腺病毒介导TRAIL基因对涎腺腺样囊性癌细胞靶向作用及机制研究
|
摘要
涎腺腺样囊性癌是口腔颌面部较常见的恶性肿瘤,具有嗜神经和血管等特性,对放疗和化疗不敏感,传统治疗方法不能取得令人满意的治疗效果,随着分子生物学技术发展,转基因治疗涎腺腺样囊性癌成为新的策略,但转基因治疗肿瘤存在特异性差的问题。近年来研究发现hTERT在永生化细胞系和85%的人肿瘤组织中都具有较高的活性,而在大多数正常体细胞中则无活性,本课题组前期研究发现hTERT在涎腺腺样囊性癌阳性率100%,而在正常涎腺组织内阴性或弱阳性。肿瘤坏死因子(TNF)相关的凋亡诱导配体(TRAIL)是TNF家族成员,能引起多种肿瘤细胞凋亡,而对正常细胞影响较小,目前,TRAIL已被应用于多种肿瘤的转基因治疗研究。
针对肿瘤转基因治疗特异性差的问题,根据hTERT和TRAIL均具有肿瘤特异性的特性,在国家自然基金面上项目和国家自然基金国际合作项目资金支持下,以同源重组法构建了AdCMV-TRAIL和AdTERT-TRAIL腺病毒载体,通过体外、体内转染涎腺腺样囊性癌细胞或正常细胞,探讨它们对涎腺腺样囊性癌的作用,结果显示通过双特异性AdTERT-TRAIL实现了TRAIL基因在SACC-83细胞中表达,进而对涎腺腺样囊性癌细胞具有肿瘤特异性杀伤作用:其对菏瘤裸鼠器官、肝脏功能和全血成分没有明显影响,这种特异性杀伤作用是由TRAIL基因激活了Caspase-3基因,从而启动了下游的凋亡途径。这就为AdTERT-TRAIL转基因治疗涎腺腺样囊性癌奠定了理论基础和实验技术基础。
Adenoid cystic carcinoma is one of the most common malignant tumor in maxillofacial region,which has the ability to infiltrate nerve,vessel,fiber,and not sensitiveness to chemotherapy,radiotherapy. It is hot topic to study the development and treatment of adenoid cystic carcinoma.With the development of biomedicine,molecular biology and completion of human genome,gene therapy become a new strategy to treat adenoid cystic carcinoma,which is to transfer the external gene to cells,correct the heredity and get impairment of gene.After 20-year research and studying,there was great progression to treat the heredity disease,metabolism disease and malignant tumor using gene therapy,and some treatment were used in clinical case.
Vector,promoter,target gene are the basic elements of gene therapy. The target expression of gene plays key role in gene therapy,which the target gene should be expressed in tumor cells,not common ones.Only in this way,the gene could become targeted expression.
The common method of targeted gene expression is to control gene expression via tumor-specific promoters in specific tissues,cells or organs.Several promoters have been identified that are more active in particular tumor types than in the tissues from which they arise,and these promoters have been exploited to target gene expression in tumors,which include the AFP promoter,CEA promoter and Tyr enzyme promoter.But these promoters are limited to specific tumor histology and cannot be used universally in tumors of various origins and most of these promoters are much weaker than that commonly used viral promoters such as the CMV promoter.Consequently,their using is hampered by the problem of low expression.Recent years,telomerase was found to be responsible for cell-immortalization and tumor-genesis.It is a specialized DNA polymerase responsible for the replication of chromosomal ends,or telomeres.Telomerase is high active in immortalized cell lines and 85% human cancers,but is inactive in most somatic cells,therefore telomerase is to be very promising not only as a tumor-specific marker but also as a target for anticancer therapy.In summary,basing this characteristic of telomerase,if using the driver of telomerase to induce the target gene,the target gene should be express in tumor cells,not the somatic cells and targeted anticancer therapy will come true.
The vector is another important part of gene therapy.With the development of gene therapy,adenovirus has become the most common one,which has several features:1.it is easy to prepare,because its structure and function are definitely understanding;2.it can infect both dividing cell and non-dividing cell;3.it can ingress different tissue;4.it can contain 10kb,or even 37 kb gene;5.high titer;6.the structure is stable and it is uneasy to insert the genome of host.So we use the adenovirus vector to transfer the target gene.
For the purpose gene of gene therapy,at the beginning,researcher liked to select oncogene or anti-oncogene as target gene,using anti-sencetherapy or transfer anti-oncogene into tumor cell and induce apoptosis of tumor cell.Now apoptosis genes are selected as targeted gene and express in tumor to active the apoptosis cell signal to kill the tumor cells.Tumor necrosis factor-related apoptosis inducing ligand(TRAIL) is a new number of TNF family(named Apo-2L),and many researchers found the TRAIL gene could induce apoptosis of many types of tumor cells,while almost no effect of normal cells.
According to overview above,we used two types of adenovirus vector,one of which contain CMV driver and TRAIL target gene in adenovirus vector and another one contain hTERT driver and TRAIL target gene,according to the feature of hTERT activity and TRAIL gene. In vitro,after transferred the AdCMV-TRAIL and AdTERT-TRAIL into adenoid cystic carcinoma cells,the proliferation and apoptosis of cells were detected by histological,molecular,MTT,FCM techniques in adenoid cystic carcinoma cells and/or HEL.In vivo,after AdTERT-TRAIL was injected into tumors of adenoid cystic carcinoma in nude mice,the tumor volumes,the survive time of nude mouse,the morphology of organs and elements of blood in nude mouse were detected,in order to illuminate the function and safety of AdTERT-TRAIL.Result showing:1.AdCMV-TRAIL could inhibit the proliferation and promote apoptosis of SACC-83 cells and ACC-2 cells of adenoid cystic carcinoma.There was no difference of proliferation and apoptosis between two cell lines;2.AdTERT-TRAIL could inhibit proliferation and enhance apoptosis of SACC-83,while not obviously effect in somatic cells of HEL;3.AdTERT-TRAIL inhibit the tumor growth of adenoid cystic carcinoma and prolong the survive time of nude mice,and there were not obviously change of morphology of organs and elements of blood in nude mice;4.The mechanism of AdTERT-TRAIL to inhibit proliferation and promote apoptosis of adenoid cystic carcinoma cells is because the transfer of TRAIL activated Caspase-3 gene and then induced a series of apoptosis of cell signal.
The innovation of this study was that dual-targeted AdTERT-TRAIL has targeted-effect to the cells of adenoid cystic carcinoma, AdTERT-TRAIL is not harmfulness to the organs,the function of liver and the elements blood system of nude mice,and AdTERT-TRAIL induces apoptosis signals by actived Caspase-3 gene after transferred into adenoid cystic carcinoma.Our research achievements provided a foundation for us to investigate the tumor-specific transgene expression ability of hTERT promoter in salivary gland tumors,as well as theory basis and practice experience for us to conduct gene therapy clinically with high efficiency,targeting effect and no trauma,which will develop a new way to treat salivary gland tumors.
针对肿瘤转基因治疗特异性差的问题,根据hTERT和TRAIL均具有肿瘤特异性的特性,在国家自然基金面上项目和国家自然基金国际合作项目资金支持下,以同源重组法构建了AdCMV-TRAIL和AdTERT-TRAIL腺病毒载体,通过体外、体内转染涎腺腺样囊性癌细胞或正常细胞,探讨它们对涎腺腺样囊性癌的作用,结果显示通过双特异性AdTERT-TRAIL实现了TRAIL基因在SACC-83细胞中表达,进而对涎腺腺样囊性癌细胞具有肿瘤特异性杀伤作用:其对菏瘤裸鼠器官、肝脏功能和全血成分没有明显影响,这种特异性杀伤作用是由TRAIL基因激活了Caspase-3基因,从而启动了下游的凋亡途径。这就为AdTERT-TRAIL转基因治疗涎腺腺样囊性癌奠定了理论基础和实验技术基础。
Adenoid cystic carcinoma is one of the most common malignant tumor in maxillofacial region,which has the ability to infiltrate nerve,vessel,fiber,and not sensitiveness to chemotherapy,radiotherapy. It is hot topic to study the development and treatment of adenoid cystic carcinoma.With the development of biomedicine,molecular biology and completion of human genome,gene therapy become a new strategy to treat adenoid cystic carcinoma,which is to transfer the external gene to cells,correct the heredity and get impairment of gene.After 20-year research and studying,there was great progression to treat the heredity disease,metabolism disease and malignant tumor using gene therapy,and some treatment were used in clinical case.
Vector,promoter,target gene are the basic elements of gene therapy. The target expression of gene plays key role in gene therapy,which the target gene should be expressed in tumor cells,not common ones.Only in this way,the gene could become targeted expression.
The common method of targeted gene expression is to control gene expression via tumor-specific promoters in specific tissues,cells or organs.Several promoters have been identified that are more active in particular tumor types than in the tissues from which they arise,and these promoters have been exploited to target gene expression in tumors,which include the AFP promoter,CEA promoter and Tyr enzyme promoter.But these promoters are limited to specific tumor histology and cannot be used universally in tumors of various origins and most of these promoters are much weaker than that commonly used viral promoters such as the CMV promoter.Consequently,their using is hampered by the problem of low expression.Recent years,telomerase was found to be responsible for cell-immortalization and tumor-genesis.It is a specialized DNA polymerase responsible for the replication of chromosomal ends,or telomeres.Telomerase is high active in immortalized cell lines and 85% human cancers,but is inactive in most somatic cells,therefore telomerase is to be very promising not only as a tumor-specific marker but also as a target for anticancer therapy.In summary,basing this characteristic of telomerase,if using the driver of telomerase to induce the target gene,the target gene should be express in tumor cells,not the somatic cells and targeted anticancer therapy will come true.
The vector is another important part of gene therapy.With the development of gene therapy,adenovirus has become the most common one,which has several features:1.it is easy to prepare,because its structure and function are definitely understanding;2.it can infect both dividing cell and non-dividing cell;3.it can ingress different tissue;4.it can contain 10kb,or even 37 kb gene;5.high titer;6.the structure is stable and it is uneasy to insert the genome of host.So we use the adenovirus vector to transfer the target gene.
For the purpose gene of gene therapy,at the beginning,researcher liked to select oncogene or anti-oncogene as target gene,using anti-sencetherapy or transfer anti-oncogene into tumor cell and induce apoptosis of tumor cell.Now apoptosis genes are selected as targeted gene and express in tumor to active the apoptosis cell signal to kill the tumor cells.Tumor necrosis factor-related apoptosis inducing ligand(TRAIL) is a new number of TNF family(named Apo-2L),and many researchers found the TRAIL gene could induce apoptosis of many types of tumor cells,while almost no effect of normal cells.
According to overview above,we used two types of adenovirus vector,one of which contain CMV driver and TRAIL target gene in adenovirus vector and another one contain hTERT driver and TRAIL target gene,according to the feature of hTERT activity and TRAIL gene. In vitro,after transferred the AdCMV-TRAIL and AdTERT-TRAIL into adenoid cystic carcinoma cells,the proliferation and apoptosis of cells were detected by histological,molecular,MTT,FCM techniques in adenoid cystic carcinoma cells and/or HEL.In vivo,after AdTERT-TRAIL was injected into tumors of adenoid cystic carcinoma in nude mice,the tumor volumes,the survive time of nude mouse,the morphology of organs and elements of blood in nude mouse were detected,in order to illuminate the function and safety of AdTERT-TRAIL.Result showing:1.AdCMV-TRAIL could inhibit the proliferation and promote apoptosis of SACC-83 cells and ACC-2 cells of adenoid cystic carcinoma.There was no difference of proliferation and apoptosis between two cell lines;2.AdTERT-TRAIL could inhibit proliferation and enhance apoptosis of SACC-83,while not obviously effect in somatic cells of HEL;3.AdTERT-TRAIL inhibit the tumor growth of adenoid cystic carcinoma and prolong the survive time of nude mice,and there were not obviously change of morphology of organs and elements of blood in nude mice;4.The mechanism of AdTERT-TRAIL to inhibit proliferation and promote apoptosis of adenoid cystic carcinoma cells is because the transfer of TRAIL activated Caspase-3 gene and then induced a series of apoptosis of cell signal.
The innovation of this study was that dual-targeted AdTERT-TRAIL has targeted-effect to the cells of adenoid cystic carcinoma, AdTERT-TRAIL is not harmfulness to the organs,the function of liver and the elements blood system of nude mice,and AdTERT-TRAIL induces apoptosis signals by actived Caspase-3 gene after transferred into adenoid cystic carcinoma.Our research achievements provided a foundation for us to investigate the tumor-specific transgene expression ability of hTERT promoter in salivary gland tumors,as well as theory basis and practice experience for us to conduct gene therapy clinically with high efficiency,targeting effect and no trauma,which will develop a new way to treat salivary gland tumors.
引文
[1] McNeish IA, Bell SJ, Lemoine NR. Gene therapy progress and prospects:cancer gene therapy using tumour suppressor genes[J]. Gene Therapy,2004,11(6):497-503.
[2] Lieberman HB.DNA damage repair and response proteins as targets for cancer therapy[J].Curr Med Chem,2008,15(4):360-367.
[3] Peng Z. Current status of gendicine in China:recombinant human Ad-p53 agent for treatment of cancers[J]. Hum Gene Ther, 2005,16(9): 1016-1027.
[4] Roth JA. Adenovirus p53 gene therapy[J]. Expert Opin Biol Ther ,2006,6(1):55-61.
[5] Decaprio JA .How the Rb tumor suppressor structure and function was revealed by the study of Adenovirus and SV40[J]. Virology, 2009,384(2):274-284.
[6] Eager R, Harle L, Nemunaitis J.Ad-MDA-7; INGN 241: a review of preclinical and clinical experience[J].Expert Opin Biol Ther,2008,8(10):1633-1643.
[7] Atencio IA, Grace M, Bordens R, et al.Biological activities of a recombinant adenovirus p53 (SCH 58500) administered by hepatic arterial infusion in a Phase 1 colorectal cancer trial[J].Cancer Gene ,2005,13(2): 169-181.
[8] Boden D, Pusch O, Silbermann R.Enhanced gene silencing of HIV-1 specific siRNA using microRNA designed hairpins[J].Nucleic Acids Res.2004.32(3): 1154-1158.
[9] Lo HL, Chang T, Yam P, et al. Inhibition of HIV-1 replication with designed miRNAs expressed from RNA polymerase II promoters[J]. Gene Ther,2007,14(4):1503-1512.
[10] Lin T, Gu J, Zhang L, et al. Targeted expression of green fluorescent protein/tumor necrosis factor-related apoptosisinducing ligand fusion protein from human telomerase reverse transcriptase promoter elicits antitumor activity without toxic effects on primary human hepatocytes[J].Cancer Res,2002,62(6):3620-3625.
[11] Armeanu S, Lauer UM, Smirnow I, et al.Adenoviral gene transfer of tumor necrosis factor-related apoptosis-inducing ligand overcomes an impaired response of hepatoma cells but causes severe apoptosis in primary human hepatocytes[J].Cancer Res, 2003,63(3):2369-2372.
[12] Chan L, HardwickNR, Guinn BA, et al. An immune edited tumour versus a tumour edited immune system: prospects for immune therapy of acute myeloid leukaemia[J].Cancer Immunol,2006,55(4): 1017-1024.
[13] Pflanz S, Timans JC, Cheung J,et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4(+) T cells[J].Immunity, 2002,16(5):779-790.
[14] Kostarelos K, Miller AD. What role can chemistry play in cationic liposome-based gene therapy research today? [J].Adv Genet,2005,53PA: 69-118.
[15] Kostarelos K, Miller AD. Synthetic, self-assembly ABCD nanoparticles; a structural paradigm for viable synthetic non-viral vectors[J]. Chem Soc Rev,2005,34: 970-994.
[16] Matsuoka H, Komazakt T,Muka IY, et al. High through put easymicroinjection with a single-cell manipulation supporting robot[J]. J Biotechnol,2005,116(2):185-194.
[17] Derouazim M, Flaction R, Girara P, et al. Generation of recombinant Chinese hamster ovary cell lines by microinjection[J]. B iotechnol Lett,2006,28(6):373-382.
[18] Gothelf A,Mirlm IR ,Gehl J. Electrochemotherapy: results of cancer treatment using enhanced delivery of bleomycin by elec2 troporation[J]. Cancer Treat Rev,2003,29(5):371-387.
[19] Ionescuzanetti C, Blatz A, Khine M, et al.Electro phoresisassisted single-cell electroporation for efficient intracellular delivery[J]. Biomed Microdevices,2008,10(1):113-116.
[20] Kusumanto YH, Mulder NH, Dam WA, et al. Improvement of in vivo transfer of plasmid DNA in muscle: comparison of electroporation versus ultrasound [J].D rug Deliv,2007,14(5):273-277.
[21] Rizzuto G, Cappelletti M, Maione D, et al. Efficient and regulated erythropoietin production by naked DNA injection and muscle electroporation[J]. Proc Natl Acad Sci USA, 1999, 96(11): 6417-6422.
[22] Mahato RI, Smith LC, and Rolland A. Pharmaceutical perspectives of nonviral gene therapy[J]. Adv Genet, 1999,41(3):95-106.
[23] Dokka S , Toledo D , Shi X , et al . Oxygen radical2mediated pulmonary toxicity induced by some cationic liposomes[J].Pharmaceuti cal Research ,2000,17(5): 521-527.
[24] Zhang J S , Liu F , Huang L. Implications of pharmacokinetic behavior of lipoplex for its inflammatory toxicity[J]. Advanced Drug Delivery Reviews ,2005,57(3):689-696.
[25] Ma Z , Li J , He F , et al.Cationic lipids enhance siRNA mediated interferon response in mice[J]. Biochem Biophys Res Commun ,2005,330 (3) : 755-765.
[26] Loisel S , Le Gall C , Doucet L , et al. Contribution of plasmid DNA to hepatotoxicity after systemic administration of lipoplexes[J].Human Gene Therapy, 2001,12(6): 685-696.
[27] Belting M , Petersson P. Protective role for proteoglycans against cationic lipid cytotoxicity allowing optimal transfection efficiency in vitro[J]. Biochem J,1999,342(Pt 2) : 281-298.
[28] Maitra A. Calcium phosphate nanoparticles: second-generation nonviral vectors in gene therapy [J]. Expert Rev Mol Diagn, 2005, 5 (6):893-905.
[29] Bisht S, Bhakta G, Maitra S, et al. pDNA loaded calcium phosphate nanoparticles: highly efficient non2viral vector for gene delivery[J].Int J Pharm, 2005,288(1): 157-168.
[30] Bergelson JM, Cunningham JA, Droguett G, et al. Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5[J].Science ,1997,275(1):1320-1323.
[31] Dechecchi MC, Melotti P, Bonizzato A, et al. Heparan sulfate glvcosaminoglycans are receptors sufficient to mediate the initial binding of adenovirus types 2 and 5[J]. J Virol,2001,75(2):8772-8780.
[32] Dechecchi MC, Tamanini A, Bonizzato A,et al. Heparan sulfate glycosaminoglycans are involved in adenovirus type 5 and 2-host cell interactions[J].Virology,2000,268(3):382-390.
[33] Chu Y, Heistad D, Cybulsky MI,et al. Vascular cell adhesion molecule-1 augments adenovirus-mediated gene transfer[J]. Arterioscler Thromb Vasc Biol,2001,21(3):238-242.
[34] Nakano MY, Greber UF. Quantitative microscopy of fluorescent adenovirus entry[J]. J Struct Biol,2000,129(1):57-68.
[35] Danthinne X, Imperiale MJ.Production of first generation adenovirus vectors: a review[J].Gene Ther,2000,7(20):1707-1714.
[36] Davison E, Diaz RM, Hart IR,et al. Integrin alpha-beta1-mediated adenovirus infection is enhanced by the integrin-activating antibody TS2/16[J].J Virol 1997,71(5):6204-6207.
[37] Li E, Brown SL, Stupack DG,et al. Integrin alpha(v)betal is an adenovirus coreceptor[J].J Virol,2001,75(6):5405-5409.
[38] Davison E, Kirby I, Whitehouse J,et al.Adenovirus type 5 uptake by lung adenocarcinoma cells in culture correlates with Ad5 fibre binding is mediated by alpha(v)betal integrin and can be modulated by changes in betal integrin function[J].J Gene Med,2001,3(6):550-559.
[39] Benihoud K, Yeh P, Perricaudet M. Adenovirus vectors for gene delivery[J].Curr Opin Biotechnol,1999,10(2):440-447.
[40] Tao N, Gao GP, Parr M,et al. Sequestration of adenoviral vector by Kupffer cells leads to a nonlinear dose response of transduction in liver[J]. Mol Ther,2001,3(4):28-35.
[41] Connelly S. Adenoviral vectors for liver-directed gene therapy[J]. Curr Opin Mol Ther,1999,1(7):565-572.
[42] Lieber A, He CY, Meuse L, et al. The role of Kupffer cell activation and viral gene expression in early liver toxicity after infusion of recombinant adenovirus vectors[J]. J Virol, 1997,71 (8):8798-8807.
[43] Alemany R, Suzuki K, Curiel DT. Blood clearance rates of adenovirus type 5 in mice[J]. J Gen Virol,2000,81 (Part 11):2605-2609.
[44] Smith TA, Idamakanti N, Marshall-Neff J, et al. Receptor interactions involved in adenoviral-mediated gene delivery after systemic administration in non-human primates[J].Hum Gene Ther,2003,14(6): 1595-1604.
[45] Smith T, Idamakanti N, Kylefjord H, et al. In vivo hepatic adenoviral gene delivery occurs independently of the coxsackievirus- adenovirus receptor[J].Mol Ther,2002,5(6):770-779.
[46] Shi J, Zheng D, Liu Y, et al. Overexpression of soluble TRAIL induces apoptosis in human lung adenocarcinoma and inhibits growth of tumor xenografts in nude mice[J].Cancer Res,2005,65(5): 1687-1692.
[47] Ma H, Liu Y, Liu S, et al.Recombinant adeno-associated virus-mediated TRAIL gene therapy suppresses liver metastatic tumors[J].Int J Cancer ,2005,116(2):314-321.
[48] Smith RH, Spano AJ,Kotin RM. The Rep78 gene product of adeno-associated virus (AAV) self-associates to form a hexameric complex in the presence of AAV ori sequences[J]. J Virol, 1997, 71(6): 4461-4471.
[49] Smith RH and Kotin RM. The Rep52 gene product of adeno-associated virus is a DNA helicase with 3'-to-5' polarity[J]. J Virol, 1998,72(6): 4874-4881.
[50] Miao CH, Snyder RO, Schowalter DB, et al The kinetics of rAAV integration in the liver[J]. Nat Genet,1998,19(1):13-15.
[51] Bueler H. Adeno-associated viral vectors for gene transfer and gene therapy[J]. Biol Chem, 1999,380(6):613-622.
[52] Chirmule N, Xiao W, Truneh A,et al. Humoral immunity to adeno-associated virus type 2 vectors following administration to murine and nonhuman primate muscle[J].J Virol, 2000,74(5): 2420-2425.
[53] Yan Z, Zhang Y, Duan D, et al. From the cover: trans-splicing vectors expand the utility of adeno- associated virus for gene therapy[J]. Proc Natl Acad Sci USA, 2000,97( 12):6716-6721.
[54] Nakai H, Storm TA, and Kay MA. Increasing the size of rAAV-mediated expression cassettes in vivo by intermolecular joining of two complementary vectors[J].Nat Biotechnol,2000,18(5):527-532.
[55] Kay MA, Glorioso JC, and Naldini L. Viral vectors for gene therapy: the art of turning infectious agents into vehicles of therapeutics[J]. Nat Med, 2001,7(1):33-40.
[56] Andreadis ST, Roth CM, Le Doux JM, et al. Large-scale processing of recombinant retroviruses for gene therapy[J]. Biotechnol Prog, 1999, 15(1): 1-11.
[57] Palu G, Parolin C, Takeuchi Y, et al. Progress with retroviral gene vectors[J].Rev Med Virol,2000,10(3): 185-202.
[58] Rizvi TA, Ali J, Phillip PS ,et al.Role of a heterologous retroviral transport element in the development of genetic complementation assay for mouse mammary tumor virus (MMTV) replication[J].Virology, 2009,385(2):464-472.
[59] Rainov NG, Ren H. Clinical trials with retrovirus mediated gene therapy—what have we learned? [J]. J Neuro-Oncol,2003,65(3):227- 236.
[60] Thomas SM, Naresh KN, Wagle AS,et al. Preclinical studies on suicide gene therapy for head/neck cancer: a novel method for evaluation of treatment efficacy[J]. Anticancer Res,1998,18(6A):4393-4398.
[61] Sandalon Z, Gnatenko DV, Bahou WF, et al. Adeno-associated virus (AAV) Rep protein enhances the generation of a recombinant mini-adenovirus (Ad) utilizing an Ad/AAV hybrid virus[J].J Virol,2000,74(22): 10381-10389.
[62]Lieber A,Steinwaerder DS,Carlson CA,et al.Integrating adenovirus-adeno -associated virus hybrid vectors devoid of all viral genes[J].J Virol,1999.73(11):9314-9324.
[63]Dariel A,Nguyen TH,Pichard V,et al.A new surgical approach to improve gene transfer in liver using lentiviral vectors[J].J Pediatr Surg,2009,44(3):517-22.
[64]Wu N,Ataai MM.Production of viral vectors for gene therapy applications[J].Curr Opin Biotechnol,2000,11(2):205-208.
[65]Strayer DS,Zern MA.Gene delivery to the liver using simian virus 40-derived vectors[J].Semin Liver Dis,1999,19(1):71-81.
[66]苏涛。hTERT启动子诱导TRAIL基因靶向表达治疗涎腺肿瘤的实验研究[D]:吉林大学口腔医学院,2005。
[67]Takakura M,Kyo S,Kanaya T,et al.Cloning of human telomerase catalytic subunit(hTERT) gene promoter and identification of proximal core promoter sequences essential for transcriptional activation in immortalized and cancer cells[J].Cancer Res,1999,59(3):551-557.
[68]Wu KJ,Grandori C,Amacker m,et al.Direct activation of TERT transcription by c-MYC[J].Nat Genet,1999,21(2):220-224.
[69]Xu D,Popov N,Hou M,et al.Switch from Myc/Max to Mad1/Max binding and decrease in histone acetylation at the telomerase reverse transcriptase promoter during differentiation of HL60 cells[J].Proc Natl Acad Sci USA,2001,98(7):5123-5133.
[70]Kyo S,Takakura M,Taira T,et al.Sp1 cooperates with c-Myc to activate transcription of the human telomerase reverse transcriptase gene(hTERT)[J].Nucleic Aeids Res,2000,28(3):669-677.
[71]Fujimoto K,kyo S,Takakura M,et at.Identification and characterization of negative regulatory elements of the human telomerase catalytic subunit(hTERT)gene promoter:possible role of MZF-2 in transcriptional repression of hTERT[J].Nucleic Acids res,2000,28(13):2557-2564.
[72]Marks PA,Richon VM,Rifkind RA.Histone deacetylase inhibitors:inducers of differentiation or apoptosis of transformed cells[J].J Natl Cancer Inst,2000,92(15):1210-1216.
[73]Hou M,Wang X,Popov N,et al.The histone deacetylase inhibitor trichostatin A derepresses the telomerase reverse transcriptase(hTERT) gene in human cells[J].Exp Cell Res,2002,274(l):25-34.
[74]Cong YS,Bacchetti S.Histone deacetylation is involved in the transcriptional repression of hTERT in normal human cells[J].J boil Chem,2000,275(46):35665-35668.
[75]Takekura M,Kyo S,Sowa Y,et al.Telomerase activation by histone deacetylase inhibitor in normal cells[J].Nucleic Acids Res,2001,29(14):3006-3011.
[76]Suenaga M,Soda H,Oka M,et al.Histone deacetytase inhibitors suppress telomerase reverse transcriptase mRNA expression in prostate cancer cells[J].Int J Cancer,2002,97(5):621-625.
[77]Possemato R,Timmons JC,Bauerlein EL,et al.Suppression of hPOT1 in diploid human cells results in an hTERT-dependent alteration of telomere length dynamics[J].Mol Cancer Res,2008,6(10):1582-1593.
[78]柯小亮,孙宏晨,臧光祥。腺病毒介导EGFP共转染p16基因对腺样囊性癌细胞的影响。北京口腔医学,2009,17(1):20-23。
[79]Akalin A,Elmore LW,Forsythe HL,et al.A novel mechanism for chaperone-mediated telomerase regulation during prostate cancer progression[J].Cancer Res,2001,61(12):4791-4796.
[80]Liu K,Hodes RJ,Weng NP.Cutting edge:telomerase activation in human T lymphocytes does not require increase in telomerase reverse transcriptase (hTERT) protein but is associated with hTERT phosphorylation and nuclear translocation[J].J immunol,2001,166(8):4826-4830.
[81]Komata T,Kondo Y,Koga S,et al.Combination therapy of malignant glioma cells with 2-5A-antisense telomerase RNA and recombinant adenovirus p53[J]. Gene Ther,2000 ,7(24):2071-2079.
[82] Mukai S, Kondo Y, Koga S,et al. 2-5A antisense telomerase RNA therapy for intracranial malignant gliomas[J]. Cancer Res ,2000 ,60(16):4461 -4467.
[83] Wang X, Zhang Z, Xu Y, et al. Inhibition of telomerase activity and induction of apoptosis in lung cancer cell by vhuman telomerase reverse transcriptase gene antisense oligodeoxynucleotide[J]. Zhonghua Nei Ke Za Zhi ,2002,41(3):175-178.
[84] Koga S, Hirohata S, Kondo Y,et al. FADD gene therapy using the human telomerase catalytic subunit (hTERT) gene promoter to restrict induction of apoptosis to tumors in vitro and in vivo[J]. Anticancer Res,2001 ,2i(3):1937-1943.
[85] Gu J,Kagawa S,Takakura M,et al. Tumor-specific transgene expression from the human telomerase reverse transcriptase promoter enables targeting of the therapeutic effects of the Bax gene to cancers[J]. cancer Res,2000,60(19):5359-5364.
[86] Gu J, Andreeff M, Roth JA, et al. hTERT promoter induces tumor-specific Bax gene expression and cell killing in syngenic mouse tumor model and prevents systemic toxicity[J]. Gene Ther,2002,9(1):30-37.
[87] Tadashi K,Yasuko k,Takao K,et al. Treatment of malignant glioma cells with the transfer of constitutively active caspase-6 using the human telomerase catalytic subunit (human telomerase reverse transcriptase) gene promoter[J] .Cancer Res,2001,61 (8):5796-5802.
[88] Koga S, Hirohata S, Kondo Y,et al. A novel telomerase-specific gene therapy:gene transfer of caspase-8 utilizing the human telomerase catalytic subunit gene promoter[J]. Hum Gene Ther 2000,11(10): 1397-1406.
[89] Komata T, Koga S, Hirohata S,et al. A novel treatment of human malignant gliomas in vitro and in vivo: FADD gene transfer under the control of the human telomerase reverse transcriptase gene promoter[J]. Int J Oncol,2001, 19(5):1015-1020.
[90]Pirocanac E,Nassirpour R,Yang M,et al.Baxoinduction gene therapy of pancreatic cancer[J].J Surg Res,2002,106(2):346-351,
[91]Majumdar AS,Hughes DE,Lichtsteiner SP,et al.The telomerase reverse transcriptase promoter drives efficacious tumor suicide gene therapy while preventing hepatotoxicity encountered with constitutive promoters[J].Gene Ther,2001,8(7):568-578.
[92]Hersey P,Zhang XD.How melanoma cells evade trail-induced apoptosis[J].Nat Rev Cancer,1(2):142-150.
[93]臧光祥,穆亚冰,孙宏晨等。腺病毒介导TRAIL基因对舌鳞状细胞癌细胞影响[J]。华西口腔医学杂志,2007,25(6):584-587。
[94]Morales JC,Ruiz-Magana MJ,Ruiz2Ruiz C.Regulation of the resistance to TRA IL induced apop tosis in human primary T lymphocytes:Role of NF2kappaB inhibition[J].Mol Immunol,2007,44(10):2587-2597.
[95]Ray P,Bauer E,Lyer M,et al.Monitoring gene therapy with reporter gene imaging[J].Simin Nucl Med,2001,31(4):312-320.
[96]Heim R,Tsien RY.Engineering green fluorescent protein for improved brightness,longer wavelengths and fluorescence resonance energy transfer [J].Curr Biol,1996,6(2):178-182.
[97]Comack BP,Valdivia RH,Falkow S.FASC-optimized mutants of the green fluorescent protein(GFP).Gene,1996,173(1):33-38.
[98]Zhang G,Gurtu V,Kain SR.An enhanced green fluorescent protein allows sensitive detection of gene transfer in mammalian cells[J].Biochem Biophys Res Commun,1996,227(3):707-711.
[99]臧光祥,孙宏晨,穆亚冰等。hTERT启动TRAIL基因腺病毒载体对人舌癌细胞影响[J]。口腔医学研究,2007,23(5):481-483。
[100]Pitti RM,Marsters SA,Ruppert S,et al.Induction of apoptosis by Apo-2 ligand,a new member of the tumor necrosis factor cytokine family[J].J Biol Chem, 1996,271 (22): 12687-12690.
[101] Wiley SR, Schooley K, Smolak PJ, et al.Identification and characterization of a new member of the TNF family that induces apoptosis[J] .Immunity,3995,3(6):673-682.
[102] Hymowitz SG, Christinger HW, Fuh G,et al. Triggering cell death: the crystal structure ofApo2L/T RAIL in a complex with death receptor 5[J]. Mol Cell, 1999,4(4):563-571.
[103] Kim M, Park SY, Pai HS,et al.Hypoxia inhibits tumor necrosis factor-related apoptosis-inducing -induced apoptosis by blocking Bax translocation[J].Cancer Res,2004,64(12):4078-4081.
[104] El-Deiry WS. Molecular cloning and functional analysis of the mouse homologue of the KILLER/DR5 tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor[J]. Cancer Res,1999,59(12):2770-2775.
[105] Zauli G, Sancilio S, Cataldi A, et al. PI23K/Akt and NF-kappa B /I kappa Bα pathways are activated in Jurkat T cells in response to TRA IL treatment [J]. J Cell Physiol,2005,202 (3):900-911.
[106] Reichle A, Vogt T.Systems biology: a therapeutic target for tumor therapy[J].Cancer Microenviron,2008,1 (1): 159-170.
[107] Vile RG, Hart IR. In vitro and in vivo targeting of gene expression to melanoma cells[J]. Cancer Res,1993,53(5):962-967.
[108] Osaki T, Tanio Y, Tachibana I,et al.Gene therapy for carcinoembryonic antigen-producing human lung cancer cells by cell type-specific expression of herpes simplex virus thymidine kinase gene[J]. Cancer Res,1994,54(20):5258-5261.
[109] Chen L, Chen D, Manome Y,et al. Breast cancer selective gene expression and therapy mediated by recombinant adenoviruses containing the DF3/MUC1 promoter[J].J Clin Invest, 1995,96(6): 2775-2782.
[110]Parr MJ,Manome Y,Tanaka T,et al.A.Tumor-selective transgene expression in vivo mediated by an E2F-responsive adenoviral vector[J].Nat Med,1997,3(10):1145-1149.
[111]胡晓文,孙宏晨,欧阳喈。涎腺肿瘤中端粒长度及端粒酶活性测定的意义[J]。现代口腔医学杂志,2002,16(2):104-106。
[112]Takeuchi H,Kanzawa T,Kondo Y,et al.Combination of caspase transfer using the human telomerase reverse transcriptase promoter and conventional therapies for malignant glioma cells[J].Int J Oncol,2004,25(1):57-63.
[113]Takeda T,Inaba H,Yamazaki M,et al.Tumor-specific gene therapy for undifferentiated thyroid carcinoma utilizing the telomerase reverse transcriptase promoter[J].J Clin Endcrinol Metab,2003,88(8):3531-3538.
[114]Lin T,Huang X,Gu J,et al.Long-term tumor-free survival from treatment with the GFP-TRAIL fusion gene expressed from the hTERT promoter in breast cancer cells[J].Oncogene,2002,21(6):8020-8028.
[115]Nakamura M,Kyo S,Kanaya T,et al.hTERT-promoter-based tumor specific expression of MCP-1 effectively sensitize cervical cancer cells to a low dose of cisplatin[J].Cancer Gene Ther,2004,11(1):1-7.
[116]杨义军,郑晓飞,朱捷,等。hTERT启动子调控osm基因表达在体外的抑癌作用[J]。癌症,2003,22(6):575-578。
[117]Rygaard J.Immunobiology of the mouse mutant "Nude".Preliminary investigations[J].Acta Pathol Microbiol Scand,1969,77(4):761-762.
[118]Danial NN,Korsmeyer SJ.Cell death:critical control points[J].Cell,2004,116(2):205-219.
[119]Shen WH,Zhou JH,Broussard SR,et al.Apoptosis:a link between cancer genetics and chemotherapy[J].Cell,2002,108(2):153-164.
[120]Ashkenazi A.Targeting death and decoy receptors of the tumour-necrosis factor superfamily[J].Nature Rev Cancer,2002,2(6):420-430.
[121]Smyth MJ,Takeda K,Hayakawa Y,et al.Nature's TRAIL—on a path to cancer immunotherapy[J].Immunity,2003,18( 1): 1 -6.
[122] Yagita H,Takeda K, Hayakawa Y,et al.TRAIL and its receptors as targets for cancer therapy[J]. Cancer Sci,2004,95(10):777-783.
[123] Falschlehner C,Emmerich CH, Gerlach B.et al. TRAIL signalling: decisions between life and death[J].Int J Biochem Cell Biol. 200739(7-8): 1462-1475.
[124] Keogh SA,Walczak H,Bouchier-Hayes L,et al.Failure of Bcl-2 to block cytochromec redistribution during TRAIL-induced apoptosis[J]. FEBS Lett,2000,471(1):93-98.
[125] Walczak H,Bouchon A,Stahl H,et al.Tumor necrosis factor-related apoptosis-inducing ligand retains its apoptosis-inducing capacity on Bcl-2- or Bcl-xL-overexpressing chemotherapyresistant tumor cells[J]. Cancer Res,2000,60(11):3051-3057.
[126] Belka C,Schmid B,Marini P, et al. Sensitization of resistant lymphoma cells to irradiation-induced apoptosis by the death ligand TRAIL[J].Oncogene,2001,20(17):2190-2196.
[127] Fulda S,Meyer E,Debatin KM. Inhibition of TRAIL-induced apoptosis by Bcl-2 overexpression[J].Oncogene,2002,21(15):2283-2294.
[128] Ashkenazi A, Pai RC, Fong S,et al.Safety and antitumor activity of recombinant soluble Apo2 ligand[J].J Clin Invest, 1999,104(2): 155-162.
[129] Chuntharapai A,Dodge K,Grimmer K,et al. Isotype-dependent inhibition of tumor growth in vivo by monoclonal antibodies to death receptor 4[J].J Immunol, 2001,166(8):4891-4898.
[130] Jacob D, Davis J, Zhu H,et al.Suppressing orthotopic pancreatic tumor growth with a fiber-modified adenovector expressing the TRAIL gene from the human telomerase reverse transcriptase promoter[J]. Clinical Cancer Research, 2004,10(10):3535-3541.
[131] Nitsch R, Bechmann I, Deisz RA,et al.Human Brain-cell death induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL)[J]. Lancet,2000,356(9232):827-828.
[132] Morel J,Audo R,Hahne M,et al.Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces rheumatoid arthritis synovial fibroblast proliferation through mitogen-activated protein kinases and phosphatidylinositol 3-kinase/Akt[J]. J Bio Chem, 2005,280(16):15709-15718.
[133] Baader E, Toloczko A, Fuchs U,et al. Tumor necrosis factor-related apoptosis-inducing Hgand-mediated proliferation of tumor cells with receptor-proximal apoptosis defects[J].Cancer Res,2005 65(17):7888-7895.
[2] Lieberman HB.DNA damage repair and response proteins as targets for cancer therapy[J].Curr Med Chem,2008,15(4):360-367.
[3] Peng Z. Current status of gendicine in China:recombinant human Ad-p53 agent for treatment of cancers[J]. Hum Gene Ther, 2005,16(9): 1016-1027.
[4] Roth JA. Adenovirus p53 gene therapy[J]. Expert Opin Biol Ther ,2006,6(1):55-61.
[5] Decaprio JA .How the Rb tumor suppressor structure and function was revealed by the study of Adenovirus and SV40[J]. Virology, 2009,384(2):274-284.
[6] Eager R, Harle L, Nemunaitis J.Ad-MDA-7; INGN 241: a review of preclinical and clinical experience[J].Expert Opin Biol Ther,2008,8(10):1633-1643.
[7] Atencio IA, Grace M, Bordens R, et al.Biological activities of a recombinant adenovirus p53 (SCH 58500) administered by hepatic arterial infusion in a Phase 1 colorectal cancer trial[J].Cancer Gene ,2005,13(2): 169-181.
[8] Boden D, Pusch O, Silbermann R.Enhanced gene silencing of HIV-1 specific siRNA using microRNA designed hairpins[J].Nucleic Acids Res.2004.32(3): 1154-1158.
[9] Lo HL, Chang T, Yam P, et al. Inhibition of HIV-1 replication with designed miRNAs expressed from RNA polymerase II promoters[J]. Gene Ther,2007,14(4):1503-1512.
[10] Lin T, Gu J, Zhang L, et al. Targeted expression of green fluorescent protein/tumor necrosis factor-related apoptosisinducing ligand fusion protein from human telomerase reverse transcriptase promoter elicits antitumor activity without toxic effects on primary human hepatocytes[J].Cancer Res,2002,62(6):3620-3625.
[11] Armeanu S, Lauer UM, Smirnow I, et al.Adenoviral gene transfer of tumor necrosis factor-related apoptosis-inducing ligand overcomes an impaired response of hepatoma cells but causes severe apoptosis in primary human hepatocytes[J].Cancer Res, 2003,63(3):2369-2372.
[12] Chan L, HardwickNR, Guinn BA, et al. An immune edited tumour versus a tumour edited immune system: prospects for immune therapy of acute myeloid leukaemia[J].Cancer Immunol,2006,55(4): 1017-1024.
[13] Pflanz S, Timans JC, Cheung J,et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4(+) T cells[J].Immunity, 2002,16(5):779-790.
[14] Kostarelos K, Miller AD. What role can chemistry play in cationic liposome-based gene therapy research today? [J].Adv Genet,2005,53PA: 69-118.
[15] Kostarelos K, Miller AD. Synthetic, self-assembly ABCD nanoparticles; a structural paradigm for viable synthetic non-viral vectors[J]. Chem Soc Rev,2005,34: 970-994.
[16] Matsuoka H, Komazakt T,Muka IY, et al. High through put easymicroinjection with a single-cell manipulation supporting robot[J]. J Biotechnol,2005,116(2):185-194.
[17] Derouazim M, Flaction R, Girara P, et al. Generation of recombinant Chinese hamster ovary cell lines by microinjection[J]. B iotechnol Lett,2006,28(6):373-382.
[18] Gothelf A,Mirlm IR ,Gehl J. Electrochemotherapy: results of cancer treatment using enhanced delivery of bleomycin by elec2 troporation[J]. Cancer Treat Rev,2003,29(5):371-387.
[19] Ionescuzanetti C, Blatz A, Khine M, et al.Electro phoresisassisted single-cell electroporation for efficient intracellular delivery[J]. Biomed Microdevices,2008,10(1):113-116.
[20] Kusumanto YH, Mulder NH, Dam WA, et al. Improvement of in vivo transfer of plasmid DNA in muscle: comparison of electroporation versus ultrasound [J].D rug Deliv,2007,14(5):273-277.
[21] Rizzuto G, Cappelletti M, Maione D, et al. Efficient and regulated erythropoietin production by naked DNA injection and muscle electroporation[J]. Proc Natl Acad Sci USA, 1999, 96(11): 6417-6422.
[22] Mahato RI, Smith LC, and Rolland A. Pharmaceutical perspectives of nonviral gene therapy[J]. Adv Genet, 1999,41(3):95-106.
[23] Dokka S , Toledo D , Shi X , et al . Oxygen radical2mediated pulmonary toxicity induced by some cationic liposomes[J].Pharmaceuti cal Research ,2000,17(5): 521-527.
[24] Zhang J S , Liu F , Huang L. Implications of pharmacokinetic behavior of lipoplex for its inflammatory toxicity[J]. Advanced Drug Delivery Reviews ,2005,57(3):689-696.
[25] Ma Z , Li J , He F , et al.Cationic lipids enhance siRNA mediated interferon response in mice[J]. Biochem Biophys Res Commun ,2005,330 (3) : 755-765.
[26] Loisel S , Le Gall C , Doucet L , et al. Contribution of plasmid DNA to hepatotoxicity after systemic administration of lipoplexes[J].Human Gene Therapy, 2001,12(6): 685-696.
[27] Belting M , Petersson P. Protective role for proteoglycans against cationic lipid cytotoxicity allowing optimal transfection efficiency in vitro[J]. Biochem J,1999,342(Pt 2) : 281-298.
[28] Maitra A. Calcium phosphate nanoparticles: second-generation nonviral vectors in gene therapy [J]. Expert Rev Mol Diagn, 2005, 5 (6):893-905.
[29] Bisht S, Bhakta G, Maitra S, et al. pDNA loaded calcium phosphate nanoparticles: highly efficient non2viral vector for gene delivery[J].Int J Pharm, 2005,288(1): 157-168.
[30] Bergelson JM, Cunningham JA, Droguett G, et al. Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5[J].Science ,1997,275(1):1320-1323.
[31] Dechecchi MC, Melotti P, Bonizzato A, et al. Heparan sulfate glvcosaminoglycans are receptors sufficient to mediate the initial binding of adenovirus types 2 and 5[J]. J Virol,2001,75(2):8772-8780.
[32] Dechecchi MC, Tamanini A, Bonizzato A,et al. Heparan sulfate glycosaminoglycans are involved in adenovirus type 5 and 2-host cell interactions[J].Virology,2000,268(3):382-390.
[33] Chu Y, Heistad D, Cybulsky MI,et al. Vascular cell adhesion molecule-1 augments adenovirus-mediated gene transfer[J]. Arterioscler Thromb Vasc Biol,2001,21(3):238-242.
[34] Nakano MY, Greber UF. Quantitative microscopy of fluorescent adenovirus entry[J]. J Struct Biol,2000,129(1):57-68.
[35] Danthinne X, Imperiale MJ.Production of first generation adenovirus vectors: a review[J].Gene Ther,2000,7(20):1707-1714.
[36] Davison E, Diaz RM, Hart IR,et al. Integrin alpha-beta1-mediated adenovirus infection is enhanced by the integrin-activating antibody TS2/16[J].J Virol 1997,71(5):6204-6207.
[37] Li E, Brown SL, Stupack DG,et al. Integrin alpha(v)betal is an adenovirus coreceptor[J].J Virol,2001,75(6):5405-5409.
[38] Davison E, Kirby I, Whitehouse J,et al.Adenovirus type 5 uptake by lung adenocarcinoma cells in culture correlates with Ad5 fibre binding is mediated by alpha(v)betal integrin and can be modulated by changes in betal integrin function[J].J Gene Med,2001,3(6):550-559.
[39] Benihoud K, Yeh P, Perricaudet M. Adenovirus vectors for gene delivery[J].Curr Opin Biotechnol,1999,10(2):440-447.
[40] Tao N, Gao GP, Parr M,et al. Sequestration of adenoviral vector by Kupffer cells leads to a nonlinear dose response of transduction in liver[J]. Mol Ther,2001,3(4):28-35.
[41] Connelly S. Adenoviral vectors for liver-directed gene therapy[J]. Curr Opin Mol Ther,1999,1(7):565-572.
[42] Lieber A, He CY, Meuse L, et al. The role of Kupffer cell activation and viral gene expression in early liver toxicity after infusion of recombinant adenovirus vectors[J]. J Virol, 1997,71 (8):8798-8807.
[43] Alemany R, Suzuki K, Curiel DT. Blood clearance rates of adenovirus type 5 in mice[J]. J Gen Virol,2000,81 (Part 11):2605-2609.
[44] Smith TA, Idamakanti N, Marshall-Neff J, et al. Receptor interactions involved in adenoviral-mediated gene delivery after systemic administration in non-human primates[J].Hum Gene Ther,2003,14(6): 1595-1604.
[45] Smith T, Idamakanti N, Kylefjord H, et al. In vivo hepatic adenoviral gene delivery occurs independently of the coxsackievirus- adenovirus receptor[J].Mol Ther,2002,5(6):770-779.
[46] Shi J, Zheng D, Liu Y, et al. Overexpression of soluble TRAIL induces apoptosis in human lung adenocarcinoma and inhibits growth of tumor xenografts in nude mice[J].Cancer Res,2005,65(5): 1687-1692.
[47] Ma H, Liu Y, Liu S, et al.Recombinant adeno-associated virus-mediated TRAIL gene therapy suppresses liver metastatic tumors[J].Int J Cancer ,2005,116(2):314-321.
[48] Smith RH, Spano AJ,Kotin RM. The Rep78 gene product of adeno-associated virus (AAV) self-associates to form a hexameric complex in the presence of AAV ori sequences[J]. J Virol, 1997, 71(6): 4461-4471.
[49] Smith RH and Kotin RM. The Rep52 gene product of adeno-associated virus is a DNA helicase with 3'-to-5' polarity[J]. J Virol, 1998,72(6): 4874-4881.
[50] Miao CH, Snyder RO, Schowalter DB, et al The kinetics of rAAV integration in the liver[J]. Nat Genet,1998,19(1):13-15.
[51] Bueler H. Adeno-associated viral vectors for gene transfer and gene therapy[J]. Biol Chem, 1999,380(6):613-622.
[52] Chirmule N, Xiao W, Truneh A,et al. Humoral immunity to adeno-associated virus type 2 vectors following administration to murine and nonhuman primate muscle[J].J Virol, 2000,74(5): 2420-2425.
[53] Yan Z, Zhang Y, Duan D, et al. From the cover: trans-splicing vectors expand the utility of adeno- associated virus for gene therapy[J]. Proc Natl Acad Sci USA, 2000,97( 12):6716-6721.
[54] Nakai H, Storm TA, and Kay MA. Increasing the size of rAAV-mediated expression cassettes in vivo by intermolecular joining of two complementary vectors[J].Nat Biotechnol,2000,18(5):527-532.
[55] Kay MA, Glorioso JC, and Naldini L. Viral vectors for gene therapy: the art of turning infectious agents into vehicles of therapeutics[J]. Nat Med, 2001,7(1):33-40.
[56] Andreadis ST, Roth CM, Le Doux JM, et al. Large-scale processing of recombinant retroviruses for gene therapy[J]. Biotechnol Prog, 1999, 15(1): 1-11.
[57] Palu G, Parolin C, Takeuchi Y, et al. Progress with retroviral gene vectors[J].Rev Med Virol,2000,10(3): 185-202.
[58] Rizvi TA, Ali J, Phillip PS ,et al.Role of a heterologous retroviral transport element in the development of genetic complementation assay for mouse mammary tumor virus (MMTV) replication[J].Virology, 2009,385(2):464-472.
[59] Rainov NG, Ren H. Clinical trials with retrovirus mediated gene therapy—what have we learned? [J]. J Neuro-Oncol,2003,65(3):227- 236.
[60] Thomas SM, Naresh KN, Wagle AS,et al. Preclinical studies on suicide gene therapy for head/neck cancer: a novel method for evaluation of treatment efficacy[J]. Anticancer Res,1998,18(6A):4393-4398.
[61] Sandalon Z, Gnatenko DV, Bahou WF, et al. Adeno-associated virus (AAV) Rep protein enhances the generation of a recombinant mini-adenovirus (Ad) utilizing an Ad/AAV hybrid virus[J].J Virol,2000,74(22): 10381-10389.
[62]Lieber A,Steinwaerder DS,Carlson CA,et al.Integrating adenovirus-adeno -associated virus hybrid vectors devoid of all viral genes[J].J Virol,1999.73(11):9314-9324.
[63]Dariel A,Nguyen TH,Pichard V,et al.A new surgical approach to improve gene transfer in liver using lentiviral vectors[J].J Pediatr Surg,2009,44(3):517-22.
[64]Wu N,Ataai MM.Production of viral vectors for gene therapy applications[J].Curr Opin Biotechnol,2000,11(2):205-208.
[65]Strayer DS,Zern MA.Gene delivery to the liver using simian virus 40-derived vectors[J].Semin Liver Dis,1999,19(1):71-81.
[66]苏涛。hTERT启动子诱导TRAIL基因靶向表达治疗涎腺肿瘤的实验研究[D]:吉林大学口腔医学院,2005。
[67]Takakura M,Kyo S,Kanaya T,et al.Cloning of human telomerase catalytic subunit(hTERT) gene promoter and identification of proximal core promoter sequences essential for transcriptional activation in immortalized and cancer cells[J].Cancer Res,1999,59(3):551-557.
[68]Wu KJ,Grandori C,Amacker m,et al.Direct activation of TERT transcription by c-MYC[J].Nat Genet,1999,21(2):220-224.
[69]Xu D,Popov N,Hou M,et al.Switch from Myc/Max to Mad1/Max binding and decrease in histone acetylation at the telomerase reverse transcriptase promoter during differentiation of HL60 cells[J].Proc Natl Acad Sci USA,2001,98(7):5123-5133.
[70]Kyo S,Takakura M,Taira T,et al.Sp1 cooperates with c-Myc to activate transcription of the human telomerase reverse transcriptase gene(hTERT)[J].Nucleic Aeids Res,2000,28(3):669-677.
[71]Fujimoto K,kyo S,Takakura M,et at.Identification and characterization of negative regulatory elements of the human telomerase catalytic subunit(hTERT)gene promoter:possible role of MZF-2 in transcriptional repression of hTERT[J].Nucleic Acids res,2000,28(13):2557-2564.
[72]Marks PA,Richon VM,Rifkind RA.Histone deacetylase inhibitors:inducers of differentiation or apoptosis of transformed cells[J].J Natl Cancer Inst,2000,92(15):1210-1216.
[73]Hou M,Wang X,Popov N,et al.The histone deacetylase inhibitor trichostatin A derepresses the telomerase reverse transcriptase(hTERT) gene in human cells[J].Exp Cell Res,2002,274(l):25-34.
[74]Cong YS,Bacchetti S.Histone deacetylation is involved in the transcriptional repression of hTERT in normal human cells[J].J boil Chem,2000,275(46):35665-35668.
[75]Takekura M,Kyo S,Sowa Y,et al.Telomerase activation by histone deacetylase inhibitor in normal cells[J].Nucleic Acids Res,2001,29(14):3006-3011.
[76]Suenaga M,Soda H,Oka M,et al.Histone deacetytase inhibitors suppress telomerase reverse transcriptase mRNA expression in prostate cancer cells[J].Int J Cancer,2002,97(5):621-625.
[77]Possemato R,Timmons JC,Bauerlein EL,et al.Suppression of hPOT1 in diploid human cells results in an hTERT-dependent alteration of telomere length dynamics[J].Mol Cancer Res,2008,6(10):1582-1593.
[78]柯小亮,孙宏晨,臧光祥。腺病毒介导EGFP共转染p16基因对腺样囊性癌细胞的影响。北京口腔医学,2009,17(1):20-23。
[79]Akalin A,Elmore LW,Forsythe HL,et al.A novel mechanism for chaperone-mediated telomerase regulation during prostate cancer progression[J].Cancer Res,2001,61(12):4791-4796.
[80]Liu K,Hodes RJ,Weng NP.Cutting edge:telomerase activation in human T lymphocytes does not require increase in telomerase reverse transcriptase (hTERT) protein but is associated with hTERT phosphorylation and nuclear translocation[J].J immunol,2001,166(8):4826-4830.
[81]Komata T,Kondo Y,Koga S,et al.Combination therapy of malignant glioma cells with 2-5A-antisense telomerase RNA and recombinant adenovirus p53[J]. Gene Ther,2000 ,7(24):2071-2079.
[82] Mukai S, Kondo Y, Koga S,et al. 2-5A antisense telomerase RNA therapy for intracranial malignant gliomas[J]. Cancer Res ,2000 ,60(16):4461 -4467.
[83] Wang X, Zhang Z, Xu Y, et al. Inhibition of telomerase activity and induction of apoptosis in lung cancer cell by vhuman telomerase reverse transcriptase gene antisense oligodeoxynucleotide[J]. Zhonghua Nei Ke Za Zhi ,2002,41(3):175-178.
[84] Koga S, Hirohata S, Kondo Y,et al. FADD gene therapy using the human telomerase catalytic subunit (hTERT) gene promoter to restrict induction of apoptosis to tumors in vitro and in vivo[J]. Anticancer Res,2001 ,2i(3):1937-1943.
[85] Gu J,Kagawa S,Takakura M,et al. Tumor-specific transgene expression from the human telomerase reverse transcriptase promoter enables targeting of the therapeutic effects of the Bax gene to cancers[J]. cancer Res,2000,60(19):5359-5364.
[86] Gu J, Andreeff M, Roth JA, et al. hTERT promoter induces tumor-specific Bax gene expression and cell killing in syngenic mouse tumor model and prevents systemic toxicity[J]. Gene Ther,2002,9(1):30-37.
[87] Tadashi K,Yasuko k,Takao K,et al. Treatment of malignant glioma cells with the transfer of constitutively active caspase-6 using the human telomerase catalytic subunit (human telomerase reverse transcriptase) gene promoter[J] .Cancer Res,2001,61 (8):5796-5802.
[88] Koga S, Hirohata S, Kondo Y,et al. A novel telomerase-specific gene therapy:gene transfer of caspase-8 utilizing the human telomerase catalytic subunit gene promoter[J]. Hum Gene Ther 2000,11(10): 1397-1406.
[89] Komata T, Koga S, Hirohata S,et al. A novel treatment of human malignant gliomas in vitro and in vivo: FADD gene transfer under the control of the human telomerase reverse transcriptase gene promoter[J]. Int J Oncol,2001, 19(5):1015-1020.
[90]Pirocanac E,Nassirpour R,Yang M,et al.Baxoinduction gene therapy of pancreatic cancer[J].J Surg Res,2002,106(2):346-351,
[91]Majumdar AS,Hughes DE,Lichtsteiner SP,et al.The telomerase reverse transcriptase promoter drives efficacious tumor suicide gene therapy while preventing hepatotoxicity encountered with constitutive promoters[J].Gene Ther,2001,8(7):568-578.
[92]Hersey P,Zhang XD.How melanoma cells evade trail-induced apoptosis[J].Nat Rev Cancer,1(2):142-150.
[93]臧光祥,穆亚冰,孙宏晨等。腺病毒介导TRAIL基因对舌鳞状细胞癌细胞影响[J]。华西口腔医学杂志,2007,25(6):584-587。
[94]Morales JC,Ruiz-Magana MJ,Ruiz2Ruiz C.Regulation of the resistance to TRA IL induced apop tosis in human primary T lymphocytes:Role of NF2kappaB inhibition[J].Mol Immunol,2007,44(10):2587-2597.
[95]Ray P,Bauer E,Lyer M,et al.Monitoring gene therapy with reporter gene imaging[J].Simin Nucl Med,2001,31(4):312-320.
[96]Heim R,Tsien RY.Engineering green fluorescent protein for improved brightness,longer wavelengths and fluorescence resonance energy transfer [J].Curr Biol,1996,6(2):178-182.
[97]Comack BP,Valdivia RH,Falkow S.FASC-optimized mutants of the green fluorescent protein(GFP).Gene,1996,173(1):33-38.
[98]Zhang G,Gurtu V,Kain SR.An enhanced green fluorescent protein allows sensitive detection of gene transfer in mammalian cells[J].Biochem Biophys Res Commun,1996,227(3):707-711.
[99]臧光祥,孙宏晨,穆亚冰等。hTERT启动TRAIL基因腺病毒载体对人舌癌细胞影响[J]。口腔医学研究,2007,23(5):481-483。
[100]Pitti RM,Marsters SA,Ruppert S,et al.Induction of apoptosis by Apo-2 ligand,a new member of the tumor necrosis factor cytokine family[J].J Biol Chem, 1996,271 (22): 12687-12690.
[101] Wiley SR, Schooley K, Smolak PJ, et al.Identification and characterization of a new member of the TNF family that induces apoptosis[J] .Immunity,3995,3(6):673-682.
[102] Hymowitz SG, Christinger HW, Fuh G,et al. Triggering cell death: the crystal structure ofApo2L/T RAIL in a complex with death receptor 5[J]. Mol Cell, 1999,4(4):563-571.
[103] Kim M, Park SY, Pai HS,et al.Hypoxia inhibits tumor necrosis factor-related apoptosis-inducing -induced apoptosis by blocking Bax translocation[J].Cancer Res,2004,64(12):4078-4081.
[104] El-Deiry WS. Molecular cloning and functional analysis of the mouse homologue of the KILLER/DR5 tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor[J]. Cancer Res,1999,59(12):2770-2775.
[105] Zauli G, Sancilio S, Cataldi A, et al. PI23K/Akt and NF-kappa B /I kappa Bα pathways are activated in Jurkat T cells in response to TRA IL treatment [J]. J Cell Physiol,2005,202 (3):900-911.
[106] Reichle A, Vogt T.Systems biology: a therapeutic target for tumor therapy[J].Cancer Microenviron,2008,1 (1): 159-170.
[107] Vile RG, Hart IR. In vitro and in vivo targeting of gene expression to melanoma cells[J]. Cancer Res,1993,53(5):962-967.
[108] Osaki T, Tanio Y, Tachibana I,et al.Gene therapy for carcinoembryonic antigen-producing human lung cancer cells by cell type-specific expression of herpes simplex virus thymidine kinase gene[J]. Cancer Res,1994,54(20):5258-5261.
[109] Chen L, Chen D, Manome Y,et al. Breast cancer selective gene expression and therapy mediated by recombinant adenoviruses containing the DF3/MUC1 promoter[J].J Clin Invest, 1995,96(6): 2775-2782.
[110]Parr MJ,Manome Y,Tanaka T,et al.A.Tumor-selective transgene expression in vivo mediated by an E2F-responsive adenoviral vector[J].Nat Med,1997,3(10):1145-1149.
[111]胡晓文,孙宏晨,欧阳喈。涎腺肿瘤中端粒长度及端粒酶活性测定的意义[J]。现代口腔医学杂志,2002,16(2):104-106。
[112]Takeuchi H,Kanzawa T,Kondo Y,et al.Combination of caspase transfer using the human telomerase reverse transcriptase promoter and conventional therapies for malignant glioma cells[J].Int J Oncol,2004,25(1):57-63.
[113]Takeda T,Inaba H,Yamazaki M,et al.Tumor-specific gene therapy for undifferentiated thyroid carcinoma utilizing the telomerase reverse transcriptase promoter[J].J Clin Endcrinol Metab,2003,88(8):3531-3538.
[114]Lin T,Huang X,Gu J,et al.Long-term tumor-free survival from treatment with the GFP-TRAIL fusion gene expressed from the hTERT promoter in breast cancer cells[J].Oncogene,2002,21(6):8020-8028.
[115]Nakamura M,Kyo S,Kanaya T,et al.hTERT-promoter-based tumor specific expression of MCP-1 effectively sensitize cervical cancer cells to a low dose of cisplatin[J].Cancer Gene Ther,2004,11(1):1-7.
[116]杨义军,郑晓飞,朱捷,等。hTERT启动子调控osm基因表达在体外的抑癌作用[J]。癌症,2003,22(6):575-578。
[117]Rygaard J.Immunobiology of the mouse mutant "Nude".Preliminary investigations[J].Acta Pathol Microbiol Scand,1969,77(4):761-762.
[118]Danial NN,Korsmeyer SJ.Cell death:critical control points[J].Cell,2004,116(2):205-219.
[119]Shen WH,Zhou JH,Broussard SR,et al.Apoptosis:a link between cancer genetics and chemotherapy[J].Cell,2002,108(2):153-164.
[120]Ashkenazi A.Targeting death and decoy receptors of the tumour-necrosis factor superfamily[J].Nature Rev Cancer,2002,2(6):420-430.
[121]Smyth MJ,Takeda K,Hayakawa Y,et al.Nature's TRAIL—on a path to cancer immunotherapy[J].Immunity,2003,18( 1): 1 -6.
[122] Yagita H,Takeda K, Hayakawa Y,et al.TRAIL and its receptors as targets for cancer therapy[J]. Cancer Sci,2004,95(10):777-783.
[123] Falschlehner C,Emmerich CH, Gerlach B.et al. TRAIL signalling: decisions between life and death[J].Int J Biochem Cell Biol. 200739(7-8): 1462-1475.
[124] Keogh SA,Walczak H,Bouchier-Hayes L,et al.Failure of Bcl-2 to block cytochromec redistribution during TRAIL-induced apoptosis[J]. FEBS Lett,2000,471(1):93-98.
[125] Walczak H,Bouchon A,Stahl H,et al.Tumor necrosis factor-related apoptosis-inducing ligand retains its apoptosis-inducing capacity on Bcl-2- or Bcl-xL-overexpressing chemotherapyresistant tumor cells[J]. Cancer Res,2000,60(11):3051-3057.
[126] Belka C,Schmid B,Marini P, et al. Sensitization of resistant lymphoma cells to irradiation-induced apoptosis by the death ligand TRAIL[J].Oncogene,2001,20(17):2190-2196.
[127] Fulda S,Meyer E,Debatin KM. Inhibition of TRAIL-induced apoptosis by Bcl-2 overexpression[J].Oncogene,2002,21(15):2283-2294.
[128] Ashkenazi A, Pai RC, Fong S,et al.Safety and antitumor activity of recombinant soluble Apo2 ligand[J].J Clin Invest, 1999,104(2): 155-162.
[129] Chuntharapai A,Dodge K,Grimmer K,et al. Isotype-dependent inhibition of tumor growth in vivo by monoclonal antibodies to death receptor 4[J].J Immunol, 2001,166(8):4891-4898.
[130] Jacob D, Davis J, Zhu H,et al.Suppressing orthotopic pancreatic tumor growth with a fiber-modified adenovector expressing the TRAIL gene from the human telomerase reverse transcriptase promoter[J]. Clinical Cancer Research, 2004,10(10):3535-3541.
[131] Nitsch R, Bechmann I, Deisz RA,et al.Human Brain-cell death induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL)[J]. Lancet,2000,356(9232):827-828.
[132] Morel J,Audo R,Hahne M,et al.Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces rheumatoid arthritis synovial fibroblast proliferation through mitogen-activated protein kinases and phosphatidylinositol 3-kinase/Akt[J]. J Bio Chem, 2005,280(16):15709-15718.
[133] Baader E, Toloczko A, Fuchs U,et al. Tumor necrosis factor-related apoptosis-inducing Hgand-mediated proliferation of tumor cells with receptor-proximal apoptosis defects[J].Cancer Res,2005 65(17):7888-7895.