摘要
研究目的:首次探讨肠道病毒柯萨奇病毒B组(CVB)及柯萨奇病毒-腺病毒受体(CAR)在人非小细胞肺癌(NSCLC)中的表达情况,探寻三者之间的关系。试图寻找NSCLC的新病因,为Ad-p53用于NSCLC的临床治疗提供理论依据。
方法:应用人体肺癌切除标本作回顾性分析,采用免疫组织化学染色方法检测120例手术切除的NSCLC组织的癌组织、癌旁和5例非癌肺组织标本中CAR及CVB的表达情况,分析CVB及CAR的表达与NSCLC的发生发展、临床病理特征及其它临床资料间的关系。
结果:
1 CAR的表达:CAR阳性染色为膜型。在非癌标本中,未发现CAR的阳性染色。鳞状细胞癌和腺癌中CAR的表达均上调,上调率分别为26.67%和31.46%,分析发现CAR的阳性表达量在两型肺癌的原发癌组织与癌旁组织中差别均有统计学意义(p＜0.05),提示CAR的阳性表达与两型肺癌有关,呈正相关(鳞状细胞癌r=0.29277,腺癌r=0.32579)。同时我们发现细支气管肺泡癌的阳性率86.38%。腺癌中如果剔除了细支气管肺泡癌成分,统计结果出现转变,即CAR的表达量在细支气管肺泡癌以外腺癌的原发癌组织与癌旁组织间差别尚不能认为有统计学意义(p＞0.05),CAR与细支气管肺泡癌以外的肺腺癌之间无关。CAR的表达与鳞状细胞癌的不同组织学分级无关。鳞状细胞癌和腺癌间CAR的表达量间差别、癌旁组织间差别亦不能认为有统计学意义(p＞0.05),我们的结果没有显示出CAR与NSCLC的某种亚型的关系更为密切。CAR在性别、年龄、肿瘤直径、淋巴结转移等方面的差别无统计学意义。
2 CVB的表达:CVB阳性染色为胞浆型。在非癌标本中,未发现CVB的阳性染色。鳞状细胞癌和腺癌中CVB的表达均上调,上调率分别为30.00%和12.36%,分析发现CVB的阳性表达量在两型肺癌的原发癌组织与癌旁组织中差别均有统计学意义(p＜0.05),提示CVB的阳性表达与两型肺癌有关,呈正相关(鳞状细胞癌r=15.09317,腺癌r=5.28281)。这一点同于CAR的结果。但是,单独分析细支气管肺泡癌、除细支气管肺泡癌外的腺癌,发现CVB的表达量与两者均无关(p＞0.05)。CVB与鳞状细胞癌的不同组织学分级同样没有关系。另外与CAR结果一致的是,鳞状细胞癌和腺癌的癌旁组织间差别没有统计学意义(p＞0.05)。但是癌间CVB的表达量间差别有统计学意义(p＜0.05),鳞状细胞癌CVB阳性率比腺癌高16.98%,这显示出CVB与鳞状细胞癌的的关系更为密切。CVB在不同性别间的表达差别有统计学意义,男性组阳性率高于女性组15.10%,而CVB与年龄、肿瘤直径、淋巴结转移等因素无关。这说明男性更容易感染CVB。
3 CAR和CVB的关系:在NSCLC中,CAR与CVB之间呈正相关(r=0.25128),其中在鳞状细胞癌、腺癌、除细支气管肺泡癌外的腺癌中,均呈现正相关(r分别为0.37741、0.29638、0.39590),但在细支气管肺泡癌的统计学分析中不能认为两者有关(p＞0.05),这需要大样本的细支气管肺泡癌加以证实。
结论:
1.非癌标本中未见CAR阳性染色。CAR的阳性表达与鳞状细胞癌呈正相关,与腺癌中的细支气管肺泡癌呈正相关,而与细支气管肺泡癌以外的肺腺癌之间无统计学相关性。与鳞状细胞癌的不同组织学分级无关。但是,我们的结果没有显示出CAR与NSCLC的某种亚型的关系更为密切。CAR与性别、年龄、肿瘤直径、淋巴结转移无关。部分解释并支持了Ad-p53的肺癌基因靶向治疗(例如对不能手术的鳞状细胞癌的局部注射治疗,气管内滴入Ad-p53治疗细支气管肺泡癌),并为肺癌的基因治疗提供了新的思路。CAR可能成为Ad-p53治疗的药敏指标。NSCLC中,CAR的表达量与CVB的感染之间呈正相关。
2.非癌标本中未见CVB阳性染色,CVB的阳性表达与两型肺癌呈正相关。与鳞状细胞癌的不同组织学分级无关。与细支气管肺泡癌无关。CVB与鳞状细胞癌的的关系比腺癌更为密切。同时,男性更容易感染CVB。而与年龄、肿瘤直径、淋巴结转移等因素无关。我们在世界范围内首次探索并得出肠道病毒与肺癌有关,为寻找肺癌的病因开拓新的领域。这点还需从病毒的遗传物质等多角度检测。
3.NSCLC中,CAR的表达量与CVB的感染之间呈正相关。
Objective To discuss expression of CVB and CAR in NSCLC,and to study the relationship among CAR,CAR and the development of NSCLC.To discover new pathogeny of lung cancer and to optimize adenovirus vector-based gene therapy.
Methods The expression of CAR and CAR in 120 cases of NSCLC,paraneoplastic epithelial tissue and 5 normal lung tissues was examined using immunohistochemistry.At the same time,the relationship among CAR and CAR expression and clinicopathologic characteristics was analyzed.
Results
1.Expression of CAR:All staining on the cell membrane,little in normal lung tissue. Compared with paraneoplastic tissue,CAR is up-regulated in tumor tissues.The possitive rate in squamous cell cancers was 26.67%,and in adenocinoma 31.46%.It shows that CAR and NSCLC are positive correlation(squamous cell cancers, r=0.29277,adenocinoma,r=0.32579).We noticed that 27 cases are positive in 32 bronchioalveolar adenocinoma,positive rate 86.38%.However,the difference in adenocinoma except bronchioalveolar adenocinomas,in stages of squamous cell cancer,in sex,age,tumor diameter、metastasis had no statistical significance had no statistical significance.The difference between tumor tissues of two types, paraneoplastic tissue,had no statistical significance.So our results did not show that CAR expression is needed for the formation of tumors by a subset of SNCLC.
2.Expression of CVB:All intracellular staining,little in normal lung tissue. Compared with paraneoplastic tissue,CVB is up-regulated in tumor tissues.The possitive rate in squamous cell cancers was 30.00%,and in adenocinoma 12.36%.It shows that CVB and NSCLC are positive correlation(squamous cell cancers, r=15.09317,adenocinoma,r=5.28281).The difference in stages of squamous cell cancer,between tumor tissues,in age,tumor diameter、metastasis had no statistical significance,but had statistical significance in paraneoplastic epithelial tissue.It shows that CVB expression is correlate with squamous cell cancers closer than adenocinoma,and with 16.98%positive rate higher than in adenocinoma.15.10% positive rate in male higher than female shows that CVB infect easier in male.
3 the correlation between CAR and CVB:CAR and CVB are positive correlation in NSCLC(r=0.25128),squamous cell cancers(r=0.37741),adenocinomas(r=0.29638), adenocinoma except bronchioalveolar adenocinomas(r=0.39590),but zero correlation in bronchioalveolar adenocinomas,maybe because of the little cases.
Conclusion
1 There is positive correlation between squamous cell cancers,bronchioalveolar adenocinomas and CAR,zero correlation between adenocinomas except bronchioalveolar adenocinomas and CAR,no relationship between stages of squamous cell cancer,sex,age,tumor diameter、metastasis and CAR.Our results did not show that CAR expression is needed for the formation a subset of SNCLC.This research provides a basis for planning a regimen of gene.
2 There is positive correlation between NSCLC and CVB,no relationship between stages of squamous cell cancer,age,tumor diameter、metastasis and CAR.Statistical significance in paraneoplastic tissue shows that CVB expression is correlate with squamous cell cancers closer than adenocinoma,and CVB infect easier in male.Zero correlation between paraneoplastic epithelial tissue of two typies.At the first time,we discovered enteroviruses could cause lung cancer,and found a new pathogeny of lung cancer.And it needs further test.
3 It is positive correlation between CAR and CVB in NSCLC.
引文
[1]Koizumi K.Current surgical strategies for lung cancer with a focus on open thoracotomy and video-assisted thoracic surgery[J].Int J Nippon Med Sch,2006,73(3):116-121.
[2]Roth JA,Grammer SF,Swisher SG,et al.Gene replacement strategies for treating non-small cell lung cancer[J].Semin Radiat Oncol,2000,10(4):333-342.
[3]Niedobitek G,Meru N,Delecluse H J.Epstein-Barr virus infection and human malignancies[J].Int J Exp Pathol,2001,82(3):149-170.
[4]冯欣姝,敖亚洲.肺癌患者咽部、血液、癌组织EBV感染及其关系初探[J].中国肿瘤临床,2005,32(5):43-46.
[5]Karakelides H,Aubry MC,Ryu J H.Cytomegalovirus pneumonia mimicking lung cancer in an immunocompetent host[J].Mayo Clin Proc,2003,78(4):488-490.
[6]CannelI E,Mittnacht S.Viral encoded cycling[J].Sentin Cancer Biol,1999,9(3):231.
[7]吴一龙,李扬秋.非小细胞肺癌组织中的人类疱疹病毒7型DNA[J].肿瘤,2000,11:401-403.
[8]Montagen J.RSV pneumonia a community-acquired infection adults[J].Lancet,1997,349(9046):149-150.
[9]Engels E A,Brock M V,Chen J,et al.Elevated incidence of lung cancer among HIV-infected individuals[J].Clin Oncol,2006,20,24(9):1383-1388.
[10]Lavole A,Wilsez M,Antoine M,et al.Lung cancer,a new challenge in the HIV-infected population[J].Lung Cancer,2006,51(1):1-11.
[11]Imai S,Nishikawa J,Kuroda M,et al.Epstein-Barr virus infection of human epithelial cells[J].Curr Top Microbiol Immunol,2001,258(1):161-184.
[12]Duensing S,Duensing A,Crum C P,et al.Human papillomavirus typy 16 E7oncoprotein-induced abnormal centrosome sunthesis is an early event in the evolving malignant phenotype[J].Cancer Res,2001,61(6):2356-2360.
[13]Speck P,Haan K M,Longnecker R,et al.Epstein-Barr virus entry into cells[J].Virology,2000,277(1):1-5.
[14]车莉,吴婉芳,马官福,等.柯萨奇病毒B组下呼吸道感染的临床研究[J].中华儿科杂志,1995,33(3):140-141.
[15]赵德超,于波,张风民,等.利用直接原位PCR法探讨柯萨奇B3病毒与心肌炎的病原学关系[J].中国地方病学杂志,2003,22:265-267.
[16]李瑞,邓星强,梁丽君,等.柯萨奇病毒B组脑膜脑炎1262例临床分析.实用儿科临床杂志,2003,5,18(5):374-376.
[17]任立群,李广生,赵志涛,等.柯萨奇病毒RNA阳性信号在克山病心肌中形态特征及其与发病的关系[J].中国地方病学杂志,2002,21:248-250.
[18]方凤,王亚莉,方超平,等.不同状态柯萨奇B3病毒暴露致气道炎症研究.中国现代医学杂志,2006,2,16(4):523-528.
[19]FANG F,LIANG JJ,SHEN Q,et al.A Study of the relationship between Coxsackievirus group B infection and asthma attack in children[J].China Practical Joumal of Clinical Pediatrics,1999,14(9):539-540.
[20]李瑞,邓星强,梁丽君,等.柯萨奇病毒B组脑膜脑炎1262例临床分析.实用儿科临床杂志,2003,5,18(5):374-376.
[21]Hotta Y,Honda T,Naito M,et al.Developmental distribution of coxsackie virus and adenovirus receptor localized in the nervous system[J].Brain Res Dev Brain Res.2003,143:1-13.
[22]Kawashima H,Ogose A,Yoshizawa T,et al.Expression of the coxsackievirus and adenovirus receptor in musculoskeletal tumors and mesenchymal tissues:efficacy of adenoviral gene therapy for osteosarcoma[J].Cancer Sci,2003,94:70-75.
[23]Honda T,Saitoh H,Masuko M,et al.The coxsackievirus -adenovirus receptor protein as a cell adhesion molecule in the developing mouse brain[J].Brain Res Mol Brain Res,2000,77:19-28.
[24]Li Y,Pong RC,Bergelson JM,et al.Loss adenoviral receptor expression in human bladder cancer cells:a potential impact on the efficacy of gene therapy[J].Cancer Res,1999,59:325-330.
[25]Ito M,Kodama M,Masuko M,et al.Expression of coxsaekievirus an d adenovirus receptor in hearts of rats with experimental autoiminune myocarditis [J].Circ Res,2000,86(3):275-280.
[26]Takatsugu Okegawa,Rey-Chen Pong,Yingming Li,et al.The Mechanism of the Growth-inhibitory Effect of Coxsackie and Adenovirus Receptor(CAR)on Human Bladder Cancer:A Functional Analysis of CAR Protein Structure[J].Cancer Research, 2001, 61(1): 6592-6600.
[27] Okegawa T, Li Y, Pong RC, et al. The dual impact of coxsackie and adenovirus receptor expression on human prostate cancer gene therapy [J]. Cancer Res, 2000, 60: 5031-5036.
[28] Rice AM, Currier MA, Adams LC, et al. Ewing sarcoma family of tumors express adenovirus receptors and are susceptible to adenovirusmediated oncolysis [J]. J Pediatr Hematol Oncol 2002, 24: 527-533.
[29] Min Qin, Shuang Chen, Tina Yu. Coxsackievirus Adenovirus Receptor Expression Predicts the Efficiency of Adenoviral Gene Transfer into Non-Small Cell Lung Cancer Xenografts [J]. Clinical Cancer Research, 2003,10(9): 4992-4999.
[30] Min Qin, Brian Escuadrol, Mariam Dohadwalal. A Novel Role for the Coxsackie Adenovirus Receptor in Mediating Tumor Formation by Lung Cancer Cells [J]. Cancer Research, 2004, 64(15): 6377-6380.
[31] Yong Wang, Shizhong Wang, Yongyi Bao, et al. Coxsackievirus and adenovirus receptor expression inn non-maligant lung tissues and clinical lung cancers [J]. J Mol Hist, 2006, 37: 153-160.
[32] Zeng J, Fournier P, Schirrmacher V. Induction of interfemn-alpha and tumor necrosis factor-related apoptosis-inducing ligand in human blood mononuclear cells by hemagglutinin-neurtmlinidase but not F protein of Newcastle disease virus [J]. Virology, 2002, 297: 19-30.
[33] Kauczor HU, Schuler M, Heussel CP, et al. CT-guided intratumoral gene therapy in non small cell lung cancer [J]. Eur Radio 1,1999, 9(2): 292—296.
[34] Swisher SG, Roth JA, Nemunaitis J, et al. Adenovirus-mediated p53 gene transfer in advanced non small cell lung cancer [J]. J Natl Cancer Inst, 1999, 91(9): 763-771.
[35] Kagawa S, Fujiwara T, Tanaka N. Clinical study of adenoviral mediated p53 gene therapy for non small cell lung cancer in Japan [J]. Gan To Kagaku Ryoho, 2003, 30(2): 193-197.
[36] Weill D, Mack M, Roth J, et al. Adenoviral-mediated p53 gene transfer to non small cell lung cancer through endobronchial injection [J]. Chest, 2000, 118(4): 966-970.
[37] Carbone DP, Adak K, Schiller J, et al. Adenovirus p53 administered by bronchoalveolar lavage in patients with bronchioalveoar cell lung carcinoma (BAC)[J]. Proc Am Soc Clin Oncol, 2003, 22 : 620a.
[38] Kim JS, Lee SH, Cho YS, et al. Ectopic expression of the coxsackievirus and adenovirus receptor increases susceptibility to adenoviral infection in the human cervical cancer cell line, SiHa [J]. Biochem Biophys Res Commun, 2001, 288(1): 240-244.
[39] Walter R, Wilson. 现代感染疾病诊断与治疗(英文版)[J]．人民卫生出版社, 2001: 371-376.
[40] Bergelson J, Cunningham J, Droguett G, et al. Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5 [J]. Science. 1997, 275: 1320-1323.
[41] Bowles KR, Gibson J, Wu J, et al. Genomic organization and chromosomal localization of the human coxsackievirus 13-adenovirus receptor gene [J]. Hum Genet, 1999(4), 105: 354-359.
[42] Wang X, Bergelson JM. Coxsackievirus and adenovirus receptor cytoplasmic and transm embrane domains are not essential for coxsackievirus and adenovirus infection [J]. J Virol, 1998, 73: 2559-2562.
[43] Shafren DR, Bates RC, Agrez M V, et al. Coxsackeviruses B1, B3 and B5 use decay accelerating factor as a receptor for cell attachment [J]. J Virol, 1995, 69(6): 3873-3877.
[44] Schmidtke M, Selinka HC, Helm A, et al. Attachment of coxsackievirus B3 variants to various cell lines : Mapping of phenotypic differences to capsid protein VP1 [J]. J Virol, 2000, 275: 77-88.
[45] Shafren DR, Williams DT, Barry RD. A decay-accelerating factor-binding strain of coxsackievirus B3 requires the coxsachievirus-adenovirus receptor protein to mediate lytic infection of Rhabdomyosarcoma cells [J]. J Virol, 1997, 71(12): 9844-9848.
[46] Cohen CJ, Shieh JT, Pickles RJ, et al. The coxsackievirus and adenovirus receptor is a transmembrane component of the tight junction [J]. Proc Natl Acad Sci USA, 2001, 98(26): 15191-15196.
[47] Okegawa T, Pong RC, Li Y, et al. The mechanism of the growth-inhibitory effect of coxsackie and adenovirus receptor (CAR) on human bladder cancer: a functional analysis of CAR protein structure [J]. Cancer Res, 2001, 61: 6592-6600.
[48] Kim M, Sumerel LA, Belousova N, et al. The coxsackievirus and adenovirus receptor acts as a tumour suppressor in malignant glioma cells [J]. Br J Cancer, 2003, 88:1411-1416.
[49]Ito T, Tokunaga K, Maruyama H, et al. Coxsackievirus and adenovirus receptor (CAR)-positive immature osteoblasts as targets of adenovirus- mediated gene transfer for fracture healing [J]. Gene therapy 2003, 10:1623-1628.
[50] Carraresi L,Martinelli R,Vannoni A, et al. Establishment and caracterization of murine small cell lung carcinoma cell lines derived from HPV-16 E6/E7 transgenic mice[J]. Cancer Lett, 2006, 23(191): 65-73.
[51] Cheng Y W, Chiou H L, Sheu G T, et al. The association of human papillomavirus 16/18 infection with lung cancer among non-smoking Taiwanese women[J]. Cancer Res, 2001, 61(7): 2799-2803.
[52] Liu M T, Chen Y R, Chen S C. Epstein-Barr virus latent membrane protein 1induces micronucleus formation, represses DNA repair and enhances sensitivity toDNA-damaging agents in human epithelial cells[J]. Oncogene, 2004,1, 23(14): 2531-2539.
[53] Engels E A, Brock M V, Chen J, et al. Elevated incidence of lung cancer among HIV-infected individuals[J]. Clin Oncol, 2006, 20, 24(9): 1383-1388.
[54] Lavole A, Wilsez M, Antoine M, et al. Lung cancer, a new challenge in the HIV-infected population [J]. Lung Cancer, 2006, 51(1): 1-11.
[55] Gillian E, Oiot, Peter Hare. Intercellular trafficking of VP22-GFP fusion proteins [J]. Gene Therapy, 1999; 6(10): 149-151.
[56] Jeromes, harms, Xinodiren, et al. Distinctions between bovine herpesivirus land VP22 tegument protein suboellular associations [J]. Journal of Virology, 2000, 74(7): 3301-3312.
[57] Swisher SG, Roth JA, KomakiR, etal. Induction of p53-regulated genes and tumor regression ln lung cancer patients after in—tratumoral delivery of adenoviral p53(IN—G 201) and radiation therapy [J]. Clin Cancer Res, 2003, 9(1): 93-101.
[58] Neyns B, Noppen M. Intratumoral gene therapy for non small cell lung cancer: current status and future directions [J]. M onaldi Arch Chest Dis, 2003, 59(4) : 287-295.
[59]何勇,刘苹.肺癌p53基因治疗临床研究进展[J].中国肺癌杂志,2003,6:512-514.
[60]Nemuaitis J,Swisher SG,Timmos T,et al.Adenovirus-mediated p53 gene transfer in sequence with eisplatin totumors oF patients with non—small-cell lung cancer[J].J Clin Oncol,2000,18:609-622.
[61]Zhang W W,Fang X,Mazur W,et al.High efficiency gene transfer and high-level expression of wild type p53 in human lung cancer cells mediated by recombinant adenovirus[J].Cancer Gene Ther,1994,1(1):5-13.
[62]Osaki S,Nakanishi Y,Takayama K,et al.Alteration of drug chemosensitivity caused by the adenovirus-mediated transfer of the wild-type p53 gene in human lung cancer cells[J].Cancer GeneTher,2000,7(2):300-307.
[63]Horio Y,Hasegawa Y,Sekido Y,et al.Synergistic effects of adenovirus expressing wild-type p53 on chemosensitivity of non-small cell lung cancer cells [J].Cancer GeneTher,2000,7(4):537-544.
[64]Schuler M,Rochlitz C,Horowitz JA,et al.A phase I st udy of adenovirus-mediated wild-type p53 gene transfer in patients with advanced non-small cell lung cancer[J].Hum Gene Ther,1998,9(14):2075-2082.
[65]Modesitt SC,Ramirez P,Zu Z,et al.Adenovirus-mediated p53 and p16 tumor suppressor therapy in ovarian cancer[J].Clim Cancer Res,2001,7(6):1 765-1 772.
[66]Kawabe S,Munshi A,Zumstein IA,et al.Adenovirus-mediated wild-type p53gene expression radiosensitizes non-small cell lung cancer cells but not normal lung fibroblasts[J].Int J Radiat Biol,2001,77(2):185-194.
[67]Nishizaki M,Meyn RE,Levy LB,et al.Synergistic inhibition of human lung cancer cell growth by adenovirus-mediated wild-type p53 gene transfer in combination with docetaxel and radiation therapeutics in vitro and in vivo[J].CIin Cancer Res,2001,7(9):2887-2897.
[68]Schuler M,Herrmann R,De Greve JI,et al.Adenovirus-mediated wild-type p53 gene transfer in patients receiving chemotherapy for advanced non small cell lung cancer:results ofa muhicenter phase 1I study[J].J Clin Oncol,2001,19(6):1 750-1 758.
[1]Koizumi K.Current surgical strategies for lung cancer with a focus on open thoracotomy and video-assisted thoracic surgery[J].Int J Nippon Med Sch,2006,73(3):116-121.
[2]Niedobitek G,Meru N,Delecluse H J.Epstein-Barr virus infection and human malignancies[J].Int J Exp Pathol,2001,82(3):149-170.
[3]冯欣姝,敖亚洲.肺癌患者咽部、血液、癌组织EBV感染及其关系初探[J].中国肿瘤临床,2005,32(5):43-46.
[4]Syrjanen K J.HPV infections and lung cancer[J].J Clin Pathol.2002,55:885.
[5]Clavel C E,Nawrocki B,Bosseaux B,et al.Dectetion and typing of human papillomavirus DNA in bronchopulmonary carcinomas by hybrid capture,a study of 185 tumors[J].Cancer,2000,88(6):1347-1352.
[6]Zefer E,Ergun M A,Alver G,et al.Detection and expression of human papillomavirus in non-small cell lung cancer[J].Respiration,2004,71(1):88-90.
[7]Burger M P,Hollema H,Gouw A S,et al.Expression of p53 protein in laryngeal squamous cell carcinoma and dysplasia:possible correlation with human papillomavirus in patients with reported cervical cytological abnormality[J].BMJ,1993,306:749.
[8]Kinoshita I,Dosaka-Akita H,Shindoh M,et al.Human papillomavirus type 18DNA and E6/E7 mRNA are detected in squamous cell carcinoma and adenocarcinoma of the lung[J].Br J Cancer,1995,71:344.
[9]姜蕊,吴翠环,郑丽瑞,等.人乳头瘤病毒感染与非小细胞肺癌发生的相关性[J].华中科技大学学报(医学版),2005,4,34(2):141-144.
[10]Ciotti M,Giuliani L,Ambrogi L,et al.Detection and expression of human papillomavirus oncogenes in non-small cell lung cancer[J].Oncol Rep,2006,16(1):183-189.
[11]Evander M,Boden E,Bjersing L,et al.Oligonucleoyide primers for DNA amplification of early region 1,6 and 7 form human papillomavirus type 6,11,16,18,31 and 33[J].Arcn Virol,1991,116:221.
[12]许春雷,赵光明.人乳头瘤病毒16型E6和E7癌蛋白在肺癌中的表达检测[J].中国肺癌杂志,2004,7(4):364-366.
[13]Karakelides H,Aubry MC,Ryu J H.Cytomegalovirus pneumonia mimicking lung cancer in an immunocompetent host[J].Mayo Clin Proc,2003,78(4):488-490.
[14]Kempf W,Adams V,Mirandola P,et al.Persistence of human herpesvirs 7 in normal tissue detected by expression of a structureal antigen[J].J Infect Dis,1998,178:84.
[15]CannelI E,Mittnacht S.Viral encoded cycling[J].Sentin Cancer Biol,1999,9(3):231.
[16]吴一龙,李扬秋.非小细胞肺癌组织中的人类疱疹病毒7型DNA[J].肿瘤,2000,11:401-403.
[17]陈杭薇,陈佩兰,李继成.等成人呼吸道合胞病毒的电镜和免疫电镜研究[J].中华结核和呼吸杂志,1993 16(5):281-283.
[18]Montagne J,R L.RSV pneumonia,a community-acquired infection in adults[J].Lancet,1997,349(9046):149-150.
[19]Engels E A,Brock M V,Chen J,et al.Elevated incidence of lung cancer among HIV-infected individuals[J].Clin Oncol,2006,20,24(9):1383-1388.
[20]Lavole A,Wilsez M,Antoine M,et al.Lung cancer,a new challenge in the HIV-infected population[J]. Lung Cancer, 2006, 51(1):1-11.
[21] Imai S, Nishikawa J, Kuroda M, et al. Epstein-Barr virus infection of human epithelial cells[J]. Curr Top Microbiol Immunol, 2001,258(1): 161-184.
[22] Duensing S, Duensing A, Crum C P, et al. Human papillomavirus typy 16 E7 oncoprotein-induced abnormal centrosome sunthesis is an early event in the evolving malignant phenotype[J]. Cancer Res, 2001, 61(6): 2356-2360.
[23] Carraresi L,Martinelli R,Vannoni A, et al. Establishment and caracterization of murine small cell lung carcinoma cell lines derived from HPV-16 E6/E7 transgenic mice[J]. Cancer Lett, 2006, 23(191): 65-73.
[24] Cheng Y W, Chiou H L, Sheu G T, et al. The association of human papillomavirus 16/18 infection with lung cancer among non-smoking Taiwanese women[J]. Cancer Res, 2001, 61(7): 2799-2803.
[25] Liu M T, Chen Y R, Chen S C. Epstein-Barr virus latent membrane protein 1induces micronucleus formation, represses DNA repair and enhances sensitivity toDNA-damaging agents in human epithelial cells[J]. Oncogene, 2004,1, 23(14): 2531-2539.
[26] Speck P, Haan K M, Longnecker R, et al. Epstein-Barr virus entry into cells[J]. Virology, 2000,277(1): 1-5.
[27] Underwood M R, Shewchuk L M, Hassell A M, et al. Searching for antiviral drugs for human papillomaviruses[J]. Antivir Ther, 2000, 5(4):242-299.
[28] Gillian E, Oiotl, Peter O'Hare. Intercellular trafficking of VP22-GFP fusion proteins[J]. Gene Therapy, 1999,6(10): 149-151.
[29] Jeromes, harms, Xinodiren, et al. Distinctions between bovine herpesivirus 1 and VP22 tegument protein suboellular associations[J]. Journal of Virology, 2000, 74(7): 3301-3312.
[30] F. C. Klinik. Can VP22 recurrent genetherapy? [J]. J Mol Med, 1999, 77: 575-576.
[31] Zeng J, Fournier P, Schirrmacher V. Induction of interfemn-alpha and tumor necrosis factor-related apoptosis-inducing ligand in human blood mononuclear cells by hemagglutinin-neurtmlinidase but not F protein of Newcastle disease virus[J]. Virology, 2002, 297: 19-30.
[32] Kauczor HU, Schuler M, Heussel CP, et al. CT-guided intratumoral gene therapy in non small cell lung cancer[J]. Eur Radio 1,1999, 9(2): 292-296.
[33] Swisher SG, Roth JA, Nemunaitis J, et al. Adenovirus-mediated p53 gene transfer in advanced non small cell lung cancer [J]. J Natl Cancer Inst, 1999, 91 (9): 763-771.
[34] Weill D, Mack M, Roth J, et al. Adenoviral-mediated p53 gene transfer to non small cell lung cancer through endobronchial injection[J]. Chest, 2000, 118(4): 966-970.
[35] Kagawa S, Fujiwara T, Tanaka N. Clinical study of adenoviral mediated p53 gene therapy for non small cell lung cancer in Japan[J]. Gan To Kagaku Ryoho, 2003, 30(2): 193-197.
[36] Carbone DP, Adak K, Schiller J, et al. Adenovirus p53 administered by bronchoalveolar lavage in patients with bronchioalveoar cell lung carcinoma (BAC ) [J]. Proc Am Soc Clin Oncol, 2003, 22 : 620a.
[37] Schuler M, Rochlitz C, Horowitz JA, et al . A phase I study of adenovirus-mediated wild-type p53 gene transfer in patients with advanced non small cell lung cancer[J]. Hum Gene Ther, 1998, 9(14): 2075-2082.
[38] Modesitt SC, Ramirez P, ZuZ, etal. Adenovirus-mediated p53 and p16 tumor suppressor therapy in ovarian cancer [J]. Clm Cancer Res, 2001, 7(6): 1765-1 772.
