摘要
研究背景
肺癌和慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)是严重危害人类健康的两种常见病和多发病,肺癌的发病率和死亡率居恶性肿瘤首位,COPD发病则呈逐年上升趋势,已是全球第4位的致死性疾病。目前肺癌和COPD的具体发病机制未明,但研究表明两者的发病可能存在一定的联系。COPD是气道慢性炎症性疾病,肺癌也是一种和慢性炎症密切相关的疾病,因此,慢性炎症可能是这种联系的一种表现形式。研究发现,73%的男性肺癌患者和53%的女性肺癌患者同时患有COPD,且有前瞻性研究显示COPD患者罹患肺癌的风险高于非COPD者。但肺癌和COPD是性质不同的两种疾病,其慢性炎症并非完全相同,参与慢性炎症的细胞及炎症因子在数量和活性上也有相应的不同。T淋巴细胞(包括CD4+和CD8+T淋巴细胞)是参与慢性炎症的重要细胞,也是细胞免疫的主要效应细胞,可进一步分化为不同的亚群,如CD4+T淋巴细胞可分化为Th1、Th2、Th17等亚群,CD8+T淋巴细胞可分化为Tc1、Tc2等亚群,各亚群在肺癌和COPD的发病中均有重要作用,并表现出不同的数量和活性。Tc17细胞是2006年由He D等首先报道的CD8+T淋巴细胞的一个新亚群,在功能上与之前发现的Th17细胞类似,也以分泌IL-17A为特征,并可通过IL-17A等细胞因子参与慢性炎症反应和肺癌的发生发展,但COPD中Tc17细胞的变化情况尚未有相关报道。
目的
本研究旨在比较肺腺癌和COPD患者外周血Tc17细胞比例变化的差异。
方法
2009年10月至2010年12月于山东大学齐鲁医院呼吸科门诊就诊的患者中选取28例肺腺癌和21例COPD患者,选取本院健康医护人员和健康查体者42例作为健康对照组,收集他们的外周血标本。采用流式细胞术检测所有外周血标本Tc17细胞比例,采用实时定量PCR(real time-PCR)技术检测外周血单个核细胞(peripheral blood mononuclear cells,PBMC)RORct mRNA表达的水平,酶联免疫吸附法(enzyme linked immunosorbent assay,ELISA)检测外周血中IL-17A.TGF-β.IL-10.IL-6等细胞因子的水平。分析外周血Tcl7细胞比例和RORct mRNA的相关性。
结果
1.流式细胞术检测显示：肺腺癌组和COPD组患者外周血Tc17细胞比例分别为0.76±0.83%和0.38±0.37%，二者均显著高于健康对照组0.23±0.17%(分别为P<0.001；P=0.029),且肺腺癌组患者外周血Tc17细胞比例显著高于COPD组(P=0.034)；
2.实时定量PCR技术结果显示：Tc17特征性转录调控因子RORct mRNA在肺腺癌组和COPD组与健康对照组相比表达均上调(p均<0.001)。
3.ELISA检测结果显示：肺腺癌患者外周血IL-17A水平显著高于健康对照(P=0.039),而COPD患者外周血IL-17A水平与健康对照相比无统计学差异(P>0.05)；肺腺癌组和COPD组患者外周血TGF-β水平均显著高于健康对照组(分别为P=0.007；P=0.001),且COPD组显著高于肺肺腺癌组(P=0.032)；COPD患者外周血IL-10水平显著高于肺腺癌患者(P=0.042)，两病例组均高于健康对照组(分别为P=0.003；P<0.001)。
4.相关性分析显示：肺腺癌组和COPD组患者外周血Tc 17细胞比例与PBMC中RORct mRNA水平均呈显著正相关(P=0.036，r=0.544；P=0.043,r=0.648)。
结论
肺腺癌和COPD患者外周血Tc17细胞比例均升高,且在肺腺癌中更明显。
Objective
To compare the frequency of Te17 cells in peripheral blood from patients with advanced lung adenocarcinoma and chronic obstructive pulmonary disease (COPD).
Methods
The frequency of Te17 cells was respectively detected from 28 patients with advanced lung adenocarcinoma,21 patients with COPD and 42 healthy volunteers by flow cytometry; Real time-PCR was used to dectect the level of RORct mRNA in peripheral blood mononuclear cells (PBMC); Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum concentration of TGF-β, IL-17A, IL-6 and IL-10. Analysis the correlationship between the frequency of Tc17 cells and the level of RORct mRNA.
Results
1.The frequency of Te17 cells from patients with andvanced lung cancer (0.76±0.83%) was significantly higher than that in patients with COPD (0.38±0.37%)(P=0.034), and both of them were significantly higher than that in healthy volunteers(0.23±0.17%)(P<0.001; P=0.029).
2. The expression of RORct mRNA was also upregulated in patients with andvanced lung cancer and patients with COPD(P<0.001; P<0.001).
3. The level of IL-17A in patients with andvanced lung cancer was significantly higher than that in healthy volunteers (P=0.039),but there was no significant difference between patients with COPD and healthy volunteers; The serum concentration of TGF-βwas both significantly higher than that in healthy volunteers (P=0.007; P=0.001),and the level of IL-10 in patients with andvanced lung cancer was significantly lower than that in COPD patients.
4. According to correlation analysis,the frequency of Te17 cells in patients with andvanced lung cancer and COPD patients were positively correlated with the level of RORct mRNA (P=0.036, r=0.544; P=0.043, r=0.648)
Conclusion
In the peripheral blood, the frequency of Te17 cells from patients with andvanced lung cancer and COPD were significantly higher, and the frequency of Te17 cells from patients with andvanced lung cancer was higher than that in patients with COPD.
引文
[1]Jemal A, Thomas A, Murray T, Thun M. Cancer statistics CA[J]. Cancer Clin,2002,52(1):23.
[2]白春学,钟.加强综合实力提高肺癌的诊治水平[J].中华结核和呼吸杂志,2008,31：882-883.
[3]C.D. Mathers, D. Loncar. Projections of global mortality and burden of disease from 2002 to 2030[J]. PLoS Med,2006,3:442.
[4]中华医学会呼吸病学分会慢性阻塞性肺疾病学组.慢性阻塞性肺疾病诊治指南(2007年修订版)[J].中华结核和呼吸杂志,2007,30(1).
[5]Ian M. Adcock, Gaetano Caramori, Peter J. Barnes. Chronic Obstructive Pulmonary Disease and Lung Cancer:New Molecular Insights[J]. Thematic Review Series,2011,81:265-284.
[6]Loganathan RS, Stover DE, Shi W, Venkatraman E. Prevalence of COPD in women compared to men around the time of diagnosis of primary lung cancer[J]. Chest,2006,129(5):1305-1312.
[7]Michelle C. Turner, Yue Chen, Daniel Krewski, Eugenia E. Calle, and Michael J. Thun. Chronic Obstructive Pulmonary Disease Is Associated with Lung Cancer Mortality in a Prospective Study of Never Smokers[J]. American Jouranl of Respiratory and Critical Care Medicine,2007,176.
[8]Rouvier E, Luciani MF, et al. CTLA-8, cloned from an activated T cell, bearing AU—rich messenger RNA instability sequences and homologous to a herpesvirus saimiri gene[J]. Immunol,1993,150:5445-5456.
[9]Liang SC, Long AJ, Bennett F. et al. An IL-17F/A heterodimer protein is produced by mouse Th17 cells and induces airway neutrophil recruitment [J]. Immunol,2007,179:7791-7799.
[10]Jones CE, Chan K. Interleukin-17 stimulates the expression of interleukin-8, growth-related oncogene-alpha and granulocytecolony- stimulating factor by human airway epithelial cells[J]. AmJ Respir Cell Mol Biol,2002.26:748-753.
[11]Kao CY, Huang F, Chen Y, Thai P, Wachi S, Kim C, Tam L, Wu R. Up-regulation of CC chemokine ligand 20 expression in human airway epithelium by IL-17 through a JAK-independent but MEK/NF-kappaB-dependent signaling pathway[J]. Immunol,2005,175:6676-6685.
[12]Numasaki M, Fukushi J. Ono M, et al. Interleukin 17 gene transfection into murine fibrosarcoma cell line MCA increases tumorigenicity correlated with enhanced tumor microuascularity[J]. Blood, 2003,101(7):2620-2627.
[13]Tartour E, Fossiez F, Joyeux I, et al. Interleukin 17, a T cell derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice[J]. Cancer Res,1999,59(15):3698-3704.
[14]Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages[J]. Nat Immunol, 2005,6(11):1123-1132.
[15]Dong C. TH17 cells in development:an updated view of their molecular identity and genetic programming[J]. Nat RevImmunol, 2008,8:337-348
[16]Roark CL, Simonian PL, Fontenot AP, Born WK, O'Brien RL Gammadelta T cells:an important source of IL-17[J]. Curr Opin Immunol,2008,20(3):353-357.
[17]王中华,周燕斌.Th17细胞分化及与疾病关系的研究新进展.国际内科学杂志[J],2009,36：242-245.
[18]He, D., L. Wu, H. K. Kim, H. Li, C. A. Elmets, and H. Xu. CD8+IL-17 producing T cells are important in effector functions for the elicitation of contact hypersensitivity responses[J]. Immunol, 2006,177:6852-6858.
[19]Y.Zhao, A.Balato, R. Fishelevich et al. Thl7/Tc17 infiltration and associated cytokine gene expression in elicitation phase of allergic contact dermatitis[J]. British Journal of Dermatology, 2009,29:1365-2133.
[20]Magdalena Huber, Sylvia Heink, Henrike Grothe et al. A Th17-like developmental process leads to CD8+Te17 cells with reduced cytotoxic activity[J]. Eur. Immunol,2009,39:1716-1725.
[21]Hamada, H., Garcia-Hernandez, M. L., Reome, J. B., Misra, S. K., Strutt, T. M., McKinstry, K. K., Cooper, A. M. et al. Tc17, a unique subset of CD8 T cells that can protect against lethal influenza challenge[J]. Immunol,2009,182:3469-3481.
[22]Bogoljub Ciric, Mohamed E1-behi, Rosalyn Cabrera et al. IL-23 Drives Pathogenic IL-17-Producing CD8+T Cells[J]. Immunol, 2009,182:5296-5305.
[23]Pridgeon C, Bugeon L, Donnelly L, Straschil U, et al. Regulation of IL-17 in chronic inflammation in the human lung[J]. Clin Sci (Lond), 2011,120(12):515-524.
[24]Zhou L, Ivanov, II, Spolski R, et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways[J]. Nat Immunol,2007,8(9):967-974.
[25]Shih-Jen Liu, Jy-Ping Tsai, et al. Induction of a distinct CD8 Tnc17 subset by transforming growth factor-β and interleukin-6[J]. Journal of Leukocyte Biology,2007,82:354-360.
[26]Liu S-J, Tsai J-P, Shen C-R, et al. Induction of a distinct CD8 Tnc17 subset by transforming growth factor and interleukin-6[J]. Leukoc Biol, 2007,82:354-360.
[27]Tajima, M., Wakita, D., Noguchi, D., Chamoto, K., Yue, Z., Fugo, K., Ishigame, H. et al. IL-6-dependent spontaneous proliferation is required for the induction of colitogenic IL-17-producing CD8+T cells[J]. Exp. Med,2008,205:1019-1027.
[28]Manel, N., Unutmaz, D., and Littman, D. The differentiation of human T(H)-17 cells requires transforming growth factorbeta and induction of the nuclear receptor RORgt[J]. Nat Immunol,2008,9:641-649.
[29]Bettelli, E., Carrier, Y., Gao, W., Korn, T.,Strom, T., Oukka, M., Weiner, H., and Kuchroo, V. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells[J]. Nature,2006,441:235-238.
[30]Veldhoen M, Hocking RJ, Atkins CJ, et al. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells[J]. Immunity,2006,24(2):179-189.
[31]Robert Sabat, Gerald Grutz, Katarzyna Warszawska, Stefan Kirscha, Ellen Wittea, Kerstin Wolka, and Jens Geginate. Biology of interleukin-10[J]. Cytokine Growth Factor Rev,2010,21 (5):331-344.
[32]Robert Sabat. IL-10 family of cytokines[J]. Cytokine Growth Factor Rev,2010,21(5):315-324.
[33]T. Guichelaar, C.B. ten Brink, P.J. van Kooten, S.E. Berlo, C.P. Broeren, W. van Eden, F. Broere, Autoantigen-specific IL-10-transduced T cells suppress chronic arthritis by promoting the endogenous regulatory IL-10 response[J]. Immunol, 2008,180:1373-1381.
[34]D.M. Durrant, D.W. Metzger. IL-12 can alleviate Th17-mediated allergic lung inflammation through induction of pulmonary IL-10 expression[J]. Mucosal Immunol,2010,3:301-311.
[1]白春学,钟.加强综合实力提高肺癌的诊治水平[J].中华结核和呼吸杂志,2008,31：882-883.
[2]白春学,张.应重视肺癌的基础研究[J].中华医学杂志,2006，86：2593-2595.
[3]Jemal A, Thomas A, Murray T, Thun M. Cancer statistics CA[J]. Cancer Clin,2002,52(1):23.
[4]Pegram MD, Pietras R, Bajamonde A, et al. Targeted therapy:wave of the future[J]. Clin Oncol,2005,23:1776-1781.
[5]汤钊猷,朱世能,赵森等.现代肿瘤学[M].上海：上海医科大学出版社，1993：117.
[6]董强刚,冯久贤,黄进肃等.血管内皮生长因子对非小细胞肺癌血道转移的影响[J].中华肿瘤杂志,2002,24：142-146.
[7]朱志华,戎铁华,曾灿光等.I-II非小细胞肺癌组织中VEGF的表达和微血管密度与预后的关系[J].癌症,2005,24(7)：865.
[8]Krause DS, Richard A, Etten V, et al. Tyrosine kinases as targets for cancer therapy[J]. New Engl Med,2005,2(353):172-187.
[9]Riese Ⅱ DJ, Stern DF. Specificity within the EGF family/ErbB receptorfamily signaling network[J]. Bioessays,1998,20:41-48.
[10]Fukuoka M, et al. Multi-institutional randomized phase Ⅱ trial of Gefitinib for previously treated patients with advanced non-small-cell lung cancer[J]. Clin Oncol,2003,21 (12):2237.
[11]Baselga J. Why the epidermal growth factor receptors The rationale for cancer therapy[J]. Oncologist,2002,7(14):2.
[12]Wang YN, Yamaguchi H, Hsu JM, et al. Nuclear trafficking of the epidermal growth factor receptor family membrane proteins[J]. Oncogene, 2010,29(28):3997-4006.
[13]Byers LA, Heymach JV. Dual targeting of the vascular endothelial growth factor and epidermal growth factor receptor pathways:rationale and clinical applications for non-small-cell lung cancer[J]. Clin Lung Cancer,2007,8(2):79-85.
[14]王洪波,陈晓光EGFR抑制剂耐药机制研究的新进展[J].国际药学研究杂志,2007,34(5)：347.
[15]Siromak FM. Studies with ZD1839 in preclinical models Ⅱ [J]. Semin Oncol,2003,30(1):12.
[16]Baselga J, Averbuch SD. ZD1839(Ireasa) as an antieaneer agent [J]. Drugs,2000,60:33.
[17]张燕华,宁华,姜洋.表皮生长因子受体酪氨酸激酶抑制剂[J].中国新药杂志,2004,13(10)：947.
[18]陈拮,戴嫒嫒,汤致强.小分子EGFR酪氨酸激酶抑制剂盐酸埃罗替尼[J].中国新药杂志,2005,14(10)：1227.
[19]RYAN A J. ZD64742 a novel inhibitor of VEGFR and EGFR tyrosinekinase activity[J]. Br Cancer,2005,92(1):6213.
[20]Thatcher N CA. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer:results from a randomized, placebo-controled, multicenter study (Iressa Survival Evaluation in Lung Cancer) [J]. Lancet,2005,336(9496).
[21]Shepherd FA RP. Erlotinib in previously treated non-small-cell lung cancer[J]. New Engl Med,2005,353(2):9.
[22]Kim ES HV. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer(INTEREST):a randomised phase III trial[J]. Lancet,2008,372(9652):1809-1818.
[23]Lee DH, Han JY, Kim HT, et al. Gefitinib is of more benefit in chemotherapy-naive patient with good performance status and adenocarcinoms histology:Retro spective analysis of 575 Korean patients[J]. Lung Cancer,2006,53(3):339-345.
[24]Suzuki R, Haseg awa Y, Baba K, et al. A phase Ⅱ study of single-agent gefitinib as first-line therapy in patient with stage IV non-small-cell lung cancer [J]. Br Cancer,2006,94(117):1599-1603.
[25]Mok TWY. Phase Ⅲ randomized, open-label, first-line study if gefitinib vs carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer(IPASS) [J]. In:European society of medical oncology congress 2008.
[26]Rosell R, Moran T, Cardenal F, Porta R, Viteri S, Molina MA, Benlloch S, Taron M. Predictive biomarkers in the management of EGFR mutant lung cancer[J]. New York Academy of Sciences,2010,1210:45-52.
[27]Giaccone G, Herbst RS, M aneqold C, et al. Gefitinib incombination with gemeitabine and cisplatin in advanced non-small-cell lung cancer:A phase Ⅲ trial-INTACT 1[J]. Clin Oncol,2004,22(5):777-784.
[28]Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib incombination with paclitaxel and carboplatin in advanced non-small-cell lung cancer:A phase Ⅲ trial-INTACT 2[J]. Clin Oncol,2004,22(5):785-794.
[29]Herbst RS, Prager D, Hermann R, et al. TRIBUTE:a phase Ⅲ trial of erlotinib hydrochloride OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced no n-small-cell lung cancer[J]. Clin Oncol,2005,23(25):5892-5899.
[30]Gatzemeier U, Pluzamka A, Szczesna A, et al. Phase Ⅲ study o f erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer:the tarceva lung cancer investigation trial [J]. Clin Oncol,2007,25(12):1545-1552.
[31]Neal JW. The SATURN trial:the value of maintenance erlotinib in patients with non-small-cell lung cancer[J]. Future Oncol, 2010,6(12):1827-32.
[32]Takeda K, Hida T, Sato T, et al. Randomized phaseⅢtrial of platinum doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer:results of a west Japan thoracic oncology group trial(WJTOG0203) [J]. Clin Oncol,2010,28(5):753-760.
[33]Spector N L, Xia W, Burris H, et al. Study of the Biologic Effects of Lapatinib, a Reversible Inhibitor of ErbB1 and ErbB2 Tyrosine Kinases, on Tumor Growth and Surivival Pathways in Patients With Advanced Malignancies[J], Clin Oncol,2005 23(11):2502.
[34]晋展.新型抗肿瘤药SU11248[J].药学进展,2005,29(6)：285.
[35]HIDALGOM. SIULL. Phase I and pharmacyologic study of OSI-774, an epidermal growth factor recaptortyrosine kinase inhibitor, in patients with advanced solid malignancies[J]. Clin Oncol,2001,19(13):3267.
[36]GORDANAY, CRAUFORAL J. Activation of tyrosine kinases in cancer[J]. Oncologist,2003,8(6):531.
[37]JOSEBL. HAMMONDL A. HER-targeted tyrosine-kinases inhibitors[J]. Oncology,2002,63(1):6216.
[38]Lee SH, Lopesde Menezes D, Vora J, et al. In vivo Target Modulation and Biological Activity of CHIR-258, a multitargeted Growth Factor Receptor Kinase Inhibitor,in Colon Cancer Models [J]. Clin Cancer Res, 2005,11(10):3633.
[39]Natale R,Bodkin D,Govindan R, et al. A comparison of the antitumour efficacy of ZD6474 and gefitinib(Iressa) in patients with NSCLC:Results of a randomized, double-blind Phase Ⅱ study[J]. Lung Cancer, 2005,9(2):37.
[40]Kim ES. Cetux imabasasing leagentor in combination with chemotherapy in lung cancer[J]. Clin Lung Cancer,2004,6(2):80-84.
[41]Ro sell R, Robinet G, Szczesna A, et al. Randomized phase Ⅱ study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/ vinorelbine alone as first-line therapy in EGFR-ex pressing advanced non-small-cell lung cancer[J]. Ann Oncol,2008,19(2):362-369.
[42]Butts CA, Bodkin EL, Middleman EL, et al. Randomized phase Ⅱ study of gemcitabine pluscisplat in orcarboplatin, thorwithout cetuximab, as first-line therapy for patients with advanced or metastatic non-small-cell lung cancer[J]. Clin Oncol,2007,25(36):5777-5784.
[43]Pirker R, Szczesna A, von Pawel J, et al. FLEX:a randomized, multi center, phase III study of cetuximab in combination with cisplatin/vinorelbine(CV) versus CV alone in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC)[J]. Clin Oncol,2008,(3).
[44]REILLYKE, ROJOF, SHEQB, et al. mTOR inhibition induce supstream receptor tyrosine k inase signaling and ctivates Akt[J]. Cancer Res, 2006,66(4):1500-1508.
[45]MASIELLO D, MOHIM G, MCKN IGHT NC, et al. Combining an mTOR antagonist and receptor tyrosine kinase inhibitors for the treatment of prostate cancer[J]. Cancer Biol Ther,2007,6 (4):195-201.
[46]BALSARA B R, PE I J, M ITSUUCH I Y, et al. Frequent activation of AKT in non-small-cell lung carcinom as and preneoplastic bronchial lesions[J]. Carcinogenesis,2004,25 (6):2053-2059.
[47]SUN SY, ROSENBERG L M, WANG X, et al. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition[J]. Cancer Res,2005,65(7):7052-7058.
[48]W ISLEZ M, SPENCER M L, IZZO JG, et al. Inhibition of mammalian target of rapamycin reverses alveolar epithelial neoplasia induced by oncogenic K-ras[J]. Cancer Res,2005,65(11):3226-3235.
[49]TONY D, FRANCESCO A M, GUIDO B, et al. Overexpression of the mammalian target of rapamycin a novel biomarker for poor survival in resected early stage non-small-cell lung cancer [J]. Thorac Oncol, 2010,5(3):314-319.
[50]PANDYA K J, DAHLBERG S, H IDALGO M, et al. A randomized, phase II trial of two dose levels of temsirolimus (CC I-779) in patients with extensive stage small-cell lung cancer who have responding or stable disease after induct ion chemotherapy:a trial of the E astern Cooperative Oncology Group (E1500). A preliminary report[J]. Thorac Oncol, 2007,2(4):1036-1041.
[51]Bjomsti MA,Houghton PJ. the ToR pathway:a target for cancel therapy[J]. Nat Rev Cancer,2004,4:335-348.
[52]Cai W, Chen x. Anti-angiogenie cancer therapy based on integrin alphavbeta3 antagonism[J]. Anticancer Agsnts Med Chem, 2006,6:407-428.
[53]Ding Q, Stew art J Jr, Prince CW, et al. Promotion of malignant astrocytoma cell migration by osteopontin expressed in the nomal brain: differences in integrin signaling during cell adhesion to osteopont in versus vetronectin[J]. Cancer Res,2002,62(18):336-5343.
[54]Eskens FA., Dumez H. Hoekstra R Phase I and pharmacokinetic study of continuous twice weekly intravenous administration of Cilengitide (EMD 121974), a novel inhibitor of the integrins alphavbeta3 and alphavbeta5 in patients with advanced solid tumours[J]. Eur Cancer, 2003,39:917-926.
[55]George S., Kasimis BS. Cogswell J Phase I study of flavopiridol in combination with Paclitaxel and Carboplatin in patients with non-small-cell lung cancer[J]. Clin Cancer,2008,9:160-165.
[56]Summy JM, Ga Hick GE. Treatment for advanced tumors:SRC reclaims center stage[J]. Clin Cancer Res,2006,12:1398-1401.
[57]Schenone S, M anetti F, Botta M. Src inhib itors andang iogenesis [J]. Cu rr Pha rm Design,2007,13:2118-2128.
[58]Frame M C. Srcin cancer:deregulation and con sequences for cell behaviour[J]. Biochim Biophys Acta,2002,1602(2):114-130.
[59]Demetri GD, Lo Russo P. MacPherson IR Phase I dose escalation and pharrnacokinetic study of dasatinib in patients with advanced solid tumors[J].2009,15:6232-6240.
[60]KarinM, CaoY, G reten FR, et al. NF-κB in cancer:from innocent bystander to major culprit [J]. Na t Rev Cancer,2002,2(4):301-310.
[61]King RW, DeshaiesR J, Peters JM, et al. How proteolysis drives the cell cycle[J]. Science,1996,274(5293):1652-1659.
[62]Schubert U, Antn LC, Gibbs J, et al. Rapid degradation of a large fraction of newly synthesized protein s by proteasomes[J]. Nature, 2000,404(6779):770-774.
[63]Lara PNJr, Koczyws M, Quinn DI, et al. Bortezomib plus docetaxel in advanced non-small-cell lung cancer and other solid tumors:a phase Ⅰ Califoria cancer Consortium trial-K. Thorac Oncol,2006,1(2):126.
[64]Fanucchi M P, Fossella F V, Belt R, et al. Randomized p has e Ⅱstudy of bortezomib alone and bortezomib in combination with docetaxel in previously treated advanced non-small-cell lung cancer[J]. Clin Oncol, 2006,24(31):5025-5033.
[65]Cascone T, Morelli MP, Morgillo F. Synergistic anti-proliferative and pro-apoptotic activity of combined therapy with bortezomib, a proteasome inhibitor, with anti-epidermal growth factor receptor (EGFR) drugs in human cancer cells[J].2008,16:698-707.
[66]Ropero S, Esteller M. The role of histone deacetylases(HDACs) in human cancer[J]. Mol Oncol,2007,1(1):19-25.
[67]Minucci S, Pelicci PG. Histone deacetylase inhibitors and thepromise of epigenetic (and more) treatments for cancer[J]. Nat Rev Cancer, 2006,6(1):38-51.
[68]Peart MJ, Smyth GK, van Laar RK, et al. Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors[J]. Proc Natl AcadSci USA, 2005,102(10):3697-3702.
[69]Richon VM, Sandhoff TW, Rifkind RA, et al. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation[J]. Proc Natl AcadSci USA, 2000,97(18):10014-10019.
[70]Joseph J, Mudduluru G, Antony S, et al. Expression profiling of sodium butyrate (NaB)-treated cells:identification of regulation of genes related to cytokine signaling and cancer metastasis by NaB[J]. Oncogene, 2004,23(37):6304-6315.
[71]Traynor AM, Dubey S. Eickhoff JC Vorinostat (NSC# 701852) in patients with relapsed non-small cell lung cancer:a Wisconsin Oncology Network phase Ⅱ study[J].2009,4:522-526.
[72]Ramalingam SS. Parise RA.Ramanathan RK Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies[J].2007,13:3605-3610.
[73]Edwards A, Li J, Atadja P, et al. Effect of the histone deacetylase inhibitor LBH589 against epidermal growth factor receptor-dependent human lung cancer cells[J]. Mol Cancer Ther,2007,6(9):2515-2524.
[74]DZIADZIUSZKO R, CAM IDGE D R, H IRSCH F R. The insulin-like growth factor pathway in lung cancer[J]. Thorac Oncol, 2008,3(8):815-818.
[75]HEW ISHM, CHAU I, CUNN INGHAM D. Insulin-like growth factor 1 receptor targeted therapeutics:novel com pounds and novel treatment strategies for cancer medicine[J]. Recent Patents Anti-cancer Drug Discov,2009,4(1):54-72.
[76]LEE H Y, MOON H, CHUN K H, et al. Effects of insulin-like growth factor binding protein-3 and farnesyl transferase inhibitor SCH 66336 on Akt express ion and apoptosis in non-small-cell lung cancer cells[J]. Natl Cancer Inst,2004,96(11):1536-1548.
[77]COH EN B D, BAKER D A, SODERSTROM C, et al. Combination therapy enhances the inhibition of tumor growth with the fully human anti-type 1 insulin-like growth factor receptor monoclonal antibody CP-751,871 [J]. Clin Cancer Res,2005,11(2):2063-2073.
[78]HALUSKA P, SHAW H M, BATZEL G N, et al. Phase dose escalation study of the anti-insulin-like growth factor I receptor monoclonal antibody CP-751,871 in patients with refractory so lid tumors[J]. Clin Cancer Res,2007,13(4):5834-5840.
[79]SODA M, CHOI Y L, ENOMOTO M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer[J]. Nature,2007,2(448):561-566.
[80]SHAW A T, YEAP B Y, M INO-KENUDSON M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK[J]. Clin Oncol,2009,27(26):4247-4253.
[81]KOIVUNEN J P, MERMEL C, ZE JNULLAHU K, et al. EML4-ALK fus ion gene and efficacy of an ALK kinase inhibitor in lung cancer[J]. Clin Cancer Res,2008,14(1):4275-4283.
[82]MA P C, JAGADEESWARAN R, JAGADEESH S, et al. Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small-cell lung cancer[J]. Cancer Res,2005,65(5):1479-1488.
[83]BOCCAC IO C, COMOGL IO P M. Invasive growth:a MET driven genetic programme for cancer and stem cells[J]. Nat Rev Cancer, 2006,6(2):637-645.
[84]ENGELMAN JA, ZE INULLAHU K, M ITSUDOM I T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling[J]. Science,2007,316 (11):1039-1043.
[85]BEAN J, BRENNAN C, SH IH JY, et al. MET amplification occurs with or without T 790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinibor erlotinib[J]. Proc Natl Acad Sci USA, 2007,104(7):20932-20937.
[86]PUR I N, KHRAMTSOV A, AHMED S, et al. A selective small molecule inhibitor of c-Met, PHA665752, inhibits tumor igenicity and ang-iogenes is inmouse lung cancer xenografts[J]. Cancer Res,2007,67(5):3529-3534.