联合应用三苯氧胺和吉非替尼对NSCLC细胞的抗增殖效应
摘要
目的:探讨雌激素受体拮抗剂TAM联合表皮生长因子受体抑制剂gefitinib对人NSCLC细胞株增殖和凋亡的影响及相关的分子机制,为联合分子靶向和激素治疗NSCLC提供理论依据。方法:以gefitinib及TAM单独或联合处理NSCLC细胞株,MTT法分析细胞增殖,流式细胞仪检测细胞凋亡。应用荧光定量PCR及Western Blot检测三种肺癌细胞株中EGFR及ERβ的表达情况,并分别检测17β-E_2,TAM对细胞中EGFR,以及EGF和gefitinib对ERβ表达的影响,同时还检测了17β-E_2对EGFR的磷酸化作用。结果:联合gefitinib和TAM增强对EGFR,ERβ阳性的A549,H1650细胞的抑制作用,促进凋亡,但对EGFR,ERβ阴性的H520细胞无明显改变。17β-E_2可促进细胞EGFR磷酸化,但抑制其表达,而TAM上调EGFR的表达。同时,EGF及gefitinib对ERβ的表达也有类似的相反的调控作用。结论:联合gefitinib和TAM能够增强对EGFR,ERβ双阳性的肺癌细胞的抑制增殖作用,这可能与细胞内EGFR信号转导途径和雌激素信号通路的交叉有关。因此,EGFR的分子靶向治疗联合激素治疗可能是肺癌治疗的一种有效途径。
Objective: To identify the effect of oestrogen receptor (ER) antagonist, tamoxifen, combination with EGFR tyrosine kinase inhibitor, gefitinib, on the proliferation and apoptosis in non-small cell lung cancer (NSCLC) cell lines and the related molecular mechanism, providing theoretical evidence for the molecular targeted treatment combination with endocrine treatment in NSCLC. Methods: The cell lines were treated with gefitinib and tamoxifen alone or in combination. We detected the cell proliferation with MTT, the cell apoptosis with flow cytometry and the expression of EGFR and ERβwith real-time PCR and western-bolt. In addition, we detect the effect of oestrogen and TAM on the expression of EGFR, the effect of EGF and gefitinib on the expression of ERβ, respectively. The effect of oestrogen on the phospho-EGFR was also detected. Results: The combination of tamoxifen and gefitinib increased the inhibition and apoptosis in EGFR and ERβpositive cell lines A549 and H1650, while showed no significant changes in EGFR and ER negative cell line H520. It was found that oestrogen can promote the phospho-EGFR protein expression, meanwhile, EGFR protein expression was down-regulated in response to estrogen and up-regulated in response to Tamoxifen in vitro. Conversely, ERβexpression was decreased in response to EGF and increased in response to gefitinib. Conclusion: The combination of tamoxifen and gefitinib can promote its antiproliferative effects on EGFR and ERβpositive lung cell lines. These results suggested that this might be involved in cross-signaling between the EGFR/ER pathways in NSCLC. In conclusion, it provided rational to combine gefitinib with hormone therapy for lung cancer treatment.
Objective: To identify the effect of oestrogen receptor (ER) antagonist, tamoxifen, combination with EGFR tyrosine kinase inhibitor, gefitinib, on the proliferation and apoptosis in non-small cell lung cancer (NSCLC) cell lines and the related molecular mechanism, providing theoretical evidence for the molecular targeted treatment combination with endocrine treatment in NSCLC. Methods: The cell lines were treated with gefitinib and tamoxifen alone or in combination. We detected the cell proliferation with MTT, the cell apoptosis with flow cytometry and the expression of EGFR and ERβwith real-time PCR and western-bolt. In addition, we detect the effect of oestrogen and TAM on the expression of EGFR, the effect of EGF and gefitinib on the expression of ERβ, respectively. The effect of oestrogen on the phospho-EGFR was also detected. Results: The combination of tamoxifen and gefitinib increased the inhibition and apoptosis in EGFR and ERβpositive cell lines A549 and H1650, while showed no significant changes in EGFR and ER negative cell line H520. It was found that oestrogen can promote the phospho-EGFR protein expression, meanwhile, EGFR protein expression was down-regulated in response to estrogen and up-regulated in response to Tamoxifen in vitro. Conversely, ERβexpression was decreased in response to EGF and increased in response to gefitinib. Conclusion: The combination of tamoxifen and gefitinib can promote its antiproliferative effects on EGFR and ERβpositive lung cell lines. These results suggested that this might be involved in cross-signaling between the EGFR/ER pathways in NSCLC. In conclusion, it provided rational to combine gefitinib with hormone therapy for lung cancer treatment.
引文
1. American Cancer Society Surveillance Research.Cancer facts and figures 2004. Atlanta (GA): American Cancer Society; 2004. p. 1-60.
2. Miettinen PJ, Berger JE, Meeses J, et al. Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature 1995;376(6538):337-41.
3. Sibilia M, Wagner EF. Strain dependent epithelial defects in mice lacking the EGF receptor. Science 1995;269(5221):234-8.
4. Threadgill DW, Dlugosz AA, Hansen LA, et al.Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 1995;269(5221):230-4.
5. Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2000; 103:211-25.
6. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001 ;2(2): 127-37.
7. Salomon DS, Brandt R, Ciardiello F, Normanno N.Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995;19(3):183-232.
8. Selvaggi G, Novello S, Torri V, et al. Epidermal growth factor receptor overexpression correlates with a poor prognosis in completely resected non-small-cell lung cancer. Ann Oncol 2004; 15:28-32.
9.Patel JD,Bach PB,Kris MG.Lung cancer in US women.A contemporary epidemic.JAMA 2004;291(14):1763-8.
10.张仁汉,陈茂森,付冰(雌二醇和三苯氧胺对小鼠肺腺癌癌基因表达的影响(中华肿瘤杂志)1998,37(3):192-3.
11.Stabile LP,Davis AL,Gubish CT,et al.Human non small cell lung tumors and cells derived from normal lung express both estrogen receptor a and h and show biological responses to estrogen.Cancer Res 2002;62(7):2141-50.
12.Kris MG,Natale RB,Herbst RS,et al.Efficacy of gefitinib,an inhibitor of the epidermal growth factor receptor tyrosine kinase,in symptomatic patients with non-small cell lung cancer:a randomized trial.JAMA 2003;290(16):2149-58.
13.Miller VA,Kris MG,Shah N,et al.Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer.J Clin Oncol 2004;22(6):1103-9.
14.Fujiwara K,Kiura K,Ueoka,et al.Dramatic effect of ZD1839("Iressa")in a patient with advanced non-small cell lung cancer and poor performance status.Lung Cancer 2003;40(1):73-6.
15.Yano S,Kanematsu T,Miki T,et al.A report of two bronchioloalveolar carcinoma cases which were rapidly improved by treatment with the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839("Iressa"). Cancer Sci 2003;94(5):453-8.
16. Hershberger PA, Vasquez AC, Siegfried JM, Nichols MD. Lung cancer cells express estrogen receptor (ER) and coactivators and undergo changes in gene expression in response to ER ligands. Proc AACR 2004;45:289.
17. Sandra Van Schaeybroeck, Joan Kyula, Donal M. Kelly, et al. Chemotherapy-induced epidermal growth factor receptor activation determines response to combined gefitinib/chemotherapy treatment in non-small cell lung cancer cells [J]. Mol Cancer Ther 2006;5(5):1154-1165.
18. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib. N Engl J Med 2004;350(21):2129-39.
19. Tracy S, Mukohara T, Hansen M, et al. Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer cell line H3255. Cancer Res 2004;64(20):7241-4.
20. Chan Zeng, Tim K. Johnson, Paul A. Bunn Jr, et al. The Effects of Cetuximab Alone and in Combination With Radiation and/or Chemotherapy in Lung Cancer. Clinical Cancer Research 2005; 11 (2 Pt 1):795-805.
21. AUGUSTINE RAUCH KA, ZHANGQ, KLEINMANM, et al. A study of vehicles for dosing rodent whole embryo culture with non aqueous soluble compounds [J]. Reprod Toxicol, 2004, 18 (3):391-398.
22. Lee AV, Cui X, Oesterreich S. Cross-talk among estrogen receptor, epidermal growth factor, and insulin-like growth factor signaling in breast cancer. Clin Cancer Res 2001;7 (12 Suppl):4429-35s.
23. Levin ER. Bidirectional signaling between the estrogen receptor and the epidermal growth factor receptor. Mol Endocrinol 2003;17(3):309-17.
24. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib. N Engl J Med 2004;350(21):2129-39.
25. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer:correlation with clinical response to gefitinib therapy. Science 2004;304(5676):1497-500.
26. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated withsensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA.2004;101(36):13306-11.
27. Mitsudomi T, Kosaka T, Endoh H, et al. Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol 2005;23(11):2513-20.
1. Lei W, Mayotte J E,Levitt MA. Enhancement of chemosensitivity and PCD by tyrosine kinase inhibitors correlates with EGFR in NSCLC [J].Anticancer Res 1999 ;19(1A) :221-228.
2. Wells A. The epidermal growth factor receptor (EGFR):A new target in cancer therapy. Signal 2000 ;1 (1) :4-9.
3. Jorissen RN , Walker F , Pouliot N , et al. Epidermal growth factor receptor : Mechanisms of activation and signalling. Exp Cell Res 2003;284 (1):31-53.
4. Vivanco I,Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2(7) :489-501.
5. Chang F, Steelman LS, Lee JT, et al. Signal transduction mediated by the Ras-Raf-MEK-ERK pathway from cytokine receptors to transcription factors :potential targeting for therapeutic intervention. Leukemia 2003 ;17(7):1263-93..
6. Calo V, Migliavacca M, Bazan V, et al. STAT proteins :From normal control of cellular events to tumorigenesis. J Cell Physiol 2003;197(2):157-68.
7. Jemal A, Thomas A, Murray T, et al. Cancer statistics ,2002. CA Cancer J Clin2002;52(1):23-47.
8. Salomon DS, Brandt R, Ciardiello F, Normanno N.Epidermal growth factor-related peptides and their receptors in human malignancies.Crit Rev Oncol Hematol 1995;19(3):183-232.
9.Selvaggi G;Novello S,Torri V,et al.Epidermal growth factor receptor overexpression correlates with a poor prognosis in completely resected non-small-cell lung cancer.Ann Oncol 2004;15:28-32.
10.郭雪君,邓伟武,黄绍光。肺癌基因和抑制基因的研究进展。中华结合和呼吸杂志,1995,18:267-269
11.Hirata A,Ogawa S,Kometsni T,et al.ZD1839(iressa)induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase[J].Cancer Res 2002;62(9):2554-60.
12.VON PAWEL J.Gefitinib(Iressa,ZD1839):a novel targeted approach for the treatment of solid tumors.Bull Cancer,2004;91(5):E70-6.
13.Sharma R,Boyer M,Clarke S,et al.Gefitinib in advanced non-small cell lung cancer.Intern Med J.2005,35(2):77-82
14.Lynch TJ,Bell DW,Sordella R,et al.Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.N Engl J Med 2004;350(21):2129-39.
15.Paez JG,Janne PA,Lee JC,et al.EGFR mutation in lung cancer:correlation with clinical reponse to gefitinib therapy.Science 2004;304(5676):1497-1500.
16. Santoro A, Cavina R, Latteri F, et al. Activity of a specific inhibitor, gefitinib (Iressa, ZD1839), of epidermal growth factor receptor in refractory non - small- cell lung cancer [J]. Ann Oncol 2004;15(1):33-7.
17. Bailey LR, Kris M, Wolf M, et al. Tumor EGFR membrane staining is not clinically relevant for predicting response inpatients receiving gefitinib monotherapy for pretreated advanced non - small cell lung cancer : IDEAL 1 and 2194th Annual Meeting of the American Association for Cancer Research :Washington DC, 2003,1362.
18. Paez JG, Janne PA , Lee JC , et al. EGFR mutations in lung cancer : Correlation with clinical response to gefitinib therapy.Science 2004;304 (5676) :1497-1500.
19. Herbst RS , Maddox AM, Rothenberg ML , et al. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well - tolerated and has activity in non - small - cell lung cancer and other solid tumors : results of a phase I trial. J Clin Oncol, 2002 , 20 (21) :4292-4302.
20. Nakagawa K, Tamura T, Negoro S , et al. Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Japanese patients with solid malignant tumors. Ann Oncol, 2003 ,14 (6) :922-930.
21. Fukuoka M, Yano S, Giaccone G, et al. Multi - institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer(The IDEAL1 Trial)[corrected].J Clin Oncol 2003;21(12):2237-46.
22.Cappuzzo F,Hirsch FR,Rossi E,et al.Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non -small cell lung cancer.J Natl Cancer Inst 2005;97(9):643-55.
23.RANSON M,HAMMOND LA,FERRY D,et al.ZD1839,a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor,is well tolerated and active in patients with solid,malignant tumors:results of a phase I trial[J].J Clin Oncol,2002,20(9):2240-50.
24.Tanovic A,Alfaro V.Gefitinib:current status in the treatment of non-small cell lung cancer.Drugs Today(Barc).2004;40(10):809-27.
25.张仁汉,陈茂森,付冰.雌二醇和三苯氧胺对小鼠肺腺癌癌基因表达的影响.中华肿瘤杂志.1998,37(3):192-3.
26.Philip TC,Dina Rm,Mary RS.Estrogen and progsetrone receptors in bronchogenic carcinoma.Cancer Res,1990,50(20):6632-5.
27.Chi L,ming-sound Tsao.Proto-ocgen and growth factor/recptor expression in the establishment of primary human non-small cell lung carcinoma cell lines.Am J Pathol,1998,142:413-6.
28.Lee TH,Chuang,Hung WC.Tamoxifen induces P21WAF1 amd P27KIPI expression in estrogen receptor-negative Lung cancer cell.Oncogene,1999,18(29):4269-72.
29. Kogan M,Musgrove EA,Sutherland RL.Modulation of the growth-inhibitory effect of pregestins and the antiestrogen hydroxyclomiphene on human cancer by epidermal growth factor and insulin.CancerRes,1989,49(1):112-6.
30. Levin ER.Bidirectional signaling between the estrogen receptor and the epidermal growth factor receptor. Mol Endocrinol 2003;17(3):309-17.
31. Lee AV, Cui X, Oesterreich S.Cross-talk among estrogen receptor, epidermal growth factor, and insulinlike growth factor signaling in breast cancer. Clin Cancer Res 2001;7(12 Suppl):4429s-4435s.
32. Britton DJ, Nicholson RI,et al. Bidirectional cross talk between ERalpha and EGFR signalling pathways regulates tamoxifen-resistant growth. Breast Cancer Res Treat. 2006;96(2):131-46.
33. Selvaggi G, Novello S, Torri V, et al. Epidermal growth factor receptor overexpression correlates with a poor prognosis in completely resected non-small-cell lung cancer. Ann Oncol 2004; 15:28-32.
34. Tanaka K, Sonoo H,et al. Additive antitumour effect of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839) and the antioestrogen fulvestrant (Faslodex, ICI 182,780) in breast cancer cells. Ann Oncol 2004;90(1):236-44.
35. Liu H, Cheng D, Weichel AK, Osipo C, Wing LK, Chen B, Louis TE, Jordan VC.Cooperative effect of gefitinib and fumitremorgin c on cell growth and chemosensitivity in estrogen receptor alpha negative fulvestrant-resistant MCF-7 cells. Int J Oncol. 2006 Nov;29(5):1237-46.
36. Zhao S, Chen X, Lu X, Yu Y, Feng Y.Epidermal growth factor receptor signaling enhanced by long-term medroxyprogesterone acetate treatment in endometrial carcinoma. Gynecol Oncol. 2007;105(1):45-54.
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38. Zhen LL, Zhu X, Zheng W, Wang XY, Wu ZY. Involvement of epidermal growth factor receptor signaling pathway in tamoxifen resistance of MCF-7 cells. Ai Zheng. 2006 Jul;25(7):839-43.
2. Miettinen PJ, Berger JE, Meeses J, et al. Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature 1995;376(6538):337-41.
3. Sibilia M, Wagner EF. Strain dependent epithelial defects in mice lacking the EGF receptor. Science 1995;269(5221):234-8.
4. Threadgill DW, Dlugosz AA, Hansen LA, et al.Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 1995;269(5221):230-4.
5. Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2000; 103:211-25.
6. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001 ;2(2): 127-37.
7. Salomon DS, Brandt R, Ciardiello F, Normanno N.Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995;19(3):183-232.
8. Selvaggi G, Novello S, Torri V, et al. Epidermal growth factor receptor overexpression correlates with a poor prognosis in completely resected non-small-cell lung cancer. Ann Oncol 2004; 15:28-32.
9.Patel JD,Bach PB,Kris MG.Lung cancer in US women.A contemporary epidemic.JAMA 2004;291(14):1763-8.
10.张仁汉,陈茂森,付冰(雌二醇和三苯氧胺对小鼠肺腺癌癌基因表达的影响(中华肿瘤杂志)1998,37(3):192-3.
11.Stabile LP,Davis AL,Gubish CT,et al.Human non small cell lung tumors and cells derived from normal lung express both estrogen receptor a and h and show biological responses to estrogen.Cancer Res 2002;62(7):2141-50.
12.Kris MG,Natale RB,Herbst RS,et al.Efficacy of gefitinib,an inhibitor of the epidermal growth factor receptor tyrosine kinase,in symptomatic patients with non-small cell lung cancer:a randomized trial.JAMA 2003;290(16):2149-58.
13.Miller VA,Kris MG,Shah N,et al.Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer.J Clin Oncol 2004;22(6):1103-9.
14.Fujiwara K,Kiura K,Ueoka,et al.Dramatic effect of ZD1839("Iressa")in a patient with advanced non-small cell lung cancer and poor performance status.Lung Cancer 2003;40(1):73-6.
15.Yano S,Kanematsu T,Miki T,et al.A report of two bronchioloalveolar carcinoma cases which were rapidly improved by treatment with the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839("Iressa"). Cancer Sci 2003;94(5):453-8.
16. Hershberger PA, Vasquez AC, Siegfried JM, Nichols MD. Lung cancer cells express estrogen receptor (ER) and coactivators and undergo changes in gene expression in response to ER ligands. Proc AACR 2004;45:289.
17. Sandra Van Schaeybroeck, Joan Kyula, Donal M. Kelly, et al. Chemotherapy-induced epidermal growth factor receptor activation determines response to combined gefitinib/chemotherapy treatment in non-small cell lung cancer cells [J]. Mol Cancer Ther 2006;5(5):1154-1165.
18. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib. N Engl J Med 2004;350(21):2129-39.
19. Tracy S, Mukohara T, Hansen M, et al. Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer cell line H3255. Cancer Res 2004;64(20):7241-4.
20. Chan Zeng, Tim K. Johnson, Paul A. Bunn Jr, et al. The Effects of Cetuximab Alone and in Combination With Radiation and/or Chemotherapy in Lung Cancer. Clinical Cancer Research 2005; 11 (2 Pt 1):795-805.
21. AUGUSTINE RAUCH KA, ZHANGQ, KLEINMANM, et al. A study of vehicles for dosing rodent whole embryo culture with non aqueous soluble compounds [J]. Reprod Toxicol, 2004, 18 (3):391-398.
22. Lee AV, Cui X, Oesterreich S. Cross-talk among estrogen receptor, epidermal growth factor, and insulin-like growth factor signaling in breast cancer. Clin Cancer Res 2001;7 (12 Suppl):4429-35s.
23. Levin ER. Bidirectional signaling between the estrogen receptor and the epidermal growth factor receptor. Mol Endocrinol 2003;17(3):309-17.
24. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib. N Engl J Med 2004;350(21):2129-39.
25. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer:correlation with clinical response to gefitinib therapy. Science 2004;304(5676):1497-500.
26. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated withsensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA.2004;101(36):13306-11.
27. Mitsudomi T, Kosaka T, Endoh H, et al. Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol 2005;23(11):2513-20.
1. Lei W, Mayotte J E,Levitt MA. Enhancement of chemosensitivity and PCD by tyrosine kinase inhibitors correlates with EGFR in NSCLC [J].Anticancer Res 1999 ;19(1A) :221-228.
2. Wells A. The epidermal growth factor receptor (EGFR):A new target in cancer therapy. Signal 2000 ;1 (1) :4-9.
3. Jorissen RN , Walker F , Pouliot N , et al. Epidermal growth factor receptor : Mechanisms of activation and signalling. Exp Cell Res 2003;284 (1):31-53.
4. Vivanco I,Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2(7) :489-501.
5. Chang F, Steelman LS, Lee JT, et al. Signal transduction mediated by the Ras-Raf-MEK-ERK pathway from cytokine receptors to transcription factors :potential targeting for therapeutic intervention. Leukemia 2003 ;17(7):1263-93..
6. Calo V, Migliavacca M, Bazan V, et al. STAT proteins :From normal control of cellular events to tumorigenesis. J Cell Physiol 2003;197(2):157-68.
7. Jemal A, Thomas A, Murray T, et al. Cancer statistics ,2002. CA Cancer J Clin2002;52(1):23-47.
8. Salomon DS, Brandt R, Ciardiello F, Normanno N.Epidermal growth factor-related peptides and their receptors in human malignancies.Crit Rev Oncol Hematol 1995;19(3):183-232.
9.Selvaggi G;Novello S,Torri V,et al.Epidermal growth factor receptor overexpression correlates with a poor prognosis in completely resected non-small-cell lung cancer.Ann Oncol 2004;15:28-32.
10.郭雪君,邓伟武,黄绍光。肺癌基因和抑制基因的研究进展。中华结合和呼吸杂志,1995,18:267-269
11.Hirata A,Ogawa S,Kometsni T,et al.ZD1839(iressa)induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase[J].Cancer Res 2002;62(9):2554-60.
12.VON PAWEL J.Gefitinib(Iressa,ZD1839):a novel targeted approach for the treatment of solid tumors.Bull Cancer,2004;91(5):E70-6.
13.Sharma R,Boyer M,Clarke S,et al.Gefitinib in advanced non-small cell lung cancer.Intern Med J.2005,35(2):77-82
14.Lynch TJ,Bell DW,Sordella R,et al.Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.N Engl J Med 2004;350(21):2129-39.
15.Paez JG,Janne PA,Lee JC,et al.EGFR mutation in lung cancer:correlation with clinical reponse to gefitinib therapy.Science 2004;304(5676):1497-1500.
16. Santoro A, Cavina R, Latteri F, et al. Activity of a specific inhibitor, gefitinib (Iressa, ZD1839), of epidermal growth factor receptor in refractory non - small- cell lung cancer [J]. Ann Oncol 2004;15(1):33-7.
17. Bailey LR, Kris M, Wolf M, et al. Tumor EGFR membrane staining is not clinically relevant for predicting response inpatients receiving gefitinib monotherapy for pretreated advanced non - small cell lung cancer : IDEAL 1 and 2194th Annual Meeting of the American Association for Cancer Research :Washington DC, 2003,1362.
18. Paez JG, Janne PA , Lee JC , et al. EGFR mutations in lung cancer : Correlation with clinical response to gefitinib therapy.Science 2004;304 (5676) :1497-1500.
19. Herbst RS , Maddox AM, Rothenberg ML , et al. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well - tolerated and has activity in non - small - cell lung cancer and other solid tumors : results of a phase I trial. J Clin Oncol, 2002 , 20 (21) :4292-4302.
20. Nakagawa K, Tamura T, Negoro S , et al. Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Japanese patients with solid malignant tumors. Ann Oncol, 2003 ,14 (6) :922-930.
21. Fukuoka M, Yano S, Giaccone G, et al. Multi - institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer(The IDEAL1 Trial)[corrected].J Clin Oncol 2003;21(12):2237-46.
22.Cappuzzo F,Hirsch FR,Rossi E,et al.Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non -small cell lung cancer.J Natl Cancer Inst 2005;97(9):643-55.
23.RANSON M,HAMMOND LA,FERRY D,et al.ZD1839,a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor,is well tolerated and active in patients with solid,malignant tumors:results of a phase I trial[J].J Clin Oncol,2002,20(9):2240-50.
24.Tanovic A,Alfaro V.Gefitinib:current status in the treatment of non-small cell lung cancer.Drugs Today(Barc).2004;40(10):809-27.
25.张仁汉,陈茂森,付冰.雌二醇和三苯氧胺对小鼠肺腺癌癌基因表达的影响.中华肿瘤杂志.1998,37(3):192-3.
26.Philip TC,Dina Rm,Mary RS.Estrogen and progsetrone receptors in bronchogenic carcinoma.Cancer Res,1990,50(20):6632-5.
27.Chi L,ming-sound Tsao.Proto-ocgen and growth factor/recptor expression in the establishment of primary human non-small cell lung carcinoma cell lines.Am J Pathol,1998,142:413-6.
28.Lee TH,Chuang,Hung WC.Tamoxifen induces P21WAF1 amd P27KIPI expression in estrogen receptor-negative Lung cancer cell.Oncogene,1999,18(29):4269-72.
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