摘要
目的表皮生长因子受体(epidermal growth factor receptor,EGFR)和环氧化酶—2(Cyclooxygenase-2,COX-2)对鼻咽癌的发生发展起着重要的作用。研制开发不同的EGFR抑制剂及COX—2抑制剂并将其用于鼻咽癌放疗的辅助治疗已成为人们关注的焦点。但单一靶点治疗的疗效不尽满意。本研究用Tarceva(EGFR-酪氨酸激酶拮抗剂)联合C elecoxib(COX-2抑制剂)处理鼻咽癌细胞株CNE-1,CNE-2,观察该联合靶向治疗方案对鼻咽癌细胞的影响。
方法用不同浓度的Tarceva(0-40umol/L、)和C elecoxib(0-100umol/L)处理鼻咽癌细胞株CNE-1,CNE-2,通过CCK-8法观察细胞生长抑制率,确定IC50。再用浓度为IC30的Tarceva和c elecoxib单独和联合处理CNE-1,CNE-2细胞,对比单独处理和联合处理时细胞生长抑制率。通过流式细胞术进行细胞周期、凋亡率的分析,western blot检测药物处理前后相关蛋白表达的差异。
结果(1)Tarceva和C elecoxib处理的CNE-1,CNE-2细胞后,出现剂量依赖性的生长抑制率增高。Celecoxib处理CNE-1,CNE-2细胞IC50约为25umol/1,Tarceva处理CNE-1细胞IC50约为30umol/l,处理CNE-2细胞IC50约为15umol/l。(2)CNE-1细胞联合用药组细胞生长抑制率与单独处理组细胞的生长抑制率之和比较差异无显著性(P＞0.05)。CNE-2细胞联合用药组细胞生长抑制率大于单独处理组细胞的生长抑制率之和(P＜0.05)。(3)联合处理组细胞G1期比例大于单独处理组(P＜0.05)。联合处理组细胞调亡率与单独处理组细胞的调亡率之和比较差异无显著性(P＞0.05)。(4)与单独处理组相比,联合处理组出现明显的p-EGFR,COX-2表达降低。
结论(1)阻断EGFR或COX-2信号通路都能抑制鼻咽癌细胞株CNE-1,CNE-2生长,诱导细胞凋亡,将细胞阻滞于G1期。(2)联合阻断EGFR和COX-2信号通路对抑制鼻咽癌细胞株CNE-2生长以及增加G1期阻滞,有协同作用。(3)联合阻断EGFR和COX-2信号通路在抑制鼻咽癌细胞株CNE-2 EGFR的磷酸化和COX-2的表达方面具有协同作用。
Objective:Epidermal growth factor receptor(EGFR)and cyclooxygenase-2(Cox-2)contribute to development of nasopharyngeal carcinoma(NPC).We can use the EGFR inhibitors or Cox-2 inhibitors to cure the NPC.But the effect of single agent is not high.This study was designed to explore the effect of a combination of EGFR-selective tyrosine kinase inhibitors(TKIs)Tarceva with a Cox-2 inhibitor (Cox-2I)celecoxib on NPC cell lines CNE-1,CNE-2.
Methods:The NPC cell lines CNE-1,CNE-2 was treated with the Tarceva and C elecoxib in a range of concentrations as single agents.Cell growth inhibition was measured by CCK-8.Then cells were treated with two drugs in fixed concentrations(Tarceva at 10 umol/L plus Celecoxib at 15 umol/L).Cell growth inhibition was measured by CCK-8.The cell cycle and apoptosis was measured by flow cytometric analysis.The exprssions of protein were also examined by using western blot after the combined treatment.
Results:(1)The cell growth was inhibited by Tarceva and C elecoxib,and such effect showed a concentration-dependent manners in a certain range.The IC50 of C elecoxib is 25umol/l.The IC50 of Tarceva to CNE-1 is 35umol/l.The IC50 to CNE-2 is 15umol/l.(2)The combination of Tarceva with Celecoxib synergistically inhibited growth of CNE-2 cell lines(P＜0.05).(3)The combination of Tarceva with Celecoxib significantly induced G1 arrest(P＜0.05),but did not have higher apoptosis than the effect of single agent(P＞0.05).(4)the combination showed strong reductions of p-EGFR and COX-2
Conclusions:(1)Blocking EGFR or COX-2 can inhibit growth of the CNE-2 cell lines,significantly induced G1 arrest and apoptosis.(2) Blocking EGFR and COX-2 Simultaneously can synergistically inhibited growth of CNE-2 cell lines,significantly induced G1 arrest.(3)Blocking EGFR and COX-2 Simultaneously synergistically reduce the level of p-EGFR and COX-2.
引文
[1] Chen Y, Liu MZ,et,al. Preliminary Results of a Prospective Randomized Trial Comparing Concurrent Chemoradiotherapy Plus Adjuvant Chemotherapy with Radiotherapy Alone in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma in Endemic Regions of China[ J ]. Int J Radiat Oncol Biol Phys. 2008 May 7. [Epub ahead of print]
[2] Tang L, Li L, Mao Y,et,al. Retropharyngeal lymph node metastasis in nasopharyngeal carcinoma detected by magnetic resonance imaging : prognostic value and staging categories[ J ].Cancer. 2008 May 5. [Epub ahead of print]
[3] Fang FM, Chien CY,et,al. Quality of Life and Survival Outcome for Patients With Nasopharyngeal Carcinoma Receiving Three-Dimensional Conformal Radiotherapy vs. Intensity-Modulated Radiotherapy-A Longitudinal Study[ J ].Int J Radiat Oncol Biol Phys. 2008 Mar 18. [Epub ahead of print]
[4] Chua DT, Nicholls JM, Sham JS, Au GK. Prognostic value of epidermal growth factor receptor expression in patients with advanced stage nasopharyngeal carcinoma treated with induction chemotherapy and radiotherapy[ J ].Int J Radiat Oncol Biol Phys. 2004 May 1;59(1):11-20.
[5] Thornburg NJ, Raab-Traub N. Induction of epidermal growth factor receptor expression by Epstein-Barr virus latent membrane protein 1 C-terminal- activating region 1 is mediated by NF-kappaB p50 homodimer/Bcl-3 complexes [ J ].J Virol. 2007 Dec;81(23):12954-12961.
[6] Wu RR, Wu SX, et,al. Phase II clinical trial of h-R3 combined radiotherapy for locoregionally advanced nasopharyngeal carcinoma[ J ].Ai Zheng. 2007 Aug;26(8):874-879.
[7] Huang SM, Bock JM, Harari PM. Epidermal growth factor receptor blockade with C225 modulates p roliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck[ J ]. Cancer Res, 1999, 59: 1935-1940.
[8] Huang SM, Li J, Armstrong EA, et al. Modulation of radiation response and tumor induced angiogenesis after epidermal growth factor receptor inhibition by ZD1839 (Iressa) [ J ]. Cancer Res,2003, 62: 4300-4306.
[9] Chinnaiyan P, Huang SM, Vallabhaneni G, et al. Mechanisms of enhanced radiation response following epidermal growth factor receptor signalinginhibition by Erlotinib(Tarceva)[J].CancerRes,2005,65:3328-3335.
[10]Cohen MH,Williams GA,Sridhara R,et al.Phase Ⅱ trial of ZD1839 in recurrent or metastatie squarancus cell carcinoma of the head and neck[J].J Clin Oncol,2003,21(10):1980-1987.
[11]Chan CM,Ma BB,Wong SC.Celecoxib induces dose dependent growth inhibition in nasopharyngeal carcinoma cell lines independent of cyclooxygenase-2 expression[J].Biomed Pharmacother,2005,59(Suppl 2):268
[12]Kadowaki H,Yamamoto T,et,al.The pathophysiological roles of COX-1 and COX-2 in the intestinal smooth muscle contractility under the anaphylactic condition[J].Biomed Res.2008 Apr;29(2):113-117.
[13]SMAKMAN N,KRANENBURG O,VOGTEN J M,et al.Cyclooxygenase-2is a target of KRASD12,which facilitates the outgrowth of murine C26colorectal liver metastases[J].Clin Cancer Res,2005,11(1):41-48.
[14]Soo R,Putti T,Tao Q,et al.Overexpression of cyclooxygenase-2 in nasopharyngeal carcinoma and association with epidermal growt h factor receptor expression[J].Arch Otolaryngol Head Neck Surg,2005,131(2):147-152.
[15]Chen WC,McBride WH,Chen SM,et al.Prediction of poor survival by cyclooxygenase22 in patient s wit h T4 nasopharyngeal cancer treated by radiation therapy:clinical and in vitro studies[J].Head Neck,2005,27(6):503-512.
[16]Chan CM,Ma BB,Wong SC.Celecoxib induces dose dependent growth inhibition in nasopharyngeal carcinoma cell lines independent of cyclooxygenase-2 expression[J].Biomed Pharmacother,2005,59(Suppl 2):268
[17]储大同.肿瘤分子靶向治疗的现状及进展[J].中国实用内科杂志2005,25(8):673-675.
[18]Half E,Broaddus R,Danenberg KD,et al.HER-2 receptor expression,localization,and activation in colorectal cancer cell lines and human tumors[J].Int J Cancer,2004,108:540-548
[19]Sekharam M,Zhao H,Sun M,et al.Insulin-like growth factor 1 receptor enhances invasion and induces resistance to apoptosis of colon cancer cells through the Akt/Bcl-x(L)pathway[J].Cancer Res,2003,63:7708-7716
[20] Chun YJ , Park S , Yang SA , et al. Activation of Fas receptor modulates cytochrome P450 3A4 expression in human colon carcinoma cells[ J ]. Toxicol Lett, 2003, 146:75-81
[21] Ohana G, Bar - Yehuda S , Arich A, et al. Inhibition of primary colon carcinoma growth and liver metastasis by the A3 adenosine receptor agonist CF101[ J ]. Br J Cancer, 2003 , 89 : 1552 -1558
[22] Hainsworth JD , Sosman JA , Spigel DR , et al. Phase II trial of bevacizumab and erlotinib in patients with metastatic renal carcinoma (RCC) [ J ] . Proc Am Soc Clin Oncol, 2004 , 22 : 382-386.
[23] Motzer RJ , Rini BI , Michaelson MD , et al. SUO 11248 , a novel tyrosine kinase inhibitor , shows antitumor activity in second-line therapy for patients with metastatic renal cell carcinoma :results of a phase 2 trial [ J ]. Proc Am Soc Clin Oncol .2004 ,22 :382-386.
[24] Drach J , Kaufmann H , Woehrer S , et al. Durable remissions after rituximab plus thalidomide for relapsed/ refractory mantle cell lymphoma[ J ]. Proc Am Soc Clin Oncol, 2004 , 22 : 578-582.
[25] Shimo T, Matsumura S,et al. Specific inhibitor of MEK-mediated cross-talk between ERK and p38 MAPK during differentiation of human osteosarcoma cells[ J ].J Cell Commun Signal. 2007 Sep;1(2):103-11.
[26] ScottM. Lippman,1Neil Gibson, et al. Combined Targeting of the Epidermal Growth Factor Receptor and Cyclooxygenase-2 Pathways[ J ].Clin Cancer Res 2005,11(17):6097-6099.
[27] DannenbergAJ, Subbaramaiah K.Targetingcyclooxygenase-2 in human neoplasia: rationale and promise[ J ].Cancer Cell 2003;4:431 -436.
[28] Backlund MG, Mann JR, HollaVR,et al.15-hydroxyprostaglandin dehydrogenase is down-regulated in colorectal cancer[ J ]. JBiol Chem 2005;280:3217-3223.
[29] Shao J, Lee SB, Guo H, Evers BM, ShengH. ProstaglandinE2 stimulates the growth of colon cancer cells via induction of amphiregulin[ J ]. Cancer Res.2003;63:5218-23.
[30] Pai R, Soreghan B, Szabo IL, Pavelka MP, Baater D,Tarnawski AS. Prostaglandin E2 transactivates EGF receptor:a novelmechanismfor promotingcolon cancer growth and gastrointestinal hypertrophy[ J ]. Nat Med.2002;8:289-93.
[31] Torrance CJ, Jackson PE, Montgomery E, et al. Combinational chemoprevention of intestinal neoplasia.Nat Med[J].2000,6:1024-1028.
[32]Harnakawa H,Nakashiro KI,et al.Basic evidence of molecular targeted therapy for oral cancer and salivary gland cancer[J].Head Neck.2008 Apr 21;30(6):800-809.
[33]Agarwala A,Fisher W,et al.Gefitinib plus celecoxib in chemotherapy-naive patients with stage ⅢB/Ⅳ non-small cell lung cancer:a phase Ⅱ study from the Hoosier Oncology Group[J].J Thorac Oncol.2008 Apr;3(4):374-379.
[34]Chen L,He Y,Huang H,et al.Selective COX-2 inhibitor celecoxib combined with EGFR-TKI ZD1839 on non-small cell lung cancer cell lines:in vitro toxicity and mechanism study.Med Oncol.2008 Jan 3.[Epub ahead of print]
[35]Gadgeel SM,Ali S,et al.Response to dual blockade of epidermal growth factor receptor(EGFR)and cycloxygenase-2 in nonsmall cell lung cancer may be dependent on the EGFR mutationalstatus of the tumor[J].Cancer.2007 Dec 15;110(12):2775-84.
[36]Buchanan FG,Holla V,et al.Targeting cyclooxygenase-2 and the epidermal growth factor receptor for the prevention and treatment of intestinal cancer[J].Cancer Res.2007 Oct 1;67(19):9380-8.
[37]Zhuo(Georgia)Chen,Xin Zhang,et al.Simultaneously Targeting Epidermal Growth Factor Receptor Tyrosine Kinase and Cyclooxygenase-2,an Efficient Approach to Inhibition of Squamous Cell Carcinoma of the Head and Neck[J].Clinical Cancer Research.2004,9:5930-5939.
[38]Soulieres D,Senzer NN,Vokes EE,et al.Multicenter phase Ⅱ study of erlotinib,an oral epidermal growth factor receptor tyrosine kinase inhibitor,in patients with recurrent or metastatic squamous cell cancer of the head and neck[J].J Clin Oncol,2004,22(1):77-85.
[39]蒋代华,郭德玉,李皓谆,邓蔚.塞来昔布抑制人鼻咽癌细胞株HNE21细胞增殖与血管内皮生长因子的表达[J].中华耳鼻咽喉头颈外科杂志2006.141(11):808-812.
[40]Herrera FG,Vidal L,et al.Molecular targeted agents combined with chemo-radiation in the treatment of locally advanced cervix cancer[J].Rev Recent Clin Trials.2008 May;3(2):111-20.
[41]Kuwai T,Nakamura T,et al.Phosphorylated epidermal growth factor receptor on tumor-associated endothelial cells is a primary target for therapy with tyrosine kinase inhibitors[J].Neoplasia.2008 May;10(5):489-500.
[42] Cheng J, ImanishiH,Amuro Y, et al. NS2398, a selective cyclooxygenase-2 inhibitor, inhibited cell growth and induced cell cycle arrest in human hepatocellular carcinomacell lines[J ]. Int J Cancer, 2002, 99 (5): 755 -761.
[43] Elder DJ, Halton DE, Playle LC, et al. The MEK/ERK pathway mediates COX-2selective NSA ID2induced apop tosis and induced COX-2 p rotein exp ression in colorectal carcinoma cells[ J ]. Int JCancer, 2002, 99 (3): 323 - 327.
[44] Poppleton HM,Wiepz GJ ,Bertics PJ , et al. Modulation of the protein tyrosine kinase activity and autophosphorylation of the epidermal growth fac2tor receptor by its juxtamembrane region. Arch Bioche Biophys ,1999 ,363(2) :227
[45] Iwamoto J, Mizokami Y , et al The effects of cyclooxygenase2-prostaglandinE2 pathway on Helicobacter pylori-induced urokinase-type plasminogen activator system in the gastric cancer cells[J]. Helicobacter. 2008 Jun;13(3):174-82.
[1]Aragon-Ching JB,Dahut WL.Chemotherapy in Androgen-Independent Prostate Cancer(AIPC):What's next after taxane progression[J]?Cancer Ther.2007;5A:151-160.
[2]KurokiM,Arakawa F,Khare PD,et al.Specific targeting strategies of cancer gene therapy using a single - chain variable fragment(scFv)with a high affinity for CEA[J].Anticancer Res,2002,20(6A):4067-4071.
[3]Olson WC,Heston WD,Rajasekaran AK.Clinical trials of cancer therapies targeting prostate-specific membrane antigen[J].Rev Recent Clin Trials.2007Sep;2(3):182-190.
[4]Fecher LA,Amaravadi RK,Flaherty KT.Yhe MAPK pathway in melanoma[J].Curr Opin Oncol.2008 Mar;20(2):183-189.Review.
[5]Caraglia M,Marra M,Meo G,Addeo SR,Tagliaferri P,Budillon A.EGF-R small inhibitors and anti-EGF-R antibodies:advantages and limits of a new avenue in anticancer therapy[J].Recent Patents Anticancer Drug Discov.2006Jun;1(2):209-222.
[6]Kuhn H,Hammerschmidt S,Wirtz H.Targeting tumorangiogenesis in lung cancer by suppression of VEGF and its receptor - results from clinical trials and novel experimental approaches[J].Curr Med Chem.2007;14(30):3157-3165.
[7]Chen Y,Liu MZ,et,al.Preliminary Results of a Prospective Randomized Trial Comparing Concurrent Chemoradiotherapy Plus Adjuvant Chemotherapy with Radiotherapy Alone in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma in Endemic Regions of China.Int J Radiat Oncol Biol Phys.2008May 7.[Epub ahead of print]
[8]Tang L,Li L,Mao Y,et,al.Retropharyngeal lymph node metastasis in nasopharyngeal carcinoma detected by magnetic resonance imaging:prognostic value and staging categories.Cancer.2008 May 5.[Epub ahead of print]
[9]Fang FM,Chien CY,et,al.Quality of Life and Survival Outcome for Patients With Nasopharyngeal Carcinoma Receiving Three-Dimensional Conformal Radiotherapy vs.Intensity-Modulated Radiotherapy-A Longitudinal Study[J]. Int J Radiat Oncol Biol Phys.2008 Mar 18.[Epub ahead of print]
[10]唐平章.头颈肿瘤的诊治现状与展望[J].中国医学科学院学报,2006,6:311-314.
[11]Bohnenkamp TA.The effects of a total laryngectomy on speech breathing[J].Curr Opin Otolaryngol Head Neck Surg.2008 Jun;16(3):200-204.
[12]Maclean J,Cotton S,Perry A.Variation in surgical methods used for total laryngectomy in Australia[J].J Laryngol Otol.2008 Apr 11:1-5.
[13]Ebihara Y,Watanabe K,Fujishiro Y,Nakao K,Yoshimoto S,Kawabata K,Asakage T.Carcinoid tumor of the larynx:clinical analysis of 33 cases in Japan[J].Acta Otolaryngol Suppl.2007 Dec;(559):145-50.
[14]Asakage T,Nakao K,Ebihara Y,Fujishiro Y,Watanabe K.A clinical study of post-cricoid carcinoma[J].Acta Otolaryngol Suppl.2007 Dec;(559):118-1122.
[15]Sesterhenn AM,Fiedler G,Muller HH,Wiegand S,Folz BJ,Wemer JA.Incidence of sinunasal disease in laryngectomized patients[J].ORL J Otorhinolaryngol Relat Spec.2008;70(3):185-188.
[16]祝学光.肿瘤分子靶向治疗进展[J].中华实验外科杂志,2005.11:1285-1286.
[17]Cohen MH,Williams GA,Sridhara R,et al.Phase Ⅱ trial of ZD 1839 in recurrent or metastatie squarancus cell carcinoma of the head and neck[J].J Clin Oncol,2003,21(10):1980-1987.
[18]Chan CM,Ma BB,Wong SC.Celecoxib induces dose dependent growth inhibition in nasopharyngeal carcinoma cell lines independent of cyclooxygenase-2 expression[J].Biomed Pharmacother,2005,59(Suppl 2):268
[19]储大同.肿瘤分子靶向治疗的现状及进展[J].中国实用内科杂志,2005,8:673-675.
[20]Wu RR,Wu SX,et,al.Phase Ⅱ clinical trial of h-R3 combined radiotherapy for locoregionally advanced nasopharyngeal carcinoma[J].Ai Zheng.2007Aug;26(8):874-879.
[21]Huang SM,Bock JM,Harari PM.Epidermal growth factor receptor blockade with C225 modulates proliferation,apoptosis,and radiosensitivity in squamous cell carcinomas of the head and neck[J].Cancer Res,1999,59:1935-1940.
[22]Huang SM,Li J,Armstrong EA,et al.Modulation of radiation response and tumor induced angiogenesis after epidermal growth factor receptor inhibition by ZD1839 (Iressa) [ J ]. Cancer Res, 2003, 62: 4300-4306.
[23] Chinnaiyan P, Huang SM, Vallabhaneni G, et al. Mechanisms of enhanced radiation response following ep idermal growth factor receptor signalinginhibition by Erlotinib ( Tarceva) [ J ]. Cancer Res, 2005, 65: 3328-3335.
[24] Ren W, Korchin B, Zhu QS, Wei C, Dicker A, Heymach J, Lazar A, Pollock RE, Lev D.Epidermal Growth Factor Receptor Blockade in Combination with Conventional Chemotherapy Inhibits Soft Tissue Sarcoma Cell Growth In vitro and In vivo[ J ].Clin Cancer Res. 2008 May 1;14(9):2785-2795.
[25] Cassier PA, Dufresne A, et,al. Imatinib mesilate for the treatment of gastrointestinal stromal tumour[ J ]. Expert Opin Pharmacother. 2008 May;9(7):1211-22.
[26] Jiang Q, Chen SS, et,al. The efficacy of imatinib mesylate for 124 patients with chronic myeloid leukemia in accelerated and blastic phase[J].Zhonghua Xue Ye Xue Za Zhi. 2007 Nov;28(11):721-726.
[27] Heinrich MC, Joensuu H, Demetri GD, et,al.Phase II, Open-Label Study Evaluating the Activity of Imatinib in Treating Life-Threatening Malignancies Known to Be Associated with Imatinib-Sensitive Tyrosine Kinases[ J ].Clin Cancer Res. 2008 May 1;14(9):2717-2725.
[28] Brauer KM, Werth D, von Schwarzenberg K, Bringmann A, Kanz L, Grunebach F, Brossart P.BCR-ABL activity is critical for the immunogenicity of chronic myelogenous leukemia cells[ J ].Cancer Res. 2007 Jun 1;67(11):5489-5497.
[29] Chen ZC, You Y, Zhu XM, Li QB, Li WM, Zou P.A clinical study of treating 120 cases of adult chronic myelocytic leukemia with imatinib mesylate ZhonghuaNei Ke ZaZhi[ J ]. 2007 Dec;46(12):1003-1006.
[30] Demetri GD.Identification and treatment of chemoresistant inoperable or metastatic GIST: experience with the selective tyrosine kinase inhibitor imatinib mesylate (STI571) [ J ].Eur J Cancer. 2002 Sep;38 Suppl 5:S52-59.
[31] 王鑫,胡超苏．鼻咽癌药物治疗进展[J]．中国肿瘤2006,15(12)：832-836．
[32] Chua DT, Nicholls JM, Sham JS, Au GK. Prognostic value of epidermal growth factor receptor expression in patients with advanced stage nasopharyngeal carcinoma treated with induction chemotherapy and radiotherapy[J].Int J Radiat Oncol Biol Phys. 2004 May 1;59(1):11-20.
[33] Thornburg NJ, Raab-Traub N. Induction of epidermal growth factor receptor expression by Epstein-Barr virus latent membrane protein 1 C-terminal-activating region 1 is mediated by NF-kappaB p50 homodimer/Bcl-3 complexes [J].J Virol. 2007 Dec;81(23): 12954-12961.
[34] Ang KK, Berkey BA, Tu X, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma[J]. Cancer Res, 2002,62(24):7350- 7356.
[35] Chua DT, Nicholls JM, Sham JS, et al. Prognostic value of epidermal growth factor receptor expression in patients with advanced stage nasopharyngeal carcinoma treated with induction chemotherapy and radiotherapy [J]. Int J Radiat Oncol Biol Phys, 2004, 59(1): 11- 20.
[36] Wadler S.Molecular targeting in pancreatic cancer[ J ].Rev Recent Clin Trials. 2007 Jan;2(1):69-75.
[37] Watkins D, Cunningham D.The role of epidermal growth factor receptor-targeted antibody therapy in previously treated colorectal cancer[ J ].Clin Colorectal Cancer. 2007 Oct;6 Suppl 2:S47-52.
[38] Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck[J]. N Engl J Med, 2006, 354(6):567- 578.
[39] Bentzen SM,Atasoy BM,Daley FM, et al. Epidermal growth factor receptor expression in pretreatment biopsies from head and neck squamous cell carcinoma as a predictive factor for a benefit from accelerated radiation therapy in a randomized controlled trial[J]. J Clin Oncol, 2005,23(24):5437- 5439.
[40] Baselga J, Trigo JM, Bourhis J, et al. Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinumbased chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of thehead and neck[J]. J Clin Oncol,2005,23(24):5568- 5577.
[41] Epstein RJ.VEGF signaling inhibitors: more pro-apoptotic than anti-angiogenic [J].Cancer Metastasis Rev. 2007 Dec;26(3-4):443-452.
[42] Riely GJ, Miller VA.Vascular endothelial growth factor trap in non small cell lung cancer[ J ].Clin Cancer Res. 2007 Aug 1;13(15):s4623-4627.
[43] Kadowaki H, Yamamoto T, et,al. The pathophysiological roles of COX-1 and COX-2 in the intestinal smooth muscle contractility under the anaphylactic condition[ J ].Biomed Res. 2008 Apr;29(2):113-117.
[44] SMAKMAN N, KRANENBURG O, VOGTEN J M, et al. Cyclooxygenase - 2 is a target of KRASD12, which facilitates the outgrowth of murine C26 colorectal liver metastases [ J ]. Clin Cancer Res, 2005,11 (1): 41 - 48.
[45] Patel S, Chiplunkar S.Role of cyclooxygenase-2 in tumor progression and immune regulation in lung cancer[ J ].Indian J Biochem Biophys. 2007 Dec;44(6):419-28.
[46] Zhuo (Georgia) Chen, Xin Zhang, et al. Simultaneously Targeting Epidermal Growth Factor Receptor Tyrosine Kinase and Cyclooxygenase-2, an Efficient Approach to Inhibition of Squamous Cell Carcinoma of the Head and Neck[ J ]. Clinical Cancer Research.2004,9:5930-5939.
[47] Soo R , Putti T , Tao Q , et al . Overexpression of cyclooxygenase-2 in nasopharyngeal carcinoma and association wit h epidermal growt h factor receptor expression [ J ] . Arch Otolaryngol Head Neck Surg , 2005 , 131 (2) : 147-152.
[48] Chen WC , McBride WH , Chen SM , et al . Prediction of poor survival by cyclooxygenase22 in patient s wit h T4 nasopharyngeal cancer treated by radiation t herapy : clinical and in vitro studies [J ] . Head Neck , 2005 , 27 (6) : 503-512.
[49] Cheng J, ImanishiH,Amuro Y, et al. NS2398, a selective cyclooxygenase-2 inhibitor, inhibited cell growth and induced cell cycle arrest in human hepatocellular carcinomacell lines[J ]. Int J Cancer, 2002, 99 (5): 755 -761.
[50] Elder DJ, Halton DE, Playle LC, et al. The MEK/ERK pathway mediates COX-2selective NSA ID2induced apop tosis and induced COX-2 p rotein exp ression in colorectal carcinoma cells[ J ]. Int JCancer, 2002, 99 (3): 323 - 327.
[51] Chan CM , Ma BB , Wong SC. Celecoxib induces dose dependent growth inhibition in nasopharyngeal carcinoma cell lines independent of cyclooxygenase-2 expression[J ] . Biomed Pharmacother ,2005 ,59 (Suppl 2) :268.
[52] Half E , Broaddus R , Danenberg KD , et al. HER - 2 receptor expression , localization , and activation in colorectal cancer cell lines and human tumors [ J ]. Int J Cancer, 2004 , 108 : 540 - 548.
[53] Sekharam M , Zhao H , Sun M , et al. Insulin - like growth factor 1 receptor enhances invasion and induces resistance to apoptosis of colon cancer cells through the Akt/ Bcl - x (L) pathway[ J ]. Cancer Res.2003 , 63 : 7708 - 7716.
[54] Chun YJ , Park S , Yang SA , et al. Activation of Fas receptor modulates cytochrome P450 3A4 expression in human colon carcinoma cells[ J ]. Toxicol Lett, 2003,146: 75-81.
[55] Ohana G, Bar - Yehuda S , Arich A , et al. Inhibition of primary colon carcinoma growth and liver metastasis by the A3 adenosine receptor agonist CF101[ J ]. Br J Cancer, 2003 , 89 : 1552 - 1558.
[56] Hainsworth JD , Sosman JA , Spigel DR , et al. Phase II trial of bevacizumab and erlotinib in patients with metastatic renal carcinoma (RCC) [ J ]. Proc Am Soc Clin Oncol, 2004 ,22 : 382-386.
[57] Motzer RJ , Rini BI , Michaelson MD , et al. SUO 11248 , a novel tyrosine kinase inhibitor , shows antitumor activity in second-line therapy for patients with metastatic renal cell carcinoma :results of a phase 2 trial [ J ]. Proc Am Soc Clin Oncol, 2004 ,22 :382-386.
[58] Drach J , Kaufmann H , Woehrer S , et al. Durable remissions after rituximab plus thalidomide for relapsed/ refractory mantle cell lymphoma[ J ]. Proc Am Soc Clin Oncol, 2004 , 22 : 578-582.
[59] DannenbergAJ, Subbaramaiah K.Targetingcyclooxygenase-2 in human neoplasia: rationale and promise[ J ].Cancer Cell 2003;4:431 -436.
[60] Backlund MG, Mann JR, HollaVR,et al.15-hydroxyprostaglandin dehydrogenase is down-regulated in colorectal cancer[ J ]. J Biol Chem 2005;280:3217-3223.
[61] Shao J, Lee SB, Guo H, Evers BM, ShengH. ProstaglandinE2 stimulates the growth of colon cancer cells via induction of amphiregulin[ J ]. Cancer Res.2003;63:5218-23.
[62] Pai R, Soreghan B, Szabo IL, Pavelka MP, Baater D,Tarnawski AS. Prostaglandin E2 transactivates EGF receptor:a novelmechanismfor promotingcolon cancer growth and gastrointestinal hypertrophy[ J ]. Nat Med.2002;8:289-93.
[63] Torrance CJ, Jackson PE, Montgomery E, et al. Combinational chemoprevention of intestinal neoplasia[ J ]. Nat Med. 2000, 6: 1024-1028.
[64] Hamakawa H, Nakashiro KI, et al. Basic evidence of molecular targeted therapy for oral cancer and salivary gland cancer.Head Neck[ J ]. 2008 Apr 21;30(6):800-809.
[65] Agarwala A, Fisher W, et al. Gefitinib plus celecoxib in chemotherapy-naive patients with stage IIIB/IV non-small cell lung cancer: a phase II study from the Hoosier Oncology Group[ J ] J Thorac Oncol. 2008 Apr;3(4):374-379.
[66] Chen L, He Y, Huang H, et al. Selective COX-2 inhibitor celecoxib combined with EGFR-TKI ZD1839 on non-small cell lung cancer cell lines: in vitro toxicity and mechanism study[ J ].Med Oncol. 2008 Jan 3. [Epub ahead of print]
[67] Gadgeel SM, Ali S, et al. Response to dual blockade of epidermal growth factor receptor (EGFR) and cycloxygenase-2 in nonsmall cell lung cancer may be dependent on the EGFR mutational status of the tumor[ J ].Cancer. 2007 Dec 15;110(12):2775-84.
[68] Buchanan FG, Holla V, et al. Targeting cyclooxygenase-2 and the epidermal growth factor receptor for the prevention and treatment of intestinal cancer[ J ].Cancer Res. 2007 Oct l;67(19):9380-8.
[69] Zhuo (Georgia) Chen, Xin Zhang, et al. Simultaneously Targeting Epidermal Growth Factor Receptor Tyrosine Kinase and Cyclooxygenase-2, an Efficient Approach to Inhibition of Squamous Cell Carcinoma of the Head and Neck[ J ]. Clinical Cancer Research.2004,9:5930-5939.
[70] Xin Zhang, l Zhuo (Georgia) Chen, Tumor Growth Inhibition by Simultaneously Blocking Epidermal Growth Factor Receptor and Cyclooxygenase-2 in a XenograftModel[ J ]. Clin Cancer Res 2005Sep,11(17):6261-6269.
