非小细胞肺癌患者胸苷酸合成酶的癌组织表达及血清含量的相关性研究
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摘要
背景及目的:非小细胞肺癌(non-small cell lung cancer,NSCLC)约有80%以上患者确诊时,已为局部晚期或晚期患者,失去了手术机会,化疗则是其治疗最有效的手段。尽管治疗取得了一些进展,但有效率只有20%—40%左右,中位生存仅为8-10月。不同的组织学类型存在着药物基因组学的不同,在不同的种族人群中、不同的个体之间存在着显著的临床疗效和毒性反应的异质性,且部分患者经受着无效以及化疗药物的毒副反应。随着肿瘤分子生物学研究的不断进展,逐渐认识到肿瘤分子基因谱表达的显著差异是指导肿瘤临床个体化化疗的基础,针对肺癌细胞特异的分子靶点选择药物进行治疗的模式,受到了广泛认同。现阶段的分期系统难以准确预测NSCLC患者的治疗结果,因此寻找肺癌的生物学标记,针对不同的组织类型采取不同的治疗模式,成为肿瘤诊断和临床治疗的研究热点。
研究表明,胸苷酸合成酶(Thymidylate synthase,TS)是提供细胞内胸苷的唯一来源,在DNA复制和细胞生长过程中起着关键的作用,在多种肿瘤组织中显示活性明显增加,是已知的抗肿瘤药物的重要有效靶点之一。临床前试验研究显示【1】TS的活性水平影响着抗TS药物对肿瘤的敏感性,其表达水平可能作为TS特异性抑制剂临床疗效的预测的一个指标,与肺腺癌患者密切相关。如何监测NSCLC患者胸甘酸合成酶TS表达水平,以便更好的指导临床药物应用,尚无明确的方法。这方面在消化道肿瘤中的研究比较多,而在肺癌中的研究相对较少。本文通过检测非小细胞肺癌患者胸甘酸合成酶TS血清含量和癌组织中TS蛋白表达水平,研究其与临床特征之间的关系,以及血清含量和蛋白表达两者之间是否存在相关性,从而探讨血清TS水平是否可以反映其在组织中的表达。
研究方法:采用酶联免疫吸附试验法(enzyme linked immunosorbent assay,ELISA)测定2009年1月—2009年9月入组的110例NSCLC患者及34例健康志愿者的血清胸苷酸合成酶TS含量;采用免疫组化方法测定入组的NSCLC患者癌组织腊块中TS蛋白表达水平,分析探讨不同的临床特征的NSCLC患者TS血清含量及蛋白表达是否存在着差异,并进一步分析胸苷酸合成酶TS血清含量及蛋白表达之间的相关性。
结果:
(1)、NSCLC患者胸苷酸合成酶TS血清含量为(68.89±67.69)pg/ml,显著高于健康志愿者的血清水平(23.15±17.08)pg/ml(P<0.05);
(2)、II、III期NSCLC患者血清胸苷酸合成酶TS含量显著高于I期患者,组间比较差异非常显著(P<0.05);
(3)、淋巴结转移者的NSCLC患者血清胸苷酸合成酶TS含量(88.88±103.47)pg/ml,显著高于无淋巴结转移者的患者水平(58.34±33.60)pg/ml ,组间比较具有非常显著的差异(P<0.05);
(4)、NSCLC癌组织中65.50%(72/110)胸苷酸合成酶TS表达阳性;其中肺鳞癌组织中TS阳性表达率为79.20%,显著高于腺癌组织中56.40%的阳性表达率(P<0.05);
(5)、肿瘤分化程度差的癌组织中胸苷酸合成酶TS阳性表达率为87.88%,显著高于中、高分化癌组织中55.84%的表达率(P<0.05);
(6)、淋巴结转移者的NSCLC癌组织胸苷酸合成酶TS蛋白表达78.95%,显著高于无淋巴结转移者组58.33%的表达阳性率(P<0.05);
(7)、血清胸苷酸合成酶TS含量与癌组织中蛋白表达之间存在强相关性(P<0.05)。
结论:
(1)、NSCLC患者胸苷酸合成酶TS血清含量显著高于健康人;
(2)、胸苷酸合成酶TS血清含量与NSCLC患者的肿瘤分期及淋巴结转移有关;
(3)、NSCLC患者癌组织中胸苷酸合成酶TS蛋白表达阳性率为65.50%,与病理类型、淋巴结转移及肿瘤分化程度有关;
(4)、胸苷酸合成酶TS蛋白表达与血清TS含量成正相关,提示NSCLC患者血清TS含量某种程度上可以反映癌组织中TS蛋白表达水平。
Background and objective: More than 80% patients are advanced stage when non-small cell lung cancer (NSCLC) is diagnosed and they misse the chance to be resected. Chemotherapy is one of the effective methods but only 20-40% patients can benefit from it with the median survival of 8-10 months. Parmacogenomics is different with variant histological types. Heterogenicity of effectiveness and toxicity can be found in different race and individual that many of the patients endure ineffective therapy and toxicity. As the study of tumor molecular biology advances, the differentiation of tumor gene pool conduct the individual chemotherapy is gradually recognized. According to specific molecular targets to select therapy are accepted extensively. The stageing system can not precisely predict the effect of the therapy to NSCLC , so research of biologic target to give different therapy to different histologic types is hot topic in dignose and therapy of lung cancer.
Thymidylate synthase(TS)is reported to be the only source of cellular thymidine which play important role in the prosees of DNA copy and cell growth. Activity of thymidine in many tumor tissue are increased and it had been one of the effective target of chemotherapy. Preclinical trial reported【1】the level of TS activity affect the drug activity to tumor. TS level may be a predictive marker of TS inhibitor effect. But how to monitor TS level to guide and value clinical therapy still has not be definitely established. Although more research reported about intestinal tumor, still less reported about lung cancer. So this paper is to study serum TS concentration and tissue TS level, analyse the relation between them and the clinical charecterisms. The objective is to investigate whether serum TS concentration can reflect its tissue level and to offer an effective method to monitor TS in NSCLC patients.
Methods: TS serum concentration and tissue expression were determined in 110 patients with NSCLC by ELISA (enzyme linked immunosorbent assay) and immunohistochemicalstaining respectively. And 34 healthy volunteers were determined TS serum concentration at the same time to be the base line. Correlation was analyzed between TS serum level and tissue expression.
Results:
(1).TS serum concentration of NSCLC patients was (68.89±67.69)pg/ml , while it was (23.15±17.08)pg/ml in the healthy. TS serum concentration was significantly increased in patients with NSCLC(P<0.05);
(2).TS serum concentration was significantly higher in patients with higher TNM stage(P<0.05);
(3).The patients with metastasized lymp node had higher TS serum leve(l88.88±103.47)pg/ml than those without metastasized lymp node(58.34±33.60)pg/ml(P<0.05);
(4).65.50%(72/110)NSCLC patients’tumor tissue expressed TS;The positive expression of TS was related with tumor histologic type.It was espectively 79.20% and 56.40% in adenocarcinoma and squamous carcinoma(P<0.05);
(5).The positive expression of TS was related with tumor differentiation (87.88% to 55.84%)(P<0.05);
(6).With or without metastasized lymp node determined different TS expression in NSCLC tumor sissue(78.95% to 58.33%) (P<0.05);
(7).Significantly correlation was found between TS serum concentration and tissue expression(P<0.05).
Conclusions:
(1).TS serum concentration was significantly increased in patients with NSCLC.
(2).Tumor TNM stage and metastasized lymp node related to TS serum concentration.
(3).65.50% of NSCLC tumor tissue expressed TS and correlated with histologic type, tumor differentiation and metastasized lymp node .
(4).TS serum concentration was significantly correlated to tumor expression. TS serum concentration could reflect its tumor expression .
研究表明,胸苷酸合成酶(Thymidylate synthase,TS)是提供细胞内胸苷的唯一来源,在DNA复制和细胞生长过程中起着关键的作用,在多种肿瘤组织中显示活性明显增加,是已知的抗肿瘤药物的重要有效靶点之一。临床前试验研究显示【1】TS的活性水平影响着抗TS药物对肿瘤的敏感性,其表达水平可能作为TS特异性抑制剂临床疗效的预测的一个指标,与肺腺癌患者密切相关。如何监测NSCLC患者胸甘酸合成酶TS表达水平,以便更好的指导临床药物应用,尚无明确的方法。这方面在消化道肿瘤中的研究比较多,而在肺癌中的研究相对较少。本文通过检测非小细胞肺癌患者胸甘酸合成酶TS血清含量和癌组织中TS蛋白表达水平,研究其与临床特征之间的关系,以及血清含量和蛋白表达两者之间是否存在相关性,从而探讨血清TS水平是否可以反映其在组织中的表达。
研究方法:采用酶联免疫吸附试验法(enzyme linked immunosorbent assay,ELISA)测定2009年1月—2009年9月入组的110例NSCLC患者及34例健康志愿者的血清胸苷酸合成酶TS含量;采用免疫组化方法测定入组的NSCLC患者癌组织腊块中TS蛋白表达水平,分析探讨不同的临床特征的NSCLC患者TS血清含量及蛋白表达是否存在着差异,并进一步分析胸苷酸合成酶TS血清含量及蛋白表达之间的相关性。
结果:
(1)、NSCLC患者胸苷酸合成酶TS血清含量为(68.89±67.69)pg/ml,显著高于健康志愿者的血清水平(23.15±17.08)pg/ml(P<0.05);
(2)、II、III期NSCLC患者血清胸苷酸合成酶TS含量显著高于I期患者,组间比较差异非常显著(P<0.05);
(3)、淋巴结转移者的NSCLC患者血清胸苷酸合成酶TS含量(88.88±103.47)pg/ml,显著高于无淋巴结转移者的患者水平(58.34±33.60)pg/ml ,组间比较具有非常显著的差异(P<0.05);
(4)、NSCLC癌组织中65.50%(72/110)胸苷酸合成酶TS表达阳性;其中肺鳞癌组织中TS阳性表达率为79.20%,显著高于腺癌组织中56.40%的阳性表达率(P<0.05);
(5)、肿瘤分化程度差的癌组织中胸苷酸合成酶TS阳性表达率为87.88%,显著高于中、高分化癌组织中55.84%的表达率(P<0.05);
(6)、淋巴结转移者的NSCLC癌组织胸苷酸合成酶TS蛋白表达78.95%,显著高于无淋巴结转移者组58.33%的表达阳性率(P<0.05);
(7)、血清胸苷酸合成酶TS含量与癌组织中蛋白表达之间存在强相关性(P<0.05)。
结论:
(1)、NSCLC患者胸苷酸合成酶TS血清含量显著高于健康人;
(2)、胸苷酸合成酶TS血清含量与NSCLC患者的肿瘤分期及淋巴结转移有关;
(3)、NSCLC患者癌组织中胸苷酸合成酶TS蛋白表达阳性率为65.50%,与病理类型、淋巴结转移及肿瘤分化程度有关;
(4)、胸苷酸合成酶TS蛋白表达与血清TS含量成正相关,提示NSCLC患者血清TS含量某种程度上可以反映癌组织中TS蛋白表达水平。
Background and objective: More than 80% patients are advanced stage when non-small cell lung cancer (NSCLC) is diagnosed and they misse the chance to be resected. Chemotherapy is one of the effective methods but only 20-40% patients can benefit from it with the median survival of 8-10 months. Parmacogenomics is different with variant histological types. Heterogenicity of effectiveness and toxicity can be found in different race and individual that many of the patients endure ineffective therapy and toxicity. As the study of tumor molecular biology advances, the differentiation of tumor gene pool conduct the individual chemotherapy is gradually recognized. According to specific molecular targets to select therapy are accepted extensively. The stageing system can not precisely predict the effect of the therapy to NSCLC , so research of biologic target to give different therapy to different histologic types is hot topic in dignose and therapy of lung cancer.
Thymidylate synthase(TS)is reported to be the only source of cellular thymidine which play important role in the prosees of DNA copy and cell growth. Activity of thymidine in many tumor tissue are increased and it had been one of the effective target of chemotherapy. Preclinical trial reported【1】the level of TS activity affect the drug activity to tumor. TS level may be a predictive marker of TS inhibitor effect. But how to monitor TS level to guide and value clinical therapy still has not be definitely established. Although more research reported about intestinal tumor, still less reported about lung cancer. So this paper is to study serum TS concentration and tissue TS level, analyse the relation between them and the clinical charecterisms. The objective is to investigate whether serum TS concentration can reflect its tissue level and to offer an effective method to monitor TS in NSCLC patients.
Methods: TS serum concentration and tissue expression were determined in 110 patients with NSCLC by ELISA (enzyme linked immunosorbent assay) and immunohistochemicalstaining respectively. And 34 healthy volunteers were determined TS serum concentration at the same time to be the base line. Correlation was analyzed between TS serum level and tissue expression.
Results:
(1).TS serum concentration of NSCLC patients was (68.89±67.69)pg/ml , while it was (23.15±17.08)pg/ml in the healthy. TS serum concentration was significantly increased in patients with NSCLC(P<0.05);
(2).TS serum concentration was significantly higher in patients with higher TNM stage(P<0.05);
(3).The patients with metastasized lymp node had higher TS serum leve(l88.88±103.47)pg/ml than those without metastasized lymp node(58.34±33.60)pg/ml(P<0.05);
(4).65.50%(72/110)NSCLC patients’tumor tissue expressed TS;The positive expression of TS was related with tumor histologic type.It was espectively 79.20% and 56.40% in adenocarcinoma and squamous carcinoma(P<0.05);
(5).The positive expression of TS was related with tumor differentiation (87.88% to 55.84%)(P<0.05);
(6).With or without metastasized lymp node determined different TS expression in NSCLC tumor sissue(78.95% to 58.33%) (P<0.05);
(7).Significantly correlation was found between TS serum concentration and tissue expression(P<0.05).
Conclusions:
(1).TS serum concentration was significantly increased in patients with NSCLC.
(2).Tumor TNM stage and metastasized lymp node related to TS serum concentration.
(3).65.50% of NSCLC tumor tissue expressed TS and correlated with histologic type, tumor differentiation and metastasized lymp node .
(4).TS serum concentration was significantly correlated to tumor expression. TS serum concentration could reflect its tumor expression .
引文
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1. Diasio RB,Johnson MR.The role of pharmacogenetics and pharmacogenomics in cancer chemotherapy with 5-fluorouracil[J].Pharmacology,2000,61(3):199.
2. Hori T,Takahashi E,Ayusawa D,et al.Regional assignme of the human thymidylate synthase(TS) gene to chromosom band 18p11.32 by nn-isotopicinsitu hybridization[J]. Hu Genet,1990,85(3):576-580.
3. Leichman CG.Thymidylate synthase as a predictor of response[J].Oncology Hunting t,1998,12(8Suppl6):43-47.
4. Fukushima M,Morita M,Ikeda K,et al. Population study of thymidylate synthase and dihydropyrimidine dehydrogenase in patient with solid tumour.Int J Mol Med.2003 Dec;12(6):839-844.
5. Kawakani K,Graziano F,Watamabe G,et al.Prognostic role of thymidylate synthase polymorphisms in gastric cancer patients treated with surgery and adjuvant chemotherapy[J].Clin Cancer Res.2005,11(10):3778-3783.
6. Chu E,Copur SM,Ju J,et al.Thymidylate synthase protein and P53 mRNA from an in vivo ribonucleoprotein complex[J].Mol Cell Biol.1999,19(2):1582-1594.
7. Ishida Y,Kawakami K,Tanska Y,et al.Association of thymidylate synthase gene polymorphism with its mRNA and protein expression and with prognosis in gastric cancer.Anticancer Res,2002,22(5):2805-2809.
8. Choi JH,Lim HY,Nan DK,et al.Expression of thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection.Br J Cancer,2001,84:186-192.
9. Bathe OF,Franceschi D,Livingstone AS,et al.Increased thymidylate synthase gene expression in liver metastases from colorectal carcinoma:implication for chemotherapentic options and survival.Cancer J Sci Am,1999,5(1):34-40.
10. Etienne MC,Chazal M,Laurent-Puig P,et al.Prognostic value of tumoral thymidylate synthase and P53 in metastatic colorectal cancer patients receiving fluorouracil-based chemotherapy:phenotypic and getotypic analyses.J Clin Oncol, 2002, 20(12): 2832-2843.
11. David Edler,Bengt Glimelius,Marja Hallstrom,et al. Thymidylate synthase expression in colorectal cancer:a prognostic and predictive marker of benefit from adjuvant Fluorouracil-based chemotherapy[J].Journal of Clinical Oncology, 2002,20(7): 1721-1728.
12. Patric G,Johnston,Heinz-Josef Lenz,et al.Thymidylate synthase gene and protein expression correlate and are associated with response to 5-Fluorouracil in human colorectal and gastric tumour[J].Cancer Research,1995,55:1407-1412.
13. HUA Dong,HUANG Zhao-hu,DENG Jian-zhong,et al.Expression of thymidylate synthase and thymidine phosphorylase in gastric cancer and their correlation with prognosis[J].China Oncology,2007;10:766-769.
14. Ishikawa Y , Kubotu T , Otani Y , et al.Thymidylate synthase and dihydropyrimidine dehydrogenase levels in gastric cancer[J].Anticancer Res,1999,19:5635-40.
15.陈贤冲,陶国华,仲崇俊等.外周血胸苷酸合成酶mRNA和二氢嘧啶脱氢酶mRNA临床价值探讨.检验医学,2009,1(24):66-68.
16. Hashimoto H,Ozeki Y,Stato M,et al.Signicance of thymidylate synthase gene expression level in patient with adenocarcinoma of the lung.[J], Cancer, 2006, 106(7): 1595-1561.
17. Nakagawa T,Otake Y,Yangihara K,et al.Expression of thymidylate synthase is correlate with prolifitive activity in non-small cell lung cancer(NSCLC)[J].Lung Cancer 2004Feb;43(2):145-149.
18. Shintani Y,Ohta M,Hirabayashi H,et al.New indicator for non-small cell lung cancer :quantitation of thymidylate synthase by real-time reverse transcriotion polymerase chain reaction[J],Int, J cancer 2003,104(6):790-795.
19. Ceppi P,Volante M,Saviozzi S,et al.Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer,2006,107(7):1589-1596.
20. Peterson P,Park K,Fossella F,et al. Is pemetrexed more effective in adenocarcinoma and large cell lung cancer than in squamous cell carcinoma? A retrospective analysis of a phase III trial of pemetrexed vs docetaxel in previously treated patients with advanced non-small cell lung cancer.J Thor Oncol,2007,2(8Suppl4):s851.
21. Takehara A,Kawakami K,Ohta N , et al.Prognostic significance of the polymorphisms in thymidylate synthase and methylente trahydrofolate reductase gene in lung cancer. Anticancer Res,2005,25(6c):4455-4461.
22. Lynch T J, Bell D W, Sordella R, et al. Activating Mutation in the EpidermalGrowth Factor Receptor Underlying Responsiveness of non-Small Cell Lung Cancer to Gefitinib[J]. N Engl J Med, 2004,350:2129-2139.
23. Paez JG,Janne PA,Lee JC,et al. EGFR mutation in lung cancer:correlation with clinical response to gefitinib therapy. Science, 2004, 304:1497-1500.
24. Tracy S, Mukohara T, Hansen M, et al. Gefitinib induces apoptosis in the EGFRL858R non-small cell lung cancer line H3255. Cancer Res, 2004, 64:7241-7244.
25. Han S W, Kin T Y, Hwang P G, et al. Preditive and prongostic impact of epidermal growth factor receptor mutation in non-small cell cancer patients treated with gefitinib[J]. J Clin Oncol, 2005,23:1-9.
26. Mitsudomi T, Kosaka T, Endoh H, et al. Mutation of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treated in patients with non-small cell lung cancer[j]. J Clin Oncol, 2005,11:2513-2520.
27. Hoshi S, Yamaguchi T. Recurrence of Non-small cell lung cancer after successful treatment with Gefitinib receptor of three cases [J]. Gan To Kagaku Ryoho, 2004,31(8):1209-1213.
28. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small cell lung cancer to gefitinib. N Engl J Med, 2005,352:786-792.
29. William P, Vincent A, Miller , et al. Acquired Resistance of Lung Adenocarcinomas to gefitinib or Erlotinib is Associated with a Second Mutation in the EGFR Kinase Domain[J]. PLOS Medicine, 2005,2(3):1-11.
30.潘虹,黄庆,付伟灵.EGFR信号通路基因突变与非小细胞肺癌的靶向性治疗[J].国际检验医学杂志,2009,9(30):869-871.
31.Shirota Y, Stoehlmacher J, Brabender J, et al. ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil Chemotherapy. J Clin Oncol 2001;19:4298-4304.
32. Lord RVN, Brabender J, Gandara D, et al. Low ERCC1 expression correlates with prolonged survival after cisplatin plus emcitabine chemotherapy in non-small-cell lung cancer. Clin Cancer Res 2002;8:2286-2291.
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12.Fukushima M,Morita M,Ikeda K,et al. Population study of thymidylate synthase and dihydropyrimidine dehydrogenase in patient with solid tumour[J]. Int J Mol Med.2003 Dec;12(6):839-844.
13.Kawakani K,Graziano F,Watamabe G,et al.Prognostic role of thymidylate synthase polymorphisms in gastric cancer patients treated with surgery and adjuvant chemotherapy[J].Clin Cancer Res.2005,11(10):3778-3783.
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21.Choi JH,Lim HY,Nan DK,et al.Expression of thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection[J].Br J Cancer,2001,84:186-192.
22.Bathe OF,Franceschi D,Livingstone AS,et al.Increased thymidylate synthase gene expression in liver metastases from colorectal carcinoma:implication forchemotherapentic options and survival[J].Cancer J Sci Am,1999,5(1):34-40.
23. Etienne MC,Chazal M,Laurent-Puig P,et al.Prognostic value of tumoral thymidylate synthase and P53 in metastatic colorectal cancer patients receiving fluorouracil-based chemotherapy:phenotypic and getotypic analyses[J].J Clin Oncol, 2002, 20(12): 2832-2843.
24.David Edler,Bengt Glimelius,Marja Hallstrom,et al. Thymidylate synthase expression in colorectal cancer:a prognostic and predictive marker of benefit from adjuvant Fluorouracil-based chemotherapy[J].Journal of Clinical Oncology,2002;20(7):1721-1728.
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1. Diasio RB,Johnson MR.The role of pharmacogenetics and pharmacogenomics in cancer chemotherapy with 5-fluorouracil[J].Pharmacology,2000,61(3):199.
2. Hori T,Takahashi E,Ayusawa D,et al.Regional assignme of the human thymidylate synthase(TS) gene to chromosom band 18p11.32 by nn-isotopicinsitu hybridization[J]. Hu Genet,1990,85(3):576-580.
3. Leichman CG.Thymidylate synthase as a predictor of response[J].Oncology Hunting t,1998,12(8Suppl6):43-47.
4. Fukushima M,Morita M,Ikeda K,et al. Population study of thymidylate synthase and dihydropyrimidine dehydrogenase in patient with solid tumour.Int J Mol Med.2003 Dec;12(6):839-844.
5. Kawakani K,Graziano F,Watamabe G,et al.Prognostic role of thymidylate synthase polymorphisms in gastric cancer patients treated with surgery and adjuvant chemotherapy[J].Clin Cancer Res.2005,11(10):3778-3783.
6. Chu E,Copur SM,Ju J,et al.Thymidylate synthase protein and P53 mRNA from an in vivo ribonucleoprotein complex[J].Mol Cell Biol.1999,19(2):1582-1594.
7. Ishida Y,Kawakami K,Tanska Y,et al.Association of thymidylate synthase gene polymorphism with its mRNA and protein expression and with prognosis in gastric cancer.Anticancer Res,2002,22(5):2805-2809.
8. Choi JH,Lim HY,Nan DK,et al.Expression of thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection.Br J Cancer,2001,84:186-192.
9. Bathe OF,Franceschi D,Livingstone AS,et al.Increased thymidylate synthase gene expression in liver metastases from colorectal carcinoma:implication for chemotherapentic options and survival.Cancer J Sci Am,1999,5(1):34-40.
10. Etienne MC,Chazal M,Laurent-Puig P,et al.Prognostic value of tumoral thymidylate synthase and P53 in metastatic colorectal cancer patients receiving fluorouracil-based chemotherapy:phenotypic and getotypic analyses.J Clin Oncol, 2002, 20(12): 2832-2843.
11. David Edler,Bengt Glimelius,Marja Hallstrom,et al. Thymidylate synthase expression in colorectal cancer:a prognostic and predictive marker of benefit from adjuvant Fluorouracil-based chemotherapy[J].Journal of Clinical Oncology, 2002,20(7): 1721-1728.
12. Patric G,Johnston,Heinz-Josef Lenz,et al.Thymidylate synthase gene and protein expression correlate and are associated with response to 5-Fluorouracil in human colorectal and gastric tumour[J].Cancer Research,1995,55:1407-1412.
13. HUA Dong,HUANG Zhao-hu,DENG Jian-zhong,et al.Expression of thymidylate synthase and thymidine phosphorylase in gastric cancer and their correlation with prognosis[J].China Oncology,2007;10:766-769.
14. Ishikawa Y , Kubotu T , Otani Y , et al.Thymidylate synthase and dihydropyrimidine dehydrogenase levels in gastric cancer[J].Anticancer Res,1999,19:5635-40.
15.陈贤冲,陶国华,仲崇俊等.外周血胸苷酸合成酶mRNA和二氢嘧啶脱氢酶mRNA临床价值探讨.检验医学,2009,1(24):66-68.
16. Hashimoto H,Ozeki Y,Stato M,et al.Signicance of thymidylate synthase gene expression level in patient with adenocarcinoma of the lung.[J], Cancer, 2006, 106(7): 1595-1561.
17. Nakagawa T,Otake Y,Yangihara K,et al.Expression of thymidylate synthase is correlate with prolifitive activity in non-small cell lung cancer(NSCLC)[J].Lung Cancer 2004Feb;43(2):145-149.
18. Shintani Y,Ohta M,Hirabayashi H,et al.New indicator for non-small cell lung cancer :quantitation of thymidylate synthase by real-time reverse transcriotion polymerase chain reaction[J],Int, J cancer 2003,104(6):790-795.
19. Ceppi P,Volante M,Saviozzi S,et al.Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer,2006,107(7):1589-1596.
20. Peterson P,Park K,Fossella F,et al. Is pemetrexed more effective in adenocarcinoma and large cell lung cancer than in squamous cell carcinoma? A retrospective analysis of a phase III trial of pemetrexed vs docetaxel in previously treated patients with advanced non-small cell lung cancer.J Thor Oncol,2007,2(8Suppl4):s851.
21. Takehara A,Kawakami K,Ohta N , et al.Prognostic significance of the polymorphisms in thymidylate synthase and methylente trahydrofolate reductase gene in lung cancer. Anticancer Res,2005,25(6c):4455-4461.
22. Lynch T J, Bell D W, Sordella R, et al. Activating Mutation in the EpidermalGrowth Factor Receptor Underlying Responsiveness of non-Small Cell Lung Cancer to Gefitinib[J]. N Engl J Med, 2004,350:2129-2139.
23. Paez JG,Janne PA,Lee JC,et al. EGFR mutation in lung cancer:correlation with clinical response to gefitinib therapy. Science, 2004, 304:1497-1500.
24. Tracy S, Mukohara T, Hansen M, et al. Gefitinib induces apoptosis in the EGFRL858R non-small cell lung cancer line H3255. Cancer Res, 2004, 64:7241-7244.
25. Han S W, Kin T Y, Hwang P G, et al. Preditive and prongostic impact of epidermal growth factor receptor mutation in non-small cell cancer patients treated with gefitinib[J]. J Clin Oncol, 2005,23:1-9.
26. Mitsudomi T, Kosaka T, Endoh H, et al. Mutation of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treated in patients with non-small cell lung cancer[j]. J Clin Oncol, 2005,11:2513-2520.
27. Hoshi S, Yamaguchi T. Recurrence of Non-small cell lung cancer after successful treatment with Gefitinib receptor of three cases [J]. Gan To Kagaku Ryoho, 2004,31(8):1209-1213.
28. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small cell lung cancer to gefitinib. N Engl J Med, 2005,352:786-792.
29. William P, Vincent A, Miller , et al. Acquired Resistance of Lung Adenocarcinomas to gefitinib or Erlotinib is Associated with a Second Mutation in the EGFR Kinase Domain[J]. PLOS Medicine, 2005,2(3):1-11.
30.潘虹,黄庆,付伟灵.EGFR信号通路基因突变与非小细胞肺癌的靶向性治疗[J].国际检验医学杂志,2009,9(30):869-871.
31.Shirota Y, Stoehlmacher J, Brabender J, et al. ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil Chemotherapy. J Clin Oncol 2001;19:4298-4304.
32. Lord RVN, Brabender J, Gandara D, et al. Low ERCC1 expression correlates with prolonged survival after cisplatin plus emcitabine chemotherapy in non-small-cell lung cancer. Clin Cancer Res 2002;8:2286-2291.
33. Rosell R, Lord RV, Taron M, et al. DNA repair and cisplatin resistance in non-small-cell lung cancer. Lung cancer 2002;38:217-227.
34.The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin based adjuvant chemotherapy in patients with completely resected non smallcell lung cancer[J]. N Engl J Med, 2004, 350(3):351-360.
35. Altaha R, Liang X, Yu J J, et al. Excision repair cross complementing group 1: Gene expression and platinum resistance[J]. Int J Mol Med, 2004, 14(5):959 970.
36.Joshi M B, Shirota Y, Danerberg K D, et al. High gene expression of TS1,GSTP1 and ERCC1 are risk factors for survival in patients treated with trimodality therapy for esophageal cancer[J]. Clin Cancer Res, 2005, 11(8):2215-2221.
37.Shirota Y, Stoehlmacher J, Brabender J, et al. ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy [ J ] . J Clin Oncol, 2001, 19(5):4298-4304.
38. Ceppi P, Volante M, Novello S, et al. ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non small cell lung cancer treated with cisplatin and gemcitabine[J]. Ann. of Onc., 2006, 17(5):1818 1825.
39. Olaussen K A, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non small-cell lung cancer and cisplatin based adjuvant chemotherapy[J]. New Eng J Med, 2006, 355(10).
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