针对HER2/neu的siRNA对非小细胞肺癌生长的抑制作用
|
摘要
肺癌死亡率在世界范围内居恶性肿瘤首位,虽然近年来一些新化疗药物的出现,其治愈率仍然<15%。HER2/neu(erbB2)基因,为表皮生长因子受体(EGFR)家族成员,其编码蛋白为185KDa,具有酪氨酸蛋白激酶活性,与EGFR高度同源。HER2/neu受体可以与家族其他成员形成异源二聚体,从而发挥强有力的肿瘤信号传导作用。研究显示,HER2/neu介导的信号传导与肿瘤的形成、增值、转移、侵袭及放化疗耐药有关。约1/3非小细胞肺癌(NSCLC)存在HER2/neu过表达,HER2/neu过表达在NSCLC形成、增值、转移、侵袭等方面的作用尚需进一步研究证实。
RNA干涉(RNAi)是双链RNA(dsRNA)介导的、序列特异的转录后基因沉默((PTGS )现象,广泛存在于多种自然界。RNAi的核心功能是抗病毒感染免疫,维持基因组中转座子的稳定性,清除异常RNA,同时参与基因表达调控。目前,RNAi技术己发展成为一种新型的基因阻断技术,用于高效特异地关闭或降低特定基因的表达,广泛用于新基因筛选、基因功能鉴定以及基因治疗等方面,在肿瘤、病毒感染等治疗方面已取得积极进展,显示了非常广阔的应用前景。但是,针对HER2/neu的RNAi对NSCLC的研究报道少见。
研究目的
本研究利用siRNA沉默肺癌细胞HER2/neu表达后,通过体外体内系列实验观察肿瘤细胞生物学行为的改变,了解HER2/neu基因在肺癌发生、发展中的作用,检测RNA干涉效果并探讨该方法应用于肺癌基因治疗的潜在药用价值,为肺癌的治疗提供一条新思路。
研究内容
1.根据人HER2/neu mRNA基因编码区序列,设计并合成针对HER2/neu的4条64nt的小发夹RNA(shRNA)模板脱氧寡核苷酸序列,首先构建针对HER2/neu的siRNA表达质粒pSUPER-siHER1和pSUPER-siHER2,并进行酶切鉴定和DNA测序;然后将构建正确的pSUPER-siHER2 H1启动子连同编码siRNA的模板序列用EcoR I和Xho I切出,再连接入去除CMV启动子的pcDNA3.0载体,构建带有新霉素抗性筛选标志的pcDNA3.0-siHER2表达质粒,并进行酶切鉴定。
Lung cancer is the leading cause of cancer death in the world. The cure rate remains <15% despite some advances in chemotherapeutic agents [2]. HER-2/neu gene also called erbB2,is a member of the epidermal growth factor receptor (EGFR)family and encodes a 185 kDa protein with tyrosine kinas activity and shows partial homology to epidermal growth factor receptor.The HER2/neu protein can dimerize with other members of the EGFR family and serves as strong oncogenic signals.The HER2/neu oncogene is over expressed in 30% of Non small cell lung cancer (NSCLC), and its signaling pathways play critical roles in tumor occurring, cancer cell growth, differentiation, metastasis, anti-apoptosis and resistance to chemotherapeutic agents.
RNA interference (RNAi) is the phenomenon of sequence-specific, post- transcriptional gene silencing (PTGS) triggered by double-stranded RNA (dsRNA). RNAi exists in extensive organisms such as Caenorhabditis elegans, plants, mammalian, and is regarded as the genome's immune system. RNAi is now recognized as a mechanism for cellular protection and cleansing: it defends the genome against molecular parasites such as viruses and transposes, while removing abundant but aberrant nonfunctional messenger RNAs, as well as regulate developmental programs in a sequence specific manner. Now RNAi has developed into a novel gene-blocking tool and used to knockdown specific gene expression efficiently in various species. Its application includes screening new genes, functional genomics and virus and cancer gene therapy in which great achievement has been made. However, there is little application report about RNAi targeting HER2/neu gene in NSCLC. Aim
To construct RNA interference vector to down-regulate HER2/neu gene and study the siRNA against HER2/neu effect on the cell cycle, tumor growth, and colony forming capability of lung adenocarcinoma cell line SPC-A-1 in vitro and tumor growth in athymic
RNA干涉(RNAi)是双链RNA(dsRNA)介导的、序列特异的转录后基因沉默((PTGS )现象,广泛存在于多种自然界。RNAi的核心功能是抗病毒感染免疫,维持基因组中转座子的稳定性,清除异常RNA,同时参与基因表达调控。目前,RNAi技术己发展成为一种新型的基因阻断技术,用于高效特异地关闭或降低特定基因的表达,广泛用于新基因筛选、基因功能鉴定以及基因治疗等方面,在肿瘤、病毒感染等治疗方面已取得积极进展,显示了非常广阔的应用前景。但是,针对HER2/neu的RNAi对NSCLC的研究报道少见。
研究目的
本研究利用siRNA沉默肺癌细胞HER2/neu表达后,通过体外体内系列实验观察肿瘤细胞生物学行为的改变,了解HER2/neu基因在肺癌发生、发展中的作用,检测RNA干涉效果并探讨该方法应用于肺癌基因治疗的潜在药用价值,为肺癌的治疗提供一条新思路。
研究内容
1.根据人HER2/neu mRNA基因编码区序列,设计并合成针对HER2/neu的4条64nt的小发夹RNA(shRNA)模板脱氧寡核苷酸序列,首先构建针对HER2/neu的siRNA表达质粒pSUPER-siHER1和pSUPER-siHER2,并进行酶切鉴定和DNA测序;然后将构建正确的pSUPER-siHER2 H1启动子连同编码siRNA的模板序列用EcoR I和Xho I切出,再连接入去除CMV启动子的pcDNA3.0载体,构建带有新霉素抗性筛选标志的pcDNA3.0-siHER2表达质粒,并进行酶切鉴定。
Lung cancer is the leading cause of cancer death in the world. The cure rate remains <15% despite some advances in chemotherapeutic agents [2]. HER-2/neu gene also called erbB2,is a member of the epidermal growth factor receptor (EGFR)family and encodes a 185 kDa protein with tyrosine kinas activity and shows partial homology to epidermal growth factor receptor.The HER2/neu protein can dimerize with other members of the EGFR family and serves as strong oncogenic signals.The HER2/neu oncogene is over expressed in 30% of Non small cell lung cancer (NSCLC), and its signaling pathways play critical roles in tumor occurring, cancer cell growth, differentiation, metastasis, anti-apoptosis and resistance to chemotherapeutic agents.
RNA interference (RNAi) is the phenomenon of sequence-specific, post- transcriptional gene silencing (PTGS) triggered by double-stranded RNA (dsRNA). RNAi exists in extensive organisms such as Caenorhabditis elegans, plants, mammalian, and is regarded as the genome's immune system. RNAi is now recognized as a mechanism for cellular protection and cleansing: it defends the genome against molecular parasites such as viruses and transposes, while removing abundant but aberrant nonfunctional messenger RNAs, as well as regulate developmental programs in a sequence specific manner. Now RNAi has developed into a novel gene-blocking tool and used to knockdown specific gene expression efficiently in various species. Its application includes screening new genes, functional genomics and virus and cancer gene therapy in which great achievement has been made. However, there is little application report about RNAi targeting HER2/neu gene in NSCLC. Aim
To construct RNA interference vector to down-regulate HER2/neu gene and study the siRNA against HER2/neu effect on the cell cycle, tumor growth, and colony forming capability of lung adenocarcinoma cell line SPC-A-1 in vitro and tumor growth in athymic
引文
1. Kurebayashi J Biological and clinical significance of HER2 overexpression in breast cancer. Breast Cancer. 2001;8(1):45-51
2. Turken, E Kunter, H Cermik, T Isitmangil, G Kandemir, M Yaylaci, and A Ozturk Prevalence and prognostic value of c-erbB2 expression in non-small cell lung cancer (NSCLC). Neoplasma, January 1, 2003; 50(4): 257-61.
3. Tiseo M,Loprevite M, Ardizzoni A. Epidermal growth factor receptor inhibitors: a new prospective in the treatment of lung cancer.Curr Med Chem Anti-Canc Agents. 2004 Mar;4(2): 139-48.
4. Mitteldorf CA, Leite KR, Meirelles MI, Gattas GJ, Camara-Lopes LH Overexpression of HER2/neu oncoprotein in cytologic specimens.Acta Cytol. 2004 Mar-Apr;48(2): 199-206
5. Amin DN, Perkins AS,Stern DF. Gene expression profiling of ErbB receptor and ligand- dependent transcription.Oncogene. 2004 Feb 19;23(7):1428-38.
6. Strauss B Best hope or last hope: access to phase III clinical trials of HER-2/neu for advanced stage breast cancer patients. J Adv Nurs. 2000 Feb;31(2):259-66
7. Perez-Soler R. HER1/EGFR targeting: refining the strategy.Oncologist. 2004 ,9(1):58-67.
8. Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy . Oncogene 2000,19,6550-65
9. Albanell J, Codony J, Rovira A, Mellado B, Gascon P. Mechanism of action of anti-HER2 monoclonal antibodies: scientific update ontrastuzumab and 2C4.Adv Exp Med Biol. 2003;532:253-68.
10. Sithanandam G, Smith GT, Masuda A, Takahashi T, Anderson LM, Fornwald LW.Cell cycle activation in lung adenocarcinoma cells by the ErbB3/phospha- tidylinositol 3-kinase/Akt pathway.Carcinogenesis. 2003 Oct;24(10):1581-92.
11. Chen CH, Chernis GA, Hoang VQ, Landgraf R. Inhibition of heregulin signaling by an aptamer that preferentially binds tothe oligomeric form of human epidermal growth factor receptor-3.Proc Natl Acad Sci U S A. 2003 Aug 5;100(16): 9226-3
12. Wingens M,Walma T,van Ingen H,Stortelers C,van Leeuwen JE,van Zoelen EJ,Vuister GW. Structural analysis of an epidermal growth factor/transforming growth factor-alpha chimera with unique ErbB binding specificity. J Biol Chem. 2003 Oct 3;278(40):39114-23.
13. Shin HS,Lee HJ,Nishida M,Lee MS,Tamura R,Yamashita S,Matsuzawa Y, Lee IK,Koh GY. Betacellulin and amphiregulin induce upregulation of cyclin D1 and DNA synthesis activity through differential signaling pathways in vascular smooth muscle cells.Circ Res. 2003 Aug 22;93(4):302-10.
14. Atalay G, Cardoso F, Awada A, Piccart MJ. Novel therapeutic strategies targeting the epidermal growth factor receptor (EGFR) family and its downstream effectors in breast cancer.Ann Oncol. 2003,14(9):1346-63.
15. Azria D,Larbouret C, Robert B, Culine S, Ychou M, Verrelle P, Dubois JB,Pelegrin A.Bull Cancer. 2003 Nov;90 Spec No:S202-12.
16. Schneeweiss A, Katretchko J, Sinn HP, Unnebrink K, Rudlowski C, Geberth M,Beldermann F, Bastert G, Strittmatter HJ. Only grading has independent impact on breast cancer survival after adjustment for pathological response to preoperative chemotherapy.Anticancer Drugs. 2004 Feb;15(2):127-35.
17. Finkle D, Quan ZR, Asghari V, Kloss J, Ghaboosi N, Mai E, Wong WL,Hollingshead P,Schwall R, Koeppen H, Erickson S. HER2-targeted therapy reduces incidence and progression of midlife mammary tumors in female murine mammary tumor virus hu HER2-transgenic mice.Clin Cancer Res. 2004 Apr 1;10(7):2499-511.
18. Srivastava M,Bubendorf L,Raffeld M,Bucher C,Torhorst J,Sauter G,Olsen C, Kallioniemi OP,Eidelman O,Pollard HB. Prognostic impact of ANX7-GTPase in metastatic and HER2-negative breast cancer patients. Clin Cancer Res. 2004 Apr 1;10(7):2344-50.
19. Fergenbaum JH, Garcia-Closas M,Hewitt SM,Lissowska J, Sakoda LC, Sherman ME. Loss of antigenicity in stored sections of breast cancer tissue microarrays.Cancer Epidemiol Biomarkers Prev.2004Apr;13(4):667-72.
20. Ding YB,Wu ZY,Wang S,Fan P,Zha XM,Zheng W,Liu XA.Expression of tyrosine kinase Syk in breast cancer and their clinical Significance Zhonghua Wai Ke Za Zhi. 2004 Mar; 42 (3):137-9. Chinese.
21. Chen FM, Hou MF, Wang JY, Chen TC, Chen DC, Huang SY, Chung YS,Lin SR. High frequency of G/C transversion on p53 gene alterations in breast cancers from Taiwan.Cancer Lett. 2004 Apr 15;207(1):59-67.
22. Eccles SA. The role of c-ErbB-2/HER2/neu in breast cancer progression and metastasis. J Mammary Gland Biol Neoplasia 2001 Oct;6(4):393-406
23. Braun, G. Schlimok, I. Heumos, G. Schaller, L. Riethdorf,G. Reithmuller, and K. Pantel (2001). erbB2 overexpressionon occult metastatic cells in bone marrow predicts poor clinical outcome of stage I–III breast cancer patients. Cancer Res.61:1890–1895.
24. Fuchs IB, Loebbecke M, Buhler H, Stoltenburg-Didinger G, Heine B, LichteneggerW, Schaller G. HER2 in brain metastases: issues of concordance, survival, and treatment.J Clin Oncol.2002 Oct 1;20(19):4130-3.
25. Jensen BV, Johansen JS, Price PA.High levels of serum HER-2/neu and YKL-40 independently reflect aggressivenessof metastatic breast cancer.Clin Cancer Res. 2003 Oct 1;9(12):4423-34.
26. Kunitomo K, Inoue S, Ichihara F, Kono K, Fujii H, Matsumoto A case of metastatic breast cancer with outgrowth of HER2-negative cells after eradication of HER2-positive cells by humanized anti-HER2 monoclonal antibody (trastuzumab) combined with docetaxel. Hum Pathol.2004 Mar;35(3):379-81
27. Penault-Llorca F. Epidermal growth factor receptors: status evaluation methods and tumor expression Bull Cancer. 2003 Nov;90 Spec No:S186-91.
28. L'Allemain G. HER-ErbB family of receptors and their ligands: mechanisms of activation,signals and deregulation in cancer Bull Cancer. 2003 Nov;90 Spec No:S179-85.
29. Gillgrass A, Cardiff RD, Sharan N, Kannan S, Muller WJ. Epidermal growth factor receptor-dependent activation of Gab1 is involved in ErbB-2-mediated mammary tumor progression.Oncogene. 2003 Dec 11;22(57):9151-5.
30. Jhabvala-Romero F, Evans A, Guo S, Denton M, Clinton GM. Herstatin inhibits heregulin-mediated breast cancer cell growth and overcomes tamoxifen resistance in breast cancer cells that overexpress HER-2.Oncogene. 2003 Nov 6;22(50):8178-86.
31. Solit DB, Scher HI, Rosen N. Hsp90 as a therapeutic target in prostate cancer. Semin Oncol. 2003 Oct;30(5):709-16. Review.
32. Hutcheson IR, Knowlden JM, Madden TA, Barrow D, Gee JM, Wakeling AE,Nicholson RI. Oestrogen receptor-mediated modulation of the EGFR/MAPK pathway intamoxifen-resistant MCF-7 cells.Breast Cancer Res Treat. 2003 Sep;81 (1):81-93.
33. Li YM, Pan Y, Wei Y, Cheng X, Zhou BP, Tan M, Zhou X, Xia W, Hortobagyi GN,Yu D, Hung MC. Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis. Cancer Cell. 2004 Nov;6 (5): 459-69.
34. Wang SC, Lien HC, Xia W, Chen IF, Lo HW, Wang Z, Ali-Seyed M, Lee DF,Bartholomeusz G, Ou- Yang F, Giri DK, Hung MC. Binding at and transactivation of the COX-2 promoter by nuclear tyrosine kinase receptor ErbB-2.Cancer Cell. 2004 Sep;6(3):251-61.
35. Qi C, Li DJ.Thermometric analysis of intra-cavitary hyperthermia for esophageal cancer.Int J Hyperthermia. 1999 Sep-Oct;15(5):399-407.
36. Fortin a Raybaud Dh.overexpression of 27kDa heat shock protein in associated with thermoresistance and chemoresistance but not radioresistance Int J Radiat Oncol Boil Bhys, 2000, 46(5):1259-1266
37. Baselga J.Clinical trials of Herceptin(trastuzumab). Eur J Cancer. 2001 Jan;37 Suppl 1:S18-24.
38. Bruskin A, Sivaev I, Persson M, Lundqvist H, Carlsson J, Sjoberg S,Radiobromination of monoclonal antibody using potassium Br(4isothiocyanatobenzyl- ammonio)-bromo-decahydro-closo-dodecaborate (Bromo- DABI). Nucl Med Biol. 2004 Feb;31(2):205-11.
39. Ishihara Y, Harada M, Azuma K, Tamura M, Shomura H, Fujii T, Itoh K,HER2/neu-derived peptides recognized by both cellular and humoral immune systems in HLA-A2+ cancer patients.Int J Oncol. 2004 Apr;24(4):967-75.
40. Wang P, Munger CM, Joshi AD, Pirruccello SJ, Joshi SS. Cytotoxicity of cord blood derived HER2/neu-specific cytotoxic T lymphocytes against human breast cancer in vitro and in vivo.Breast Cancer Res Treat. 2004 Jan;83(1):15-23.
41. Mellstedt H. Monoclonal antibodies in human cancer.Drugs Today (Barc). 2003;39 Suppl C:1-16. Review.
42. Tsai SW,Sun Y,Williams LE,Raubitschek AA,Wu AM,Shively JE. Biodistribution and radioimmunotherapy of human breast cancer xenografts withradiometal-labeled DOTA conjugated anti-HER2/neu antibody 4D5.Bioconjug Chem. 2000 May-Jun;11(3):327-34.
43. Tsai CM, Yu D, Chang KT et al. Enhanced chemoresistance by elevation of p185neu levels in HER-2/neu-transfected human lung cancer cells. J Natl Cancer Inst 1995; 87: 682–4.
44. Yang G, Cai KQ, Thompson-Lanza JA.,et al. Inhibition of Breast and Ovarian Tumor Growth through Multiple Signaling Pathways by Using Retrovirus-mediated Small Interfering RNA against Her-2/neu Gene Expression [J]. The J Biol and Chem, 2004;279(6):4339-45.
45. Choudhury A, Charo J, Parapuram SK, Hunt RC, Hunt DM, Seliger B, Kiessling R.Small interfering RNA (siRNA) inhibits the expression of the Her2/neu gene,upregulates HLA class I and induces apoptosis of Her2/neu positive tumor cell lines. Int J Cancer. 2004 Jan 1;108(1):71-7
46. Cohen EE, Lingen MW, Martin LE, Harris PL, Brannigan BW, Haserlat SM, Okimoto RA, Sgroi DC, Dahiya S, Muir B, Clark JR, Rocco JW, Vokes EE, Haber DA, Bell DW. Response of some head and neck cancers to epidermal growth factor receptor tyrosine kinase inhibitors may be linked to mutation of ERBB2 rather than EGFR.Clin Cancer Res. 2005 Nov 15;11(22):8105-8.
47. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A, et al.Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science.1989 May 12;244(4905):707-12.
48. Winters ZE, Leek RD, Bradburn MJ, Norbury CJ, Harris AL.Cytoplasmic p21WAF1/CIP1 expression is correlated with HER-2/ neu in breast cancer and is an independent predictor of prognosis.Breast Cancer Res.2003;5(6):R242-9.
49. Cappuzzo F, Toschi L, Domenichini I, Bartolini S, Ceresoli GL, Rossi E, Ludovini V, Cancellieri A, Magrini E, Bemis L, Franklin WA, Crino L, Bunn PA Jr, Hirsch FR, Varella-Garcia M. HER3 genomic gain and sensitivity to gefitinib in advanced non-small-cell lung cancer patients.Br J Cancer. 2005 Dec 12;93(12):1334-40.
50. Turken O, Kunter E, Cermik H, Isitmangil T, Kandemir G, Yaylaci M, Ozturk A. Prevalence and prognostic value of c-erbB2 expression in non-small cell lung cancer (NSCLC).Neoplasma. 2003,50(4):257-61.
51. Caterina Pellegrini, Monica Falleni,Antonio Marchetti, Barbara Cassani,MonicaMiozzo, Fiamma Buttitta,Massimo Roncalli, Guido Coggi, and Silvano Bosari.HER-2/Neu alterations in Non-Small Cell Lung Cancer:A Comprehensive Evaluation by Real Time Reverse Transcription-PCR, Fluorescence in Situ. Hybridization, and Immunohistochemistry. Clinical Cancer Res 2003, 9: 3645–52.
52. Bunn PA Jr, Helfrich B, Soriano AF et al. Expression of Her-2/neu in human lung cancer cell lines by immunohistochemistry and fluorescence in situ hybridization and its relationship to in vitro cytotoxicity by trastuzumab and chemotherapeutic agents. Clin Cancer Res 2001; 7: 3239–3250.
53. Tsai CM, Yu D, Chang KT et al. Enhanced chemoresistance by elevation of p185neu levels in HER-2/neu-transfected human lung cancer cells.J Natl Cancer Inst 1995; 87: 682–684.
54. Arribas J, Baselga J. Who will benefit from treatment against EGFR? Lancet Oncol. 2005 May;6(5):257-8.
55. Cappuzzo F, Varella-Garcia M, Shigematsu H, Domenichini I, Bartolini S, Ceresoli GL, Rossi E, Ludovini V, Gregorc V, Toschi L, Franklin WA, Crino L, Gazdar AF, Bunn PA Jr, Hirsch FR. Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients.J Clin Oncol. 2005 Aug 1;23(22):5007-18.
56. Caterina Pellegrini, Monica Falleni,Antonio Marchetti, Barbara Cassani,Monica Miozzo, Fiamma Buttitta,Massimo Roncalli, Guido Coggi, and Silvano Bosari. HER-2/Neu alterations in Non-Small Cell Lung Cancer:A Comprehensive Evaluation by Real Time Reverse Transcription-PCR, Fluorescence in Situ .Hybridization, and Immunohistochemistry. Clinical Cancer Res 2003, 9: 3645–52.
57. Brattstrom D, Wester K, Bergqvist M, Hesselius P, Malmstrom PU, Nordgren H, Wagenius G, Brodin O. HER-2, EGFR, COX-2 expression status correlated to microvessel density and survival in resected non-small cell lung cancer.Acta Oncol. 2004;43(1):80-6.
58. Kim ES, Johnson ED. Novel combinations with docetaxel in the treatment of non-small-cell lung cancer.Clin Lung Cancer. 2005 Dec;7 Suppl 3:S83-6. Review.
59. Krug LM, Miller VA, Patel J, Crapanzano J, Azzoli CG, Gomez J, Kris MG, Heelan RT, Pizzo B, Tyson L, Sheehan C, Ross JS, Venkatraman E. Randomized phase II study ofweekly docetaxel plus trastuzumab versus weekly paclitaxel plus trastuzumab in patients with previously untreated advanced nonsmall cell lung carcinoma.Cancer. 2005 Nov 15;104 (10): 2149-55.
60. Cappuzzo F, Varella-Garcia M, Shigematsu H, Domenichini I, Bartolini S, Ceresoli GL, Rossi E, Ludovini V, Gregorc V, Toschi L, Franklin WA, Crino L, Gazdar AF, Bunn PA Jr, Hirsch FR. Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients.J Clin Oncol. 2005 Aug 1;23(22):5007-18.
61. Altundag O, Altundag K, Ozcakar B, Silay YS. HER2/neu intragenic kinase domain mutations may be major determinant of response to trastuzumab or specific kinase inhibitors in non-small cell lung cancer patients. Lung Cancer. 2005 Aug;49(2): 279-80.
62. Tateishi M., Ishida T., Mitsudomi T., Kaneko S., Sugimachi K. Prognostic value of c-erbB-2 protein expression in human lung adenocarcinoma and squamous cell carcinoma. Eur. J. Cancer, 1991,27: 1372-5.
63. Tateishi M, Ishida T, Kohdono S, Hamatake M, Fukuyama Y, Sugimachi K. Prognostic influence of the co-expression of epidermal growth factor receptor and c-erbB-2 protein in human lung adenocarcinoma.Surg Oncol. 1994 Apr;3(2):109-13.
64. Nakamura, Kawasaki N, Taguchi M, Kabasawa K. Association of HER-2 overexpression with prognosis in nonsmall cell lung carcinoma: a metaanalysis.Cancer. 2005 May 1;103(9):1865-73.
65. Gatzemeier U, Groth G, Butts C et al. Randomized phase II trial of gemcitabine/ cisplatin with or without trastuzumab in Her2-positive non small-cell lung cancer. Ann Oncol Ann Oncol 2002; 13 (suppl 5): 2-9.
66. Lara PN Jr, Laptalo L, Longmate J, Lau DH, Gandour-Edwards R, Gumerlock PH,Doroshow JH, Gandara DR; California Cancer Consortium.Trastuzumab plus docetaxel in HER2/neu-positive non-small-cell lung cancer: a California Cancer Consortium screening and phase II trial. Clin Lung Cancer. 2004 Jan;5(4):231-6.
67. Gatzemeier U, Groth G, Butts C, Van Zandwijk N, Shepherd F, Ardizzoni A, Barton C, Ghahramani P, Hirsh V.Randomized phase II trial of gemcitabine- cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer.Ann Oncol. 2004Jan;15(1):19-27.
68. Krug LM, Miller VA, Patel J, Crapanzano J, Azzoli CG, Gomez J, Kris MG, Heelan RT, Pizzo B, Tyson L, Sheehan C, Ross JS, Venkatraman E. Randomized phase II study of weekly docetaxel plus trastuzumab versus weekly paclitaxel plus trastuzumab in patients with previously untreated advanced nonsmall cell lung carcinoma.Cancer. 2005 Nov 15;104(10):2149-55.
69. Cappuzzo F, Gregorc V, Rossi E, Cancellieri A, Magrini E, Paties CT, Ceresoli G, Lombardo L, Bartolini S, Calandri C, de Rosa M, Villa E, Crino L. Gefitinib in pretreated non-small-cell lung cancer (NSCLC): analysis of efficacy and correlation with HER2 and epidermal growth factor receptor expression in locally advanced or metastatic NSCLC.J Clin Oncol. 2003 Jul 15;21(14):2658-63.
70. Corey J. Langer, Patricia Stephenson, Ann Thor, Mark Vangel, David H. Johnson. Trastuzumab in the Treatment of Advanced Non-Small-Cell Lung Cancer: Is There a Role? Focus on Eastern Cooperative Oncology Group Study 2598 .Journal of Clinical Oncology, Vol 22, No 7 (April 1), 2004: pp. 1180-1187
71. Clamon G, Herndon J, Kern J, Govindan R, Garst J, Watson D, Green M; Cancer and Leukemia Group B. Lack of trastuzumab activity in nonsmall cell lung carcinoma with overexpression of erb-B2: 39810: a phase II trial of Cancer and Leukemia Group B. Cancer. 2005 Apr 15;103(8):1670-5
72. Normanno N, Di Maio M, Perrone F, Campiglio M. Molecular markers to predict response to gefitinib: EGFR, ErbB-2, or more?J Clin Oncol. 2004 May 15;22(10): 2035-6
73. Cappuzzo F, Magrini E, Ceresoli GL, Bartolini S, Rossi E, Ludovini V, Gregorc V, Ligorio C, Cancellieri A, Damiani S, Spreafico A, Paties CT, Lombardo L, Calandri C, Bellezza G, Tonato M, Crino L. Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer.J Natl Cancer Inst. 2004 Aug 4;96(15): 1133-41.
74. Lee JW Lee JW, Soung YH, Kim SY, Park WS, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH. Absence of the ERBB2 kinase domain mutation in lung adenocarcinomas in Korean patients.Int J Cancer. 2005 Sep 10;116(4):652-3.
75. Zabrecky JR, Lam T, McKenzie SJ, Carney W.The extracellular domain of p185/neu is released from the surface of human breast carcinoma cells, SK-BR-3. J Biol Chem. 1991 Jan 25;266(3):1716-20
76. Scott GK, Robles R, Park JW, Montgomery PA, Daniel J, Holmes WE, Lee J, Keller GA, Li WL, Fendly BM, et al. A truncated intracellular HER2/neu receptor produced by alternative RNA processing affects growth of human carcinoma cells.Mol Cell Biol. 1993 Apr;13(4):2247-57.
77. Alper O, Yamaguchi K, Hitomi J, Honda S, Matsushima T, Abe K The presence of c-erbB-2 gene product-related protein in culture medium conditioned by breast cancer cell line SK-BR-3. Cell Growth Differ. 1990 Dec;1(12):591-9.
78. Wang L, Liu B, Schmidt M, Lu Y, Wels W, Fan Z.Antitumor effect of an HER2-specific antibody-toxin fusion protein on human prostate cancer cells.Prostate. 2001 Apr;47(1):21-8.
79. Lin-Tao Jia, Li-Hong Zhang, Cui-Juan Yu, Jing Zhao, Yan-Ming Xu, Jun-Hao Gui, Ming Jin, Zong-Ling Ji, Wei-Hong Wen, Cheng-Ji Wang, Si-Yi Chen and An-Gang Yang.Specific Tumoricidal Activity of a Secreted Proapoptotic Protein Consisting of HER2 Antibody and Constitutively Active Caspase-3. Cancer Res. 2003 Jun 15;63(12):3257-62
80. Zhao J, Zhang LH, Jia LT, Zhang L, Xu YM, Wang Z, Yu CJ, Peng WD, Wen WH, Wang CJ, Chen SY, Yang AG. Secreted antibody/granzyme B fusion protein stimulates selective killing of HER2 over-expressing tumor cells. J Biol Chem. 2004 May 14;279(20):21343-8.
81. Yang AG, Chen SY. A new class of antigen-specific killer cells.Nat Biotechnol. 1997 Jan;15(1):46-51.
82. Xu YM, Wang LF, Jia LT, Qiu XC, Zhao J, Yu CJ, Zhang R, Zhu F, Wang CJ, Jin BQ,Chen SY, Yang AG.A caspase-6 and anti-human epidermal growth factor receptor-2 (HER2) antibodychimeric molecule suppresses the growth of HER2-overexpressing tumors.J Immunol. 2004 Jul 1;173(1):61-7.
83. Schiffer IB, Gebhard S, Heimerdinger CK, Heling A, Hast J, Wollscheid U, Seliger B, Tanner B, Gilbert S, Beckers T, Baasner S, Brenner W, Spangenberg C, Prawitt D, Trost T, Schreiber WG, Zabel B, Thelen M, Lehr HA, Oesch F, Hengstler JG Switching off HER-2/neu in a tetracycline-controlled mouse tumor model leads toapoptosis and tumor-size-dependent remission. Cancer Res. 2003 Nov ; 63(21): 7221-31.
84. Couzin Jennifer.Breakthrough of the year. Small RNAs make big splash.Science. 2002 Dec 20;298(5602): 2296-7.
85. Bosher ,M,Labouesse M.RNA interference: genetic wand and genetic watchdog.Nat Cell Biol. 2000 Feb;2(2):E31-6.
86. Plasterk RH.RNA silencing: the genome's immune system.Science. 2002 May 17;296 (5571): 1263-5.
87. ,Hannon GJ.RNA interference.Nature. 2002 Jul 11;418(6894):244-51.
88. McManus MT, Sharp PA.Gene silencing in mammals by small interfering RNAs.Nat Rev Genet. 2002 Oct;3(10):737-47.
89. Jorgensen R. Altered gene expression in plants due to trans interaction between homologous genes. Trends Biotechnol, 1990,8(12):340-4.
90. Cogoni C, Romano N, Macino G.. Suppression of gene expression by homologous transgenes. Antonie-Van-Leeuwenhoek, 1994, 65(3):205-209.
91. Guo S and Kemphues KJ. Par-1, a gene required for establishing polarity in C.elegans embryos encodes a putative Ser/Thr kinase that is asymmetrically distributed. Cell, 1995, 81(4):611-620.
92. Fire A, Xu S, Montgomery MK, et al. Potent and specific genetic interference by double-stranded RNA in caenorhabditis elegans. Nature, 1998, 391(6669): 806-811.Svoboda P, Stein P, Hayashi H, et al. Selctive reduction of dormant material mRNAs in mouse oocytes by RNA interference. Development, 2000, 127(19): 4147-4156
93. Hamilton AJ, Baulcombe DC .A species of small antisense RNA in posttranscriptional gene silencing in plants.Science. 1999 Oct 29;286(5441):950-2.Zamore PD, Tuschl T, Sharp PA, Bartel DP.RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals.Cell. 2000 Mar 31;101 (1):25-33.
94. Zamore PD, Tuschl T, Sharp PA, Bartel DP. RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals.Cell. 2000 Mar 31;101(1):25-33.
95. Hammond SM, Bernstein E, Beach D, Hannon GJ.An RNA-directed nucleasemediates post-transcriptional gene silencing in Drosophila cells.Nature. 2000 Mar 16;404(6775):293-6.
96. Elbashir SM, Lendeckel W, Tuschl T. RNA interference is mediated by 21-and
22-nucleotide RNAs.Genes Dev. 2001 Jan 15;15(2):188-200
97. Wianny F , Zernicka-Goetz M . Spcific interference with gene function by double-stranded RNA in early mouse development.Nat Cell Biol, 2000, 2(2):70-75.
98. Svoboda P, Stein P, Hayashi H, et al. Selctive reduction of dormant material mRNAs in mouse oocytes by RNA interference. Development, 2000, 127(19): 4147-4156.
99. Elbashir SM, Harborth J, Lendeckel W, et al. Duplexes of 21-nucleotide RNAs mediates RNA interference in cultured mammalian. Nature, 2001, 411(6836): 494-498.
100. Mello CC, Conte D Jr. Revealing the world of RNA interference.Nature. 2004 Sep 16;43 1(7006):338-42.
101. Meister G, Tuschl T. Mechanisms of gene silencing by double-stranded RNA. Nature. 2004 Sep 16;431(7006):343-9.
102. Matzke M, Matzke AJ, Kooter JM.RNA: guiding gene silencing.Science. 2001 Aug 10;
293 (5532):1080-3.
103. Plasterk RH. RNA silencing: The genome’s immune system. Science, 2002,
296(17):263-1265.
104. Nykanen A, Haley B, Zamore PD.ATP requirements and small interfering RNA structure in the RNA interference pathway.Cell. 2001 Nov 2;107(3):309-21.
105. Lee RC, Feinbaum RL, Ambros V.The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14.Cell. 1993 Dec 3;75(5):843-54.
106. Reinhart BJ,Slack FJ,Basson M,et a1.The 21-nucleotide lct-7 RNA regulates developmental timing in Caenorhabditis elegans.Nature,2000,403(6672):901-6.
107. Smallridge R.A small fortune. Nat Rev Mol Cell Biol. 2001 Dec;2(12):867.
108. 108Tabara H,Sarkissian M,Kelly WG.The rde-l gene.RNA interference,and transposon silencing in C.elegans.Cell,1999,99:123-32.
109. Lau NC,Lim LP,Welnstein EG,et a1.An abundant class of tiny RNAs with probable regulatory roles in caenorhabditis elegans.Science,2001,294(1 o):858-862.
110. Misteli T.RNA keeps time from wotln to man.Trends in Cell Biolgy,2001.1 1:57.
111. Ketting RF, Plasterk RH. What's new about RNAi? Meeting on siRNAs and miRNAs.EMBO Rep. 2004 Aug;5(8):762-5.
112. Izquierdo M.Short interfering RNAs as a tool for cancer gene therapy.Cancer Gene Ther. 2005 Mar;12(3):217-27.
113. 3Dennis C.The brave new world of RNA.Nature,2002,418:122-4.
114. Baulcombe D.RNA silencing in plants.Nature. 2004 Sep 16;431(7006):356-63.
115. Lu R, Maduro M, Li F, Li HW, Broitman-Maduro G, Li WX, Ding SW. Animal virus replication and RNAi-mediated antiviral silencing in Caenorhabditis elegans.Nature. 2005 Aug 18;436(7053):1040-3.
116. Caplen NJ. RNAi as a gene therapy approach.Expert Opin Biol Ther. 2003 Jul;3(4):575-86. Review
117. Ketting RF,Fischer SE,Berustein E,Sijen T,Hannon GJ,Plasterk RH.Dicer functions in RNA interference an d in synthesis of small RNA involved in developmental timing in C elegans.Genes Dev,200l,15:2654 ～59.
118. Volpe TA,Kidner C,Hall IM,Teng G,Grewal SI,Martienssen RA.Regulation of heterochromatin silencing and histone H3 lysine-9 methylation by RNAi.Science, 2002,297:1833～37
119. Tijsterman M, Ketting RF, Plasterk RH .The genetics of RNA silencing.Annu Rev Genet. 2002;36:489-519.
120. Doench JG, Petersen CP,Sharp PA.SiRNAs can function as miRNAs.Genes Dev,2003,17:438～42
121. Ambres V,MicroRNA pathways in flies and worms: growth,death,fat,stress,and timing.Cell,2003,I13:673～76
122. Mette MF, Aufsatz W, van der Winden J, Matzke MA, Matzke AJ. Transcriptional silencing and promoter methylation triggered by double-stranded RNA.EMBO J. 2000 Oct 2;19 (19): 5194-201.
123. Jones L, Hamilton AJ, Voinnet O, Thomas CL, Maule AJ, Baulcombe DC. RNA-DNA interactions and DNA methylation in post-transcriptional gene silencing.Plant Cell. 1999 Dec;11(12):2291-301.
124. Elbashir SM, Martinez J, Patkaniowska A, Lendeckel W, Tuschl T. Functional anatomy of siRNAs for mediating efficient RNAi in Drosophila melanogaster embryolysate.EMBO J. 2001 Dec 3;20(23):6877-88.
125. Bohula EA, Salisbury AJ, Sohail M, Playford MP, Riedemann J, Southern EM, Macaulay VM. The efficacy of small interfering RNAs targeted to the type 1 insulin-like growth factor receptor (IGF1R) is influenced by secondary structure in the IGF1R transcript. J Biol Chem. 2003 May 2;278(18):15991-7.
126. Banan M, Puri N. The ins and outs of RNAi in mammalian cells.Curr Pharm Biotechnol. 2004 Oct;5(5):441-50. Review.
127. Yang N, Zhang L, Kazazian HH Jr. L1 retrotransposon-mediated stable gene silencing.Nucleic Acids Res. 2005 Mar 30;33(6):e57.
128. Jackson AL, Bartz SR, Schelter J, Kobayashi SV, Burchard J, Mao M, Li B, Cavet G, Linsley PS. Expression profiling reveals off-target gene regulation by RNAi. Nat Biotechnol. 2003 Jun;21(6):635-7.
129. Czauderna F, Fechtner M, Dames S, Aygun H, Klippel A, Pronk GJ, Giese K, Kaufmann J. Structural variations and stabilising modifications of synthetic siRNAs in mammalian cells.Nucleic Acids Res. 2003 Jun 1;31(11):2705-16.
130. Braasch DA, Jensen S, Liu Y, Kaur K, Arar K, White MA, Corey DR. RNA interference in mammalian cells by chemically-modified RNA.Biochemistry. 2003 Jul 8;42(26):7967-75.
131. Yotnda P, Davis AR, Hicks MJ, Templeton NS, Brenner MK. Liposomal enhancement of the antitumor activity of conditionally replication-competent adenoviral plasmids.Mol Ther. 2004 Apr;9(4):489-95.
132. Izquierdo M. Short interfering RNAs as a tool for cancer gene therapy.Cancer Gene Ther. 2005 Mar;12(3):217-27. Review
133. 李庆霞,刘家云,黄红艳,许彦鸣,贾林涛,赵晶,王成济,杨安钢.针对 survivin表达的siRNA对人乳腺癌SKBr-3细胞中survivin基因的干涉作用. 中国肿瘤生物治疗杂志,2004;11(4):277-280
134. Cottrell TR, Doering TL.Silence of the strands: RNA interference in eukaryotic Trends Microbiol. 2003 Jan;11(1):37-43. Review
135. Zhang L, Yang N, Mohamed-Hadley A, Rubin SC, Coukos G. Vector-based RNAi, a novel tool for isoform-specific knock-down of VEGF and anti-angiogenesis gene therapy of cancer.Biochem Biophys Res Commun. 2003 Apr 18;303(4):1169-78.
136. Yen L, Svendsen J, Lee JS, Gray JT, Magnier M, Baba T, D'Amato RJ, Mulligan RC. Exogenous control of mammalian gene expression through modulation of RNA self-cleavage. Nature. 2004 Sep 23;431(7007):471-6.
137. Klein C, Bock CT, Wedemeyer H, Wustefeld T, Locarnini S, Dienes HP, Kubicka S, Manns MP, Trautwein C. Inhibition of hepatitis B virus replication in vivo by nucleoside analogues and siRNA.Gastroenterology. 2003 Jul;125(1):9-18.
138. McCaffrey AP, Nakai H, Pandey K, Huang Z, Salazar FH, Xu H, Wieland SF, Marion PL, Kay MA. Inhibition of hepatitis B virus in mice by RNA interference.Nat Biotechnol. 2003 Jun;21(6):639-44.
139. Zhang X, Shan P, Jiang D, Noble PW, Abraham NG, Kappas A, Lee PJ. Small interfering RNA targeting heme oxygenase-1 enhances ischemia-reperfusion- induced lung apoptosis. J Biol Chem. 2004, 12;279(11):10677-84.
140. Song E, Zhu P, Lee SK, Chowdhury D, Kussman S, Dykxhoorn DM, Feng Y, Palliser D, Weiner DB, Shankar P, Marasco WA, Lieberman J. Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nat Biotechnol. 2005 Jun;23(6):709-17.
141. Zhu G, Gilchrist R, Borley N, et al. Reduction of TSG101 protein has a negative impact on tumor cell growth. Int J Cancer, 2004, 109(4):541-7.
142. Hart S, Fischer OM, Ullrich A. Cannabinoids induce cancer cell proliferation via tumor necrosis factor alpha converting enzyme (TACE/ADAM17)-mediated transactivation of the epidermal growth factor receptor. Cancer Res, 2004, 64(6): 1943-50.
143. Yague E, Higgins CF, Raguz S.Complete reversal of multidrug resistance by stable expression of small interfering RNAs targeting MDR1. Gene Ther, 2004, 11(14):1170-4.
144. Wu H,Hait W.N.,and Yang JM..Small interfering RNA-induced suppression of MDR1(P-glocoprotein)restores sensitivity to multidrug-resistant cancer cells. Cancer Res, 2003, 63(7):1515-9.
145. Lima RT, Martins LM, Guimaraes JE, et al. Specific downregulation of bcl-2 and xIAP by RNAi enhances the effects of chemotherapeutic agents in MCF-7 human breast cancer cells. Cancer Gene Ther, 2004, 11(5):309-16.
146. Zhang L, Yang N, Mohamed-Hadley A, et al. Vector-based RNAi, a novel tool for isoform-specific knock-down of VEGF and anti-angiogenesis gene therapy of cancer. Biochem Biophys Res Commun, 2003, 303(4): 1169-78.
147. Filleur S, Courtin A, Ait-Si-Ali S, et al. SiRNA-mediated inhibition of vascular endothelial growth factor severely limits tumor resistence to antiangiogenic thrombospondin-1 and slows tumor vascularization and growth. Cancer Res, 2003, 63(14):3919-22.
148. Crnkovic-Mertens I, Hoppe-Seyler F, Butz K. Induction of apoptosis in tumor cells by siRNA-mediated silencing of the livin/ML-IAP/KIAP gene. Oncogene, 2003, 22(51): 8330-6.
149. Wilda M, Fuchs U, Wossmann W, et al. Killing of leukemia cells with a BCR/ABL fusion gene by RNA interference (RNAi). Oncogene, 2002, 21(37): 5716-24.
150. Nagy P, Arndt-Jovin DJ, Jovin TM. Small interfering RNAs suppress the expression of endogenous and GFP-fused epidermal growth factor receptor (erbB1) and induce apoptosis in erbB1-overexpressing cells. Exp Cell Res, 2003, 15;285(1):39-49.
151. Lin SL, Chuong CM, Ying SY. A Novel mRNA-cDNA interference phenomenon for silencing bcl-2 expression in human LNCaP cells. Biochem Biophys Res Commun, 2001, 28(3): 639-644.
152. 张敏,张新,白春学.RNA 干扰技术抑制非小细胞肺癌表皮生长因子受体的表达. 中华内科杂志,2004,43(5):45-48.
153. Yin JQ, Gao J, Shao R, et al. siRNA agents inhibit oncogene expression and attenuate human tumor cell growth. J Exp Ther Oncol, 2003, 3(4):194-204.
154. 刘家云, 贾林涛, 王成济, 杨安钢. RNAi—dsRNA 介导的基因沉默. 国外医学遗传学分册, 2004; 27(1):4-1
155. van Rij RP, Andino R. The silent treatment: RNAi as a defense against virus infection in mammals.Trends Biotechnol. 2006;24(4):186-93
156. Stevenson M. Therapeutic potential of RNA interference. N Engl J Med. 2004 Oct 21;351(17):1772-7.
157. Sledz CA, Williams BR. RNA interference in biology and disease.Blood. 2005 Aug 1;106(3):787-94.
158. Paroo Z, Corey DR. Challenges for RNAi in vivo.Trends Biotechnol. 2004 Aug;22(8):390-4.
159. Ma J, Kahwaji CI, Ni Z, Vaziri ND, Purdy RE. Effects of simulated microgravity on arterial nitric oxide synthase and nitrate and nitrite content.J Appl Physiol. 2003,94(1):83-92.
160. 任新玲,沈丽英,金伯泉,戚好文,马进. 表皮生长因子受体单克隆抗体体内外抗肺癌作用的研究. 肿瘤,2000;20(1):35-37.
161. Chalfie M, Tu Y, Euskirchen G, et al. Green fluorescent protein as a marker for gene expression. Science, 1994, 263(5148):802-805.
2. Turken, E Kunter, H Cermik, T Isitmangil, G Kandemir, M Yaylaci, and A Ozturk Prevalence and prognostic value of c-erbB2 expression in non-small cell lung cancer (NSCLC). Neoplasma, January 1, 2003; 50(4): 257-61.
3. Tiseo M,Loprevite M, Ardizzoni A. Epidermal growth factor receptor inhibitors: a new prospective in the treatment of lung cancer.Curr Med Chem Anti-Canc Agents. 2004 Mar;4(2): 139-48.
4. Mitteldorf CA, Leite KR, Meirelles MI, Gattas GJ, Camara-Lopes LH Overexpression of HER2/neu oncoprotein in cytologic specimens.Acta Cytol. 2004 Mar-Apr;48(2): 199-206
5. Amin DN, Perkins AS,Stern DF. Gene expression profiling of ErbB receptor and ligand- dependent transcription.Oncogene. 2004 Feb 19;23(7):1428-38.
6. Strauss B Best hope or last hope: access to phase III clinical trials of HER-2/neu for advanced stage breast cancer patients. J Adv Nurs. 2000 Feb;31(2):259-66
7. Perez-Soler R. HER1/EGFR targeting: refining the strategy.Oncologist. 2004 ,9(1):58-67.
8. Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy . Oncogene 2000,19,6550-65
9. Albanell J, Codony J, Rovira A, Mellado B, Gascon P. Mechanism of action of anti-HER2 monoclonal antibodies: scientific update ontrastuzumab and 2C4.Adv Exp Med Biol. 2003;532:253-68.
10. Sithanandam G, Smith GT, Masuda A, Takahashi T, Anderson LM, Fornwald LW.Cell cycle activation in lung adenocarcinoma cells by the ErbB3/phospha- tidylinositol 3-kinase/Akt pathway.Carcinogenesis. 2003 Oct;24(10):1581-92.
11. Chen CH, Chernis GA, Hoang VQ, Landgraf R. Inhibition of heregulin signaling by an aptamer that preferentially binds tothe oligomeric form of human epidermal growth factor receptor-3.Proc Natl Acad Sci U S A. 2003 Aug 5;100(16): 9226-3
12. Wingens M,Walma T,van Ingen H,Stortelers C,van Leeuwen JE,van Zoelen EJ,Vuister GW. Structural analysis of an epidermal growth factor/transforming growth factor-alpha chimera with unique ErbB binding specificity. J Biol Chem. 2003 Oct 3;278(40):39114-23.
13. Shin HS,Lee HJ,Nishida M,Lee MS,Tamura R,Yamashita S,Matsuzawa Y, Lee IK,Koh GY. Betacellulin and amphiregulin induce upregulation of cyclin D1 and DNA synthesis activity through differential signaling pathways in vascular smooth muscle cells.Circ Res. 2003 Aug 22;93(4):302-10.
14. Atalay G, Cardoso F, Awada A, Piccart MJ. Novel therapeutic strategies targeting the epidermal growth factor receptor (EGFR) family and its downstream effectors in breast cancer.Ann Oncol. 2003,14(9):1346-63.
15. Azria D,Larbouret C, Robert B, Culine S, Ychou M, Verrelle P, Dubois JB,Pelegrin A.Bull Cancer. 2003 Nov;90 Spec No:S202-12.
16. Schneeweiss A, Katretchko J, Sinn HP, Unnebrink K, Rudlowski C, Geberth M,Beldermann F, Bastert G, Strittmatter HJ. Only grading has independent impact on breast cancer survival after adjustment for pathological response to preoperative chemotherapy.Anticancer Drugs. 2004 Feb;15(2):127-35.
17. Finkle D, Quan ZR, Asghari V, Kloss J, Ghaboosi N, Mai E, Wong WL,Hollingshead P,Schwall R, Koeppen H, Erickson S. HER2-targeted therapy reduces incidence and progression of midlife mammary tumors in female murine mammary tumor virus hu HER2-transgenic mice.Clin Cancer Res. 2004 Apr 1;10(7):2499-511.
18. Srivastava M,Bubendorf L,Raffeld M,Bucher C,Torhorst J,Sauter G,Olsen C, Kallioniemi OP,Eidelman O,Pollard HB. Prognostic impact of ANX7-GTPase in metastatic and HER2-negative breast cancer patients. Clin Cancer Res. 2004 Apr 1;10(7):2344-50.
19. Fergenbaum JH, Garcia-Closas M,Hewitt SM,Lissowska J, Sakoda LC, Sherman ME. Loss of antigenicity in stored sections of breast cancer tissue microarrays.Cancer Epidemiol Biomarkers Prev.2004Apr;13(4):667-72.
20. Ding YB,Wu ZY,Wang S,Fan P,Zha XM,Zheng W,Liu XA.Expression of tyrosine kinase Syk in breast cancer and their clinical Significance Zhonghua Wai Ke Za Zhi. 2004 Mar; 42 (3):137-9. Chinese.
21. Chen FM, Hou MF, Wang JY, Chen TC, Chen DC, Huang SY, Chung YS,Lin SR. High frequency of G/C transversion on p53 gene alterations in breast cancers from Taiwan.Cancer Lett. 2004 Apr 15;207(1):59-67.
22. Eccles SA. The role of c-ErbB-2/HER2/neu in breast cancer progression and metastasis. J Mammary Gland Biol Neoplasia 2001 Oct;6(4):393-406
23. Braun, G. Schlimok, I. Heumos, G. Schaller, L. Riethdorf,G. Reithmuller, and K. Pantel (2001). erbB2 overexpressionon occult metastatic cells in bone marrow predicts poor clinical outcome of stage I–III breast cancer patients. Cancer Res.61:1890–1895.
24. Fuchs IB, Loebbecke M, Buhler H, Stoltenburg-Didinger G, Heine B, LichteneggerW, Schaller G. HER2 in brain metastases: issues of concordance, survival, and treatment.J Clin Oncol.2002 Oct 1;20(19):4130-3.
25. Jensen BV, Johansen JS, Price PA.High levels of serum HER-2/neu and YKL-40 independently reflect aggressivenessof metastatic breast cancer.Clin Cancer Res. 2003 Oct 1;9(12):4423-34.
26. Kunitomo K, Inoue S, Ichihara F, Kono K, Fujii H, Matsumoto A case of metastatic breast cancer with outgrowth of HER2-negative cells after eradication of HER2-positive cells by humanized anti-HER2 monoclonal antibody (trastuzumab) combined with docetaxel. Hum Pathol.2004 Mar;35(3):379-81
27. Penault-Llorca F. Epidermal growth factor receptors: status evaluation methods and tumor expression Bull Cancer. 2003 Nov;90 Spec No:S186-91.
28. L'Allemain G. HER-ErbB family of receptors and their ligands: mechanisms of activation,signals and deregulation in cancer Bull Cancer. 2003 Nov;90 Spec No:S179-85.
29. Gillgrass A, Cardiff RD, Sharan N, Kannan S, Muller WJ. Epidermal growth factor receptor-dependent activation of Gab1 is involved in ErbB-2-mediated mammary tumor progression.Oncogene. 2003 Dec 11;22(57):9151-5.
30. Jhabvala-Romero F, Evans A, Guo S, Denton M, Clinton GM. Herstatin inhibits heregulin-mediated breast cancer cell growth and overcomes tamoxifen resistance in breast cancer cells that overexpress HER-2.Oncogene. 2003 Nov 6;22(50):8178-86.
31. Solit DB, Scher HI, Rosen N. Hsp90 as a therapeutic target in prostate cancer. Semin Oncol. 2003 Oct;30(5):709-16. Review.
32. Hutcheson IR, Knowlden JM, Madden TA, Barrow D, Gee JM, Wakeling AE,Nicholson RI. Oestrogen receptor-mediated modulation of the EGFR/MAPK pathway intamoxifen-resistant MCF-7 cells.Breast Cancer Res Treat. 2003 Sep;81 (1):81-93.
33. Li YM, Pan Y, Wei Y, Cheng X, Zhou BP, Tan M, Zhou X, Xia W, Hortobagyi GN,Yu D, Hung MC. Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis. Cancer Cell. 2004 Nov;6 (5): 459-69.
34. Wang SC, Lien HC, Xia W, Chen IF, Lo HW, Wang Z, Ali-Seyed M, Lee DF,Bartholomeusz G, Ou- Yang F, Giri DK, Hung MC. Binding at and transactivation of the COX-2 promoter by nuclear tyrosine kinase receptor ErbB-2.Cancer Cell. 2004 Sep;6(3):251-61.
35. Qi C, Li DJ.Thermometric analysis of intra-cavitary hyperthermia for esophageal cancer.Int J Hyperthermia. 1999 Sep-Oct;15(5):399-407.
36. Fortin a Raybaud Dh.overexpression of 27kDa heat shock protein in associated with thermoresistance and chemoresistance but not radioresistance Int J Radiat Oncol Boil Bhys, 2000, 46(5):1259-1266
37. Baselga J.Clinical trials of Herceptin(trastuzumab). Eur J Cancer. 2001 Jan;37 Suppl 1:S18-24.
38. Bruskin A, Sivaev I, Persson M, Lundqvist H, Carlsson J, Sjoberg S,Radiobromination of monoclonal antibody using potassium Br(4isothiocyanatobenzyl- ammonio)-bromo-decahydro-closo-dodecaborate (Bromo- DABI). Nucl Med Biol. 2004 Feb;31(2):205-11.
39. Ishihara Y, Harada M, Azuma K, Tamura M, Shomura H, Fujii T, Itoh K,HER2/neu-derived peptides recognized by both cellular and humoral immune systems in HLA-A2+ cancer patients.Int J Oncol. 2004 Apr;24(4):967-75.
40. Wang P, Munger CM, Joshi AD, Pirruccello SJ, Joshi SS. Cytotoxicity of cord blood derived HER2/neu-specific cytotoxic T lymphocytes against human breast cancer in vitro and in vivo.Breast Cancer Res Treat. 2004 Jan;83(1):15-23.
41. Mellstedt H. Monoclonal antibodies in human cancer.Drugs Today (Barc). 2003;39 Suppl C:1-16. Review.
42. Tsai SW,Sun Y,Williams LE,Raubitschek AA,Wu AM,Shively JE. Biodistribution and radioimmunotherapy of human breast cancer xenografts withradiometal-labeled DOTA conjugated anti-HER2/neu antibody 4D5.Bioconjug Chem. 2000 May-Jun;11(3):327-34.
43. Tsai CM, Yu D, Chang KT et al. Enhanced chemoresistance by elevation of p185neu levels in HER-2/neu-transfected human lung cancer cells. J Natl Cancer Inst 1995; 87: 682–4.
44. Yang G, Cai KQ, Thompson-Lanza JA.,et al. Inhibition of Breast and Ovarian Tumor Growth through Multiple Signaling Pathways by Using Retrovirus-mediated Small Interfering RNA against Her-2/neu Gene Expression [J]. The J Biol and Chem, 2004;279(6):4339-45.
45. Choudhury A, Charo J, Parapuram SK, Hunt RC, Hunt DM, Seliger B, Kiessling R.Small interfering RNA (siRNA) inhibits the expression of the Her2/neu gene,upregulates HLA class I and induces apoptosis of Her2/neu positive tumor cell lines. Int J Cancer. 2004 Jan 1;108(1):71-7
46. Cohen EE, Lingen MW, Martin LE, Harris PL, Brannigan BW, Haserlat SM, Okimoto RA, Sgroi DC, Dahiya S, Muir B, Clark JR, Rocco JW, Vokes EE, Haber DA, Bell DW. Response of some head and neck cancers to epidermal growth factor receptor tyrosine kinase inhibitors may be linked to mutation of ERBB2 rather than EGFR.Clin Cancer Res. 2005 Nov 15;11(22):8105-8.
47. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A, et al.Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science.1989 May 12;244(4905):707-12.
48. Winters ZE, Leek RD, Bradburn MJ, Norbury CJ, Harris AL.Cytoplasmic p21WAF1/CIP1 expression is correlated with HER-2/ neu in breast cancer and is an independent predictor of prognosis.Breast Cancer Res.2003;5(6):R242-9.
49. Cappuzzo F, Toschi L, Domenichini I, Bartolini S, Ceresoli GL, Rossi E, Ludovini V, Cancellieri A, Magrini E, Bemis L, Franklin WA, Crino L, Bunn PA Jr, Hirsch FR, Varella-Garcia M. HER3 genomic gain and sensitivity to gefitinib in advanced non-small-cell lung cancer patients.Br J Cancer. 2005 Dec 12;93(12):1334-40.
50. Turken O, Kunter E, Cermik H, Isitmangil T, Kandemir G, Yaylaci M, Ozturk A. Prevalence and prognostic value of c-erbB2 expression in non-small cell lung cancer (NSCLC).Neoplasma. 2003,50(4):257-61.
51. Caterina Pellegrini, Monica Falleni,Antonio Marchetti, Barbara Cassani,MonicaMiozzo, Fiamma Buttitta,Massimo Roncalli, Guido Coggi, and Silvano Bosari.HER-2/Neu alterations in Non-Small Cell Lung Cancer:A Comprehensive Evaluation by Real Time Reverse Transcription-PCR, Fluorescence in Situ. Hybridization, and Immunohistochemistry. Clinical Cancer Res 2003, 9: 3645–52.
52. Bunn PA Jr, Helfrich B, Soriano AF et al. Expression of Her-2/neu in human lung cancer cell lines by immunohistochemistry and fluorescence in situ hybridization and its relationship to in vitro cytotoxicity by trastuzumab and chemotherapeutic agents. Clin Cancer Res 2001; 7: 3239–3250.
53. Tsai CM, Yu D, Chang KT et al. Enhanced chemoresistance by elevation of p185neu levels in HER-2/neu-transfected human lung cancer cells.J Natl Cancer Inst 1995; 87: 682–684.
54. Arribas J, Baselga J. Who will benefit from treatment against EGFR? Lancet Oncol. 2005 May;6(5):257-8.
55. Cappuzzo F, Varella-Garcia M, Shigematsu H, Domenichini I, Bartolini S, Ceresoli GL, Rossi E, Ludovini V, Gregorc V, Toschi L, Franklin WA, Crino L, Gazdar AF, Bunn PA Jr, Hirsch FR. Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients.J Clin Oncol. 2005 Aug 1;23(22):5007-18.
56. Caterina Pellegrini, Monica Falleni,Antonio Marchetti, Barbara Cassani,Monica Miozzo, Fiamma Buttitta,Massimo Roncalli, Guido Coggi, and Silvano Bosari. HER-2/Neu alterations in Non-Small Cell Lung Cancer:A Comprehensive Evaluation by Real Time Reverse Transcription-PCR, Fluorescence in Situ .Hybridization, and Immunohistochemistry. Clinical Cancer Res 2003, 9: 3645–52.
57. Brattstrom D, Wester K, Bergqvist M, Hesselius P, Malmstrom PU, Nordgren H, Wagenius G, Brodin O. HER-2, EGFR, COX-2 expression status correlated to microvessel density and survival in resected non-small cell lung cancer.Acta Oncol. 2004;43(1):80-6.
58. Kim ES, Johnson ED. Novel combinations with docetaxel in the treatment of non-small-cell lung cancer.Clin Lung Cancer. 2005 Dec;7 Suppl 3:S83-6. Review.
59. Krug LM, Miller VA, Patel J, Crapanzano J, Azzoli CG, Gomez J, Kris MG, Heelan RT, Pizzo B, Tyson L, Sheehan C, Ross JS, Venkatraman E. Randomized phase II study ofweekly docetaxel plus trastuzumab versus weekly paclitaxel plus trastuzumab in patients with previously untreated advanced nonsmall cell lung carcinoma.Cancer. 2005 Nov 15;104 (10): 2149-55.
60. Cappuzzo F, Varella-Garcia M, Shigematsu H, Domenichini I, Bartolini S, Ceresoli GL, Rossi E, Ludovini V, Gregorc V, Toschi L, Franklin WA, Crino L, Gazdar AF, Bunn PA Jr, Hirsch FR. Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients.J Clin Oncol. 2005 Aug 1;23(22):5007-18.
61. Altundag O, Altundag K, Ozcakar B, Silay YS. HER2/neu intragenic kinase domain mutations may be major determinant of response to trastuzumab or specific kinase inhibitors in non-small cell lung cancer patients. Lung Cancer. 2005 Aug;49(2): 279-80.
62. Tateishi M., Ishida T., Mitsudomi T., Kaneko S., Sugimachi K. Prognostic value of c-erbB-2 protein expression in human lung adenocarcinoma and squamous cell carcinoma. Eur. J. Cancer, 1991,27: 1372-5.
63. Tateishi M, Ishida T, Kohdono S, Hamatake M, Fukuyama Y, Sugimachi K. Prognostic influence of the co-expression of epidermal growth factor receptor and c-erbB-2 protein in human lung adenocarcinoma.Surg Oncol. 1994 Apr;3(2):109-13.
64. Nakamura, Kawasaki N, Taguchi M, Kabasawa K. Association of HER-2 overexpression with prognosis in nonsmall cell lung carcinoma: a metaanalysis.Cancer. 2005 May 1;103(9):1865-73.
65. Gatzemeier U, Groth G, Butts C et al. Randomized phase II trial of gemcitabine/ cisplatin with or without trastuzumab in Her2-positive non small-cell lung cancer. Ann Oncol Ann Oncol 2002; 13 (suppl 5): 2-9.
66. Lara PN Jr, Laptalo L, Longmate J, Lau DH, Gandour-Edwards R, Gumerlock PH,Doroshow JH, Gandara DR; California Cancer Consortium.Trastuzumab plus docetaxel in HER2/neu-positive non-small-cell lung cancer: a California Cancer Consortium screening and phase II trial. Clin Lung Cancer. 2004 Jan;5(4):231-6.
67. Gatzemeier U, Groth G, Butts C, Van Zandwijk N, Shepherd F, Ardizzoni A, Barton C, Ghahramani P, Hirsh V.Randomized phase II trial of gemcitabine- cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer.Ann Oncol. 2004Jan;15(1):19-27.
68. Krug LM, Miller VA, Patel J, Crapanzano J, Azzoli CG, Gomez J, Kris MG, Heelan RT, Pizzo B, Tyson L, Sheehan C, Ross JS, Venkatraman E. Randomized phase II study of weekly docetaxel plus trastuzumab versus weekly paclitaxel plus trastuzumab in patients with previously untreated advanced nonsmall cell lung carcinoma.Cancer. 2005 Nov 15;104(10):2149-55.
69. Cappuzzo F, Gregorc V, Rossi E, Cancellieri A, Magrini E, Paties CT, Ceresoli G, Lombardo L, Bartolini S, Calandri C, de Rosa M, Villa E, Crino L. Gefitinib in pretreated non-small-cell lung cancer (NSCLC): analysis of efficacy and correlation with HER2 and epidermal growth factor receptor expression in locally advanced or metastatic NSCLC.J Clin Oncol. 2003 Jul 15;21(14):2658-63.
70. Corey J. Langer, Patricia Stephenson, Ann Thor, Mark Vangel, David H. Johnson. Trastuzumab in the Treatment of Advanced Non-Small-Cell Lung Cancer: Is There a Role? Focus on Eastern Cooperative Oncology Group Study 2598 .Journal of Clinical Oncology, Vol 22, No 7 (April 1), 2004: pp. 1180-1187
71. Clamon G, Herndon J, Kern J, Govindan R, Garst J, Watson D, Green M; Cancer and Leukemia Group B. Lack of trastuzumab activity in nonsmall cell lung carcinoma with overexpression of erb-B2: 39810: a phase II trial of Cancer and Leukemia Group B. Cancer. 2005 Apr 15;103(8):1670-5
72. Normanno N, Di Maio M, Perrone F, Campiglio M. Molecular markers to predict response to gefitinib: EGFR, ErbB-2, or more?J Clin Oncol. 2004 May 15;22(10): 2035-6
73. Cappuzzo F, Magrini E, Ceresoli GL, Bartolini S, Rossi E, Ludovini V, Gregorc V, Ligorio C, Cancellieri A, Damiani S, Spreafico A, Paties CT, Lombardo L, Calandri C, Bellezza G, Tonato M, Crino L. Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer.J Natl Cancer Inst. 2004 Aug 4;96(15): 1133-41.
74. Lee JW Lee JW, Soung YH, Kim SY, Park WS, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH. Absence of the ERBB2 kinase domain mutation in lung adenocarcinomas in Korean patients.Int J Cancer. 2005 Sep 10;116(4):652-3.
75. Zabrecky JR, Lam T, McKenzie SJ, Carney W.The extracellular domain of p185/neu is released from the surface of human breast carcinoma cells, SK-BR-3. J Biol Chem. 1991 Jan 25;266(3):1716-20
76. Scott GK, Robles R, Park JW, Montgomery PA, Daniel J, Holmes WE, Lee J, Keller GA, Li WL, Fendly BM, et al. A truncated intracellular HER2/neu receptor produced by alternative RNA processing affects growth of human carcinoma cells.Mol Cell Biol. 1993 Apr;13(4):2247-57.
77. Alper O, Yamaguchi K, Hitomi J, Honda S, Matsushima T, Abe K The presence of c-erbB-2 gene product-related protein in culture medium conditioned by breast cancer cell line SK-BR-3. Cell Growth Differ. 1990 Dec;1(12):591-9.
78. Wang L, Liu B, Schmidt M, Lu Y, Wels W, Fan Z.Antitumor effect of an HER2-specific antibody-toxin fusion protein on human prostate cancer cells.Prostate. 2001 Apr;47(1):21-8.
79. Lin-Tao Jia, Li-Hong Zhang, Cui-Juan Yu, Jing Zhao, Yan-Ming Xu, Jun-Hao Gui, Ming Jin, Zong-Ling Ji, Wei-Hong Wen, Cheng-Ji Wang, Si-Yi Chen and An-Gang Yang.Specific Tumoricidal Activity of a Secreted Proapoptotic Protein Consisting of HER2 Antibody and Constitutively Active Caspase-3. Cancer Res. 2003 Jun 15;63(12):3257-62
80. Zhao J, Zhang LH, Jia LT, Zhang L, Xu YM, Wang Z, Yu CJ, Peng WD, Wen WH, Wang CJ, Chen SY, Yang AG. Secreted antibody/granzyme B fusion protein stimulates selective killing of HER2 over-expressing tumor cells. J Biol Chem. 2004 May 14;279(20):21343-8.
81. Yang AG, Chen SY. A new class of antigen-specific killer cells.Nat Biotechnol. 1997 Jan;15(1):46-51.
82. Xu YM, Wang LF, Jia LT, Qiu XC, Zhao J, Yu CJ, Zhang R, Zhu F, Wang CJ, Jin BQ,Chen SY, Yang AG.A caspase-6 and anti-human epidermal growth factor receptor-2 (HER2) antibodychimeric molecule suppresses the growth of HER2-overexpressing tumors.J Immunol. 2004 Jul 1;173(1):61-7.
83. Schiffer IB, Gebhard S, Heimerdinger CK, Heling A, Hast J, Wollscheid U, Seliger B, Tanner B, Gilbert S, Beckers T, Baasner S, Brenner W, Spangenberg C, Prawitt D, Trost T, Schreiber WG, Zabel B, Thelen M, Lehr HA, Oesch F, Hengstler JG Switching off HER-2/neu in a tetracycline-controlled mouse tumor model leads toapoptosis and tumor-size-dependent remission. Cancer Res. 2003 Nov ; 63(21): 7221-31.
84. Couzin Jennifer.Breakthrough of the year. Small RNAs make big splash.Science. 2002 Dec 20;298(5602): 2296-7.
85. Bosher ,M,Labouesse M.RNA interference: genetic wand and genetic watchdog.Nat Cell Biol. 2000 Feb;2(2):E31-6.
86. Plasterk RH.RNA silencing: the genome's immune system.Science. 2002 May 17;296 (5571): 1263-5.
87. ,Hannon GJ.RNA interference.Nature. 2002 Jul 11;418(6894):244-51.
88. McManus MT, Sharp PA.Gene silencing in mammals by small interfering RNAs.Nat Rev Genet. 2002 Oct;3(10):737-47.
89. Jorgensen R. Altered gene expression in plants due to trans interaction between homologous genes. Trends Biotechnol, 1990,8(12):340-4.
90. Cogoni C, Romano N, Macino G.. Suppression of gene expression by homologous transgenes. Antonie-Van-Leeuwenhoek, 1994, 65(3):205-209.
91. Guo S and Kemphues KJ. Par-1, a gene required for establishing polarity in C.elegans embryos encodes a putative Ser/Thr kinase that is asymmetrically distributed. Cell, 1995, 81(4):611-620.
92. Fire A, Xu S, Montgomery MK, et al. Potent and specific genetic interference by double-stranded RNA in caenorhabditis elegans. Nature, 1998, 391(6669): 806-811.Svoboda P, Stein P, Hayashi H, et al. Selctive reduction of dormant material mRNAs in mouse oocytes by RNA interference. Development, 2000, 127(19): 4147-4156
93. Hamilton AJ, Baulcombe DC .A species of small antisense RNA in posttranscriptional gene silencing in plants.Science. 1999 Oct 29;286(5441):950-2.Zamore PD, Tuschl T, Sharp PA, Bartel DP.RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals.Cell. 2000 Mar 31;101 (1):25-33.
94. Zamore PD, Tuschl T, Sharp PA, Bartel DP. RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals.Cell. 2000 Mar 31;101(1):25-33.
95. Hammond SM, Bernstein E, Beach D, Hannon GJ.An RNA-directed nucleasemediates post-transcriptional gene silencing in Drosophila cells.Nature. 2000 Mar 16;404(6775):293-6.
96. Elbashir SM, Lendeckel W, Tuschl T. RNA interference is mediated by 21-and
22-nucleotide RNAs.Genes Dev. 2001 Jan 15;15(2):188-200
97. Wianny F , Zernicka-Goetz M . Spcific interference with gene function by double-stranded RNA in early mouse development.Nat Cell Biol, 2000, 2(2):70-75.
98. Svoboda P, Stein P, Hayashi H, et al. Selctive reduction of dormant material mRNAs in mouse oocytes by RNA interference. Development, 2000, 127(19): 4147-4156.
99. Elbashir SM, Harborth J, Lendeckel W, et al. Duplexes of 21-nucleotide RNAs mediates RNA interference in cultured mammalian. Nature, 2001, 411(6836): 494-498.
100. Mello CC, Conte D Jr. Revealing the world of RNA interference.Nature. 2004 Sep 16;43 1(7006):338-42.
101. Meister G, Tuschl T. Mechanisms of gene silencing by double-stranded RNA. Nature. 2004 Sep 16;431(7006):343-9.
102. Matzke M, Matzke AJ, Kooter JM.RNA: guiding gene silencing.Science. 2001 Aug 10;
293 (5532):1080-3.
103. Plasterk RH. RNA silencing: The genome’s immune system. Science, 2002,
296(17):263-1265.
104. Nykanen A, Haley B, Zamore PD.ATP requirements and small interfering RNA structure in the RNA interference pathway.Cell. 2001 Nov 2;107(3):309-21.
105. Lee RC, Feinbaum RL, Ambros V.The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14.Cell. 1993 Dec 3;75(5):843-54.
106. Reinhart BJ,Slack FJ,Basson M,et a1.The 21-nucleotide lct-7 RNA regulates developmental timing in Caenorhabditis elegans.Nature,2000,403(6672):901-6.
107. Smallridge R.A small fortune. Nat Rev Mol Cell Biol. 2001 Dec;2(12):867.
108. 108Tabara H,Sarkissian M,Kelly WG.The rde-l gene.RNA interference,and transposon silencing in C.elegans.Cell,1999,99:123-32.
109. Lau NC,Lim LP,Welnstein EG,et a1.An abundant class of tiny RNAs with probable regulatory roles in caenorhabditis elegans.Science,2001,294(1 o):858-862.
110. Misteli T.RNA keeps time from wotln to man.Trends in Cell Biolgy,2001.1 1:57.
111. Ketting RF, Plasterk RH. What's new about RNAi? Meeting on siRNAs and miRNAs.EMBO Rep. 2004 Aug;5(8):762-5.
112. Izquierdo M.Short interfering RNAs as a tool for cancer gene therapy.Cancer Gene Ther. 2005 Mar;12(3):217-27.
113. 3Dennis C.The brave new world of RNA.Nature,2002,418:122-4.
114. Baulcombe D.RNA silencing in plants.Nature. 2004 Sep 16;431(7006):356-63.
115. Lu R, Maduro M, Li F, Li HW, Broitman-Maduro G, Li WX, Ding SW. Animal virus replication and RNAi-mediated antiviral silencing in Caenorhabditis elegans.Nature. 2005 Aug 18;436(7053):1040-3.
116. Caplen NJ. RNAi as a gene therapy approach.Expert Opin Biol Ther. 2003 Jul;3(4):575-86. Review
117. Ketting RF,Fischer SE,Berustein E,Sijen T,Hannon GJ,Plasterk RH.Dicer functions in RNA interference an d in synthesis of small RNA involved in developmental timing in C elegans.Genes Dev,200l,15:2654 ～59.
118. Volpe TA,Kidner C,Hall IM,Teng G,Grewal SI,Martienssen RA.Regulation of heterochromatin silencing and histone H3 lysine-9 methylation by RNAi.Science, 2002,297:1833～37
119. Tijsterman M, Ketting RF, Plasterk RH .The genetics of RNA silencing.Annu Rev Genet. 2002;36:489-519.
120. Doench JG, Petersen CP,Sharp PA.SiRNAs can function as miRNAs.Genes Dev,2003,17:438～42
121. Ambres V,MicroRNA pathways in flies and worms: growth,death,fat,stress,and timing.Cell,2003,I13:673～76
122. Mette MF, Aufsatz W, van der Winden J, Matzke MA, Matzke AJ. Transcriptional silencing and promoter methylation triggered by double-stranded RNA.EMBO J. 2000 Oct 2;19 (19): 5194-201.
123. Jones L, Hamilton AJ, Voinnet O, Thomas CL, Maule AJ, Baulcombe DC. RNA-DNA interactions and DNA methylation in post-transcriptional gene silencing.Plant Cell. 1999 Dec;11(12):2291-301.
124. Elbashir SM, Martinez J, Patkaniowska A, Lendeckel W, Tuschl T. Functional anatomy of siRNAs for mediating efficient RNAi in Drosophila melanogaster embryolysate.EMBO J. 2001 Dec 3;20(23):6877-88.
125. Bohula EA, Salisbury AJ, Sohail M, Playford MP, Riedemann J, Southern EM, Macaulay VM. The efficacy of small interfering RNAs targeted to the type 1 insulin-like growth factor receptor (IGF1R) is influenced by secondary structure in the IGF1R transcript. J Biol Chem. 2003 May 2;278(18):15991-7.
126. Banan M, Puri N. The ins and outs of RNAi in mammalian cells.Curr Pharm Biotechnol. 2004 Oct;5(5):441-50. Review.
127. Yang N, Zhang L, Kazazian HH Jr. L1 retrotransposon-mediated stable gene silencing.Nucleic Acids Res. 2005 Mar 30;33(6):e57.
128. Jackson AL, Bartz SR, Schelter J, Kobayashi SV, Burchard J, Mao M, Li B, Cavet G, Linsley PS. Expression profiling reveals off-target gene regulation by RNAi. Nat Biotechnol. 2003 Jun;21(6):635-7.
129. Czauderna F, Fechtner M, Dames S, Aygun H, Klippel A, Pronk GJ, Giese K, Kaufmann J. Structural variations and stabilising modifications of synthetic siRNAs in mammalian cells.Nucleic Acids Res. 2003 Jun 1;31(11):2705-16.
130. Braasch DA, Jensen S, Liu Y, Kaur K, Arar K, White MA, Corey DR. RNA interference in mammalian cells by chemically-modified RNA.Biochemistry. 2003 Jul 8;42(26):7967-75.
131. Yotnda P, Davis AR, Hicks MJ, Templeton NS, Brenner MK. Liposomal enhancement of the antitumor activity of conditionally replication-competent adenoviral plasmids.Mol Ther. 2004 Apr;9(4):489-95.
132. Izquierdo M. Short interfering RNAs as a tool for cancer gene therapy.Cancer Gene Ther. 2005 Mar;12(3):217-27. Review
133. 李庆霞,刘家云,黄红艳,许彦鸣,贾林涛,赵晶,王成济,杨安钢.针对 survivin表达的siRNA对人乳腺癌SKBr-3细胞中survivin基因的干涉作用. 中国肿瘤生物治疗杂志,2004;11(4):277-280
134. Cottrell TR, Doering TL.Silence of the strands: RNA interference in eukaryotic Trends Microbiol. 2003 Jan;11(1):37-43. Review
135. Zhang L, Yang N, Mohamed-Hadley A, Rubin SC, Coukos G. Vector-based RNAi, a novel tool for isoform-specific knock-down of VEGF and anti-angiogenesis gene therapy of cancer.Biochem Biophys Res Commun. 2003 Apr 18;303(4):1169-78.
136. Yen L, Svendsen J, Lee JS, Gray JT, Magnier M, Baba T, D'Amato RJ, Mulligan RC. Exogenous control of mammalian gene expression through modulation of RNA self-cleavage. Nature. 2004 Sep 23;431(7007):471-6.
137. Klein C, Bock CT, Wedemeyer H, Wustefeld T, Locarnini S, Dienes HP, Kubicka S, Manns MP, Trautwein C. Inhibition of hepatitis B virus replication in vivo by nucleoside analogues and siRNA.Gastroenterology. 2003 Jul;125(1):9-18.
138. McCaffrey AP, Nakai H, Pandey K, Huang Z, Salazar FH, Xu H, Wieland SF, Marion PL, Kay MA. Inhibition of hepatitis B virus in mice by RNA interference.Nat Biotechnol. 2003 Jun;21(6):639-44.
139. Zhang X, Shan P, Jiang D, Noble PW, Abraham NG, Kappas A, Lee PJ. Small interfering RNA targeting heme oxygenase-1 enhances ischemia-reperfusion- induced lung apoptosis. J Biol Chem. 2004, 12;279(11):10677-84.
140. Song E, Zhu P, Lee SK, Chowdhury D, Kussman S, Dykxhoorn DM, Feng Y, Palliser D, Weiner DB, Shankar P, Marasco WA, Lieberman J. Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nat Biotechnol. 2005 Jun;23(6):709-17.
141. Zhu G, Gilchrist R, Borley N, et al. Reduction of TSG101 protein has a negative impact on tumor cell growth. Int J Cancer, 2004, 109(4):541-7.
142. Hart S, Fischer OM, Ullrich A. Cannabinoids induce cancer cell proliferation via tumor necrosis factor alpha converting enzyme (TACE/ADAM17)-mediated transactivation of the epidermal growth factor receptor. Cancer Res, 2004, 64(6): 1943-50.
143. Yague E, Higgins CF, Raguz S.Complete reversal of multidrug resistance by stable expression of small interfering RNAs targeting MDR1. Gene Ther, 2004, 11(14):1170-4.
144. Wu H,Hait W.N.,and Yang JM..Small interfering RNA-induced suppression of MDR1(P-glocoprotein)restores sensitivity to multidrug-resistant cancer cells. Cancer Res, 2003, 63(7):1515-9.
145. Lima RT, Martins LM, Guimaraes JE, et al. Specific downregulation of bcl-2 and xIAP by RNAi enhances the effects of chemotherapeutic agents in MCF-7 human breast cancer cells. Cancer Gene Ther, 2004, 11(5):309-16.
146. Zhang L, Yang N, Mohamed-Hadley A, et al. Vector-based RNAi, a novel tool for isoform-specific knock-down of VEGF and anti-angiogenesis gene therapy of cancer. Biochem Biophys Res Commun, 2003, 303(4): 1169-78.
147. Filleur S, Courtin A, Ait-Si-Ali S, et al. SiRNA-mediated inhibition of vascular endothelial growth factor severely limits tumor resistence to antiangiogenic thrombospondin-1 and slows tumor vascularization and growth. Cancer Res, 2003, 63(14):3919-22.
148. Crnkovic-Mertens I, Hoppe-Seyler F, Butz K. Induction of apoptosis in tumor cells by siRNA-mediated silencing of the livin/ML-IAP/KIAP gene. Oncogene, 2003, 22(51): 8330-6.
149. Wilda M, Fuchs U, Wossmann W, et al. Killing of leukemia cells with a BCR/ABL fusion gene by RNA interference (RNAi). Oncogene, 2002, 21(37): 5716-24.
150. Nagy P, Arndt-Jovin DJ, Jovin TM. Small interfering RNAs suppress the expression of endogenous and GFP-fused epidermal growth factor receptor (erbB1) and induce apoptosis in erbB1-overexpressing cells. Exp Cell Res, 2003, 15;285(1):39-49.
151. Lin SL, Chuong CM, Ying SY. A Novel mRNA-cDNA interference phenomenon for silencing bcl-2 expression in human LNCaP cells. Biochem Biophys Res Commun, 2001, 28(3): 639-644.
152. 张敏,张新,白春学.RNA 干扰技术抑制非小细胞肺癌表皮生长因子受体的表达. 中华内科杂志,2004,43(5):45-48.
153. Yin JQ, Gao J, Shao R, et al. siRNA agents inhibit oncogene expression and attenuate human tumor cell growth. J Exp Ther Oncol, 2003, 3(4):194-204.
154. 刘家云, 贾林涛, 王成济, 杨安钢. RNAi—dsRNA 介导的基因沉默. 国外医学遗传学分册, 2004; 27(1):4-1
155. van Rij RP, Andino R. The silent treatment: RNAi as a defense against virus infection in mammals.Trends Biotechnol. 2006;24(4):186-93
156. Stevenson M. Therapeutic potential of RNA interference. N Engl J Med. 2004 Oct 21;351(17):1772-7.
157. Sledz CA, Williams BR. RNA interference in biology and disease.Blood. 2005 Aug 1;106(3):787-94.
158. Paroo Z, Corey DR. Challenges for RNAi in vivo.Trends Biotechnol. 2004 Aug;22(8):390-4.
159. Ma J, Kahwaji CI, Ni Z, Vaziri ND, Purdy RE. Effects of simulated microgravity on arterial nitric oxide synthase and nitrate and nitrite content.J Appl Physiol. 2003,94(1):83-92.
160. 任新玲,沈丽英,金伯泉,戚好文,马进. 表皮生长因子受体单克隆抗体体内外抗肺癌作用的研究. 肿瘤,2000;20(1):35-37.
161. Chalfie M, Tu Y, Euskirchen G, et al. Green fluorescent protein as a marker for gene expression. Science, 1994, 263(5148):802-805.