华,仲崇俊,曹兴建,等.外周血TSmRNA和DP-DmRNA临床应用价值探讨[J].中国实验诊断学,2008,12(12):1548-1551.
[22]Fleming RA,Milano G,Thyss A,et al.Correlation between dihydropyrimidine dehydrogenase activity in peripheral mononuclear cells and systemic clearance of fluorouracil in cancer patients[J].Cancer Res,1992,52(10):2899-2902.
[23]Lenz HJ,Leichman CG,Danenberg KD,et al.Thymidylate synthase mRNA level in adenocarcinoma of the stomach:a predictor for primary tumor response and overall survival[J].J Clin Oncol,1996,14(1):176-182.
[24]郑积华.TS和DPD mRNA对替吉奥治疗晚期胃癌的疗效预测[J].实用癌症杂志,2014,29(7):789-790,793.
[25]张丹,陈妍妍.TS水平在晚期胃癌患者中对替吉奥化疗疗效的影响[J].中国医药科学,2016,6(12):166-168.
[2]Chen W,Zheng R,Baade PD,et al.Cancer statistics in China,2015[J].CA Cancer J Clin,2016,66(2):115-132.
[3]Kubota T.5-fluorouracil and dihydropyrimidine dehydrogenase[J].Int J Clin Oncol,2003,8(3):127-131.
[4]Peters GJ,Backus HH,Freemantle S,et al.Induction of thymidylate synthase as a 5-fluorouracil resistance mechanism[J].Biochim Biophys Acta,2002,1587(2-3):194-205.
[5]练炼,慎晓明,周冲,等.胃癌患者血清DPD mRNA和TS mRNA表达对替吉奥疗效预测价值分析[J].中华肿瘤防治杂志,2015,22(5):368-372.
[6]Lee JL,Kang YK,Kang HJ,et al.A randomised multicentre phaseⅡtrial of capecitabine vs S-1 as first-line treatment in elderly patients with metastatic or recurrent unresectable gastric cancer[J].Br J Cancer,2008,99(4):584-590.
[7]Seol YM,Song MK,Choi YJ,et al.Oral fluoropyrimidines(capecitabine or S-1)and cisplatin as first line treatment in elderly patients with advanced gastric cancer:a retrospective study[J].Jpn J Clin Oncol,2009,39(1):43-48.
[8]Kim GM,Jeung HC,Rha SY,et al.A randomized phaseⅡtrial of S-1-oxaliplatin versus capecitabine-oxaliplatin in advanced gastric cancer[J].Eur J Cancer,2012,48(4):518-526.
[9]Eisenhauer EA,Therasse P,Bogaerts J,et al.New response evaluation criteria in solid tumours:Revised RE-CIST guideline(version 1.1)[J].Eur J Cancer,2009,45(2):228-247.
[10]迪丽拜尔·吾守,艾克白尔江·艾尼瓦尔,木合塔尔·吾布力卡斯木,等.胸苷酸合成酶和二氢嘧啶脱氢酶的表达与乳腺癌临床病理特征及预后的相关性[J].江苏大学学报(医学版),2018,28(5):414-417,422.
[11]Rogoza-Mateja W,Domagala P,Kaczmarczyk M,et al.Immunohistochemical analysis of thymidylate synthase expression in gastric carcinoma:correlation with clinicopathological parameters and survival[J].Histol Histopathol,2017,32(2):193-201.
[12]Okuda K,Tatematsu T,Yano M,et al.The relationship between the expression of thymidylate synthase,dihydropyrimidine dehydrogenase,orotate phosphoribosyltransferase,excision repair crosscomplementation group 1 and classⅢβ-tubulin,and the therapeutic effect of S-1 or carboplatin plus paclitaxel in non-small-cell lung cancer[J].Mol Clin Oncol,2018,9(1):21-29.
[13]张静,周子娇.替吉奥治疗胃癌的临床疗效与外周血内DPD mRNA和TS mRNA表达水平的相关性[J].胃肠病学和肝病学杂志,2016,25(11):1248-1252.
[14]Lauren P.The two histological main types of gastric carcinomas:diffuse and so called intestinal-type carcinoma:an attempt at a histo-clinical classification[J].Acta Pathol Microbiol Scand,1965,64:31-49.
[15]曹文君,李敏,李慧娟.肠型胃癌和弥漫型胃癌的临床特点及预后研究[J].中国全科医学,2017,20(13):1587-1591.
[16]艾晓晴,贾喜花,王晓博,等.DPD和p53蛋白在结肠癌中的表达及预后分析[J].中国热带医学,2015,15(11):1379-1382.
[17]Yu KH,Wang WX,Ding YM,et al.Polymorphism of thymidylate synthase gene associated with its protein expression in human colon cancer[J].World J Gastroenterol,2008,14(4):617-621.
[18]Ishikawa Y,Kubota T,Otani Y,et al.Dihydropyrimidine dehydrogenase and messenger RNA levels in gastric cancer:possible predictor for sensitivity to 5-fluorouracil[J].Jpn J Cancer Res,2010,91(1):105-112.
[19]Hisamitsu K,Tsujitani SK,Fukuda K,et al.Expression of dihydropyrimidine dehydrogenase in cancer cells but not in stromal cells predicts the efficacy of fluorouracil treatment in patients with gastric carcinoma[J].Anticancer Res,2004,24(4):2495-2501.
[20]Chazal M,Etienne MC,Renée N,et al.Link between dihydropyrimidine dehydrogenase activity in peripheral blood mononuclear cells and liver[J].Clin Cancer Res,1996,2(3):507-510.
[21]陶国华,仲崇俊,曹兴建,等.外周血TSmRNA和DP-DmRNA临床应用价值探讨[J].中国实验诊断学,2008,12(12):1548-1551.
[22]Fleming RA,Milano G,Thyss A,et al.Correlation between dihydropyrimidine dehydrogenase activity in peripheral mononuclear cells and systemic clearance of fluorouracil in cancer patients[J].Cancer Res,1992,52(10):2899-2902.
[23]Lenz HJ,Leichman CG,Danenberg KD,et al.Thymidylate synthase mRNA level in adenocarcinoma of the stomach:a predictor for primary tumor response and overall survival[J].J Clin Oncol,1996,14(1):176-182.
[24]郑积华.TS和DPD mRNA对替吉奥治疗晚期胃癌的疗效预测[J].实用癌症杂志,2014,29(7):789-790,793.
[25]张丹,陈妍妍.TS水平在晚期胃癌患者中对替吉奥化疗疗效的影响[J].中国医药科学,2016,6(12):166-168.