以腺相关病毒为载体的肿瘤特异启动子驱动的TRAIL靶向杀伤作用研究
摘要
基因治疗,尤其是肿瘤的基因治疗目前是人们关注的热点。重组AAV病毒载体由于其独有的优势而在近些年来被认为是最理想的病毒载体之一,本实验室利用重组AAV病毒进行肝癌及肺癌的基因治疗研究也取得了一些比较理想的结果。在基因治疗中,靶向性是非常重要的问题。在我们既往利用的重组AAV病毒载体中,外源基因的表达是通过CAG启动子来驱动的,CAG启动子是一个组成型启动子,在几乎所有细胞中都能驱动外源基因的表达,缺乏良好的选择性,因此,我们希望对CAG启动子进行改造,来更好的实现以重组AAV病毒为载体的靶向基因治疗,以避免外源基因对正常组织器官的伤害。本研究中,我们构建了两种肿瘤特异启动子,即人端粒酶逆转录酶单位(hTERT)启动子和存活因子(survivin)启动子,比较研究了它们在体内、体外驱动外源基因表达的情况及对细胞生命活动的影响。(一)含有肿瘤特异启动子的重组AAV载体的构建及其活性研究
我们构建了hTERT启动子或survivin启动子与AAV2的重组质粒载体。通过报告基因EGFP的表达比较了两种肿瘤特异启动子在不同肝细胞癌(HCC)细胞株及人原代正常肝细胞(PHH)中的活性,结果表明hTERT启动子与survivin启动子均能驱动EGFP基因在HCC细胞中的表达,hTERT启动子驱动的EGFP表达在SMMC-7721、BEL-7402、HepG2和Hep3B肝癌细胞中的平均荧光强度分别为44.4%、32.7%、35.2%和12.9%,survivin启动子驱动的EGFP表达在四株细胞中的平均荧光强度为25.4%、21.8%、13.5%和11.7%,虽然这两种启动子之间的活性有所差别,但它们在PHH中均没有活性,平均荧光强度在5%以下。此外,两启动子驱动的TRAIL基因还可引起不同程度的HCC细胞存活率降低,而对PHH并无影响。进一步,我们又对hTERT启动子在包括肺癌、结肠癌、乳腺癌、宫颈癌、肝癌、白血病等不同种类的肿瘤细胞株及正常细胞中的活性进行检测。结果表明,hTERT启动子在多种肿瘤细胞中均有活性,而在正常细胞中则没有,说明它具有良好的肿瘤特异选择性。
(二)含有肿瘤特异启动子的重组病毒的制备及其功能研究
我们还通过包装纯化重组AAV病毒颗粒,进一步研究了hTERT启动子驱动的AAV.TRAIL重组病毒单独作用或与化疗药物5-Fu联合作用的情况。经对重组病毒侵染后的肿瘤细胞及正常细胞DNA、mRNA及蛋白分析的结果表明,hTERT启动子可驱动TRAIL基因在肿瘤细胞中特异表达。抗肿瘤活性分析表明,重组病毒侵染72小时后,肝细胞癌SMMC-7721细胞、肺癌A549细胞、宫颈癌Hela细胞和正常人肝细胞PHH的凋亡率分别为:SMMC-7721 57.4%、A549 22.9%、Hela 33.3%、PHH 4.9%。应用裸鼠移植瘤模型进行的体内研究结果表明,hTERT启动子驱动的TRAIL基因表达明显抑制SMMC-7721人肝细胞癌在小鼠体内的生长,5×10~(11))Gps重组病毒可使肿瘤增长抑制率达77%,而且,hTERT启动子驱动的TRAIL基因表达也能明显抑制A549人肺腺癌细胞在小鼠体内的生长。
应用化疗药物5-Fu与重组病毒联合给药结果表明,40mg/kg的5-Fu能增强重组病毒抗肿瘤作用,肿瘤增长的抑制率达到90%。免疫组织化学分析显示,5-Fu能增强肿瘤组织中TRAIL受体DR5的表达。
此外,我们还观察到hTERT启动子驱动的TRAIL表达具有给药途径的选择性,即局部瘤内注射有效而系统给药(尾静脉注射和肌肉注射)则无效。
我们还对hTERT驱动的AAV.TRAIL进行了安全性检测。病理分析及转氨酶测定表明,无论是瘤内注射还是系统给药,重组病毒对动物正常组织器官尤其是肝脏没有影响,说明在hTERT启动子驱动下,重组病毒是安全的。
综上,我们的研究表明肿瘤特异启动子能特异性驱动外源基因在肿瘤细胞中的表达及效应。在肿瘤特异启动子驱动下,重组AAV病毒能使外源基因TRAIL安全有效的发挥作用,这为实现以重组AAV病毒为载体的肿瘤靶向性基因治疗提供了新的思路。
Gene therapy represents an attractive approach to treating cancers.For a good cancer gene therapy delivery system,an ideal vector is absolutely necessary for effective and safe therapeutic.Among quite a few viral vectors which have been tested in recent years,Adeno-associated virus(AAV) is considered to be the most promising vector due to its nonpathogenic property,wide tropisms,non immunogenecity to host and long-term transgene expression.Experimental and clinical trials using recombinant AAV(rAAV) as the delivery vehicles have been proved to be an effective way in gene therapy.However, in gene therapy,especially in treating tumors,the most concerned problem is how to limit the cytotoxic exogenous gene expression in the tumors without harm to normal cells.Since the wide host range infectivity of rAAV may become a disadvantage for its applications in cancer gene therapy,due to its nonselective tissue transduction,safety issue of rAAV as the vector of carrying exogenous genes,which are often toxic to both cancer and normal cells in treating tumors,must be considered.
Using tumor-specific promoters has been proved to be a potential way to control the exogenous genes in limited sites.Human telomerase reverse transcriptase(hTERT) is considered to be the most crucial unit in telomerase activity,which is present in a majority of human cancers.The hTERT promoter has been proved to be able to controlling the expression and effect of exogenous genes in tumors without implication of normal tissues.Survivin is the member of the inhibitors of apoptosis(IAP),which is expressed in various human cancers but not in normal adult human tissues.As its expression is activated transcriptionally,the promoter of survivin was used as a cancer-specific promoter in cancer gene therapy.
In recent years,TNF-related apoptosis-inducing ligand(TRAIL),as an inducer of tumor cell apoptosis,has been proven to be a promising agent for cancer treatment. However,the potential utility and safety of TRAIL has been questioned because its potential toxicity on normal human cells(e.g.hepatocytes) and the mechanism of the related toxicity still hangs in doubt.From a point of clinical view,safety is the most critical problem in developing a drug.Thus,how to control the effect of TRAIL specifically on tumor cells appears to be imperative.Several studies have proved the tumor-specific efficiency of TRAIL mediated by hTERT promoter using adenovirus or plasmids.However,the capability of rAAV-mediated TRAIL expression driven by hTERT promoter to lead tumor-specific killing effect is unknown.Therefore,in the present study,by using rAAV2 as the vector,we tested whether hTERT promoter and survivin promoter are promising candidates in rAAV-mediated tumor-specific therapy.
First all,we constructed the EGFP report gene and soluble TRAIL gene controlled by hTERT promoter(about 284bp) or survivin promoter(about 980bp) in rAAV2 vector, repectively.The specificity of EGFP or TRAIL expression driven by the two promoters was tested in human hepatocellular carcinoma(HCC) cells and primary human hepatocyte(PHH).It showed that hTERT and survivin promoter were both efficient in driving tumor-specific expression of EGFP gene in HCC cells and the activity of hTERT promoter seemed higher compared with that of survivin,but both the two promoters had no acitivity in PHH.The apoptosis of HCC induced by TRAIL expression under the control of tumor-specific promoters was proved that hTERT promoter was more efficient in driving the exogenous gene expression than that of survivin promoter.
The second,we tested the activity of hTERT promoter in immortal cell line HEK293 and various tumor cell lines,including human carcinoma of lung,breast,colon, cervix,and lymphoma etc.and human kidney proximal tubular cells(HKC).The result demonstrated that hTERT promoter was active in all the tumor cells although they were not same.Moreover,the AAV.hTERT.TRAIL leaded to apoptosis of various tumor cells, including A549,Hela,SMMC-7721,but not in PHH.
Thirdly,in vivo study was carried out and proved that hTERT promoter mediated the surppression of tumor formation and growth by apoptosis without toxic to normal tissues,suggesting it is a promising construct for cancer gene therapy.
Fatherly,we studied the effect of combination of AAV.hTERT.TRAIL and chemotherapeutic drugs 5-Fu in vivo.The result showed that the combination of the AAV.hTERT.TRAIL and 5-Fu suppressed the tumor growth more efficiently than either one agent,indicating a novel strategy of AAV-mediated gene threpay combined with chemotherapeutic drugs for cancer treatment.
我们构建了hTERT启动子或survivin启动子与AAV2的重组质粒载体。通过报告基因EGFP的表达比较了两种肿瘤特异启动子在不同肝细胞癌(HCC)细胞株及人原代正常肝细胞(PHH)中的活性,结果表明hTERT启动子与survivin启动子均能驱动EGFP基因在HCC细胞中的表达,hTERT启动子驱动的EGFP表达在SMMC-7721、BEL-7402、HepG2和Hep3B肝癌细胞中的平均荧光强度分别为44.4%、32.7%、35.2%和12.9%,survivin启动子驱动的EGFP表达在四株细胞中的平均荧光强度为25.4%、21.8%、13.5%和11.7%,虽然这两种启动子之间的活性有所差别,但它们在PHH中均没有活性,平均荧光强度在5%以下。此外,两启动子驱动的TRAIL基因还可引起不同程度的HCC细胞存活率降低,而对PHH并无影响。进一步,我们又对hTERT启动子在包括肺癌、结肠癌、乳腺癌、宫颈癌、肝癌、白血病等不同种类的肿瘤细胞株及正常细胞中的活性进行检测。结果表明,hTERT启动子在多种肿瘤细胞中均有活性,而在正常细胞中则没有,说明它具有良好的肿瘤特异选择性。
(二)含有肿瘤特异启动子的重组病毒的制备及其功能研究
我们还通过包装纯化重组AAV病毒颗粒,进一步研究了hTERT启动子驱动的AAV.TRAIL重组病毒单独作用或与化疗药物5-Fu联合作用的情况。经对重组病毒侵染后的肿瘤细胞及正常细胞DNA、mRNA及蛋白分析的结果表明,hTERT启动子可驱动TRAIL基因在肿瘤细胞中特异表达。抗肿瘤活性分析表明,重组病毒侵染72小时后,肝细胞癌SMMC-7721细胞、肺癌A549细胞、宫颈癌Hela细胞和正常人肝细胞PHH的凋亡率分别为:SMMC-7721 57.4%、A549 22.9%、Hela 33.3%、PHH 4.9%。应用裸鼠移植瘤模型进行的体内研究结果表明,hTERT启动子驱动的TRAIL基因表达明显抑制SMMC-7721人肝细胞癌在小鼠体内的生长,5×10~(11))Gps重组病毒可使肿瘤增长抑制率达77%,而且,hTERT启动子驱动的TRAIL基因表达也能明显抑制A549人肺腺癌细胞在小鼠体内的生长。
应用化疗药物5-Fu与重组病毒联合给药结果表明,40mg/kg的5-Fu能增强重组病毒抗肿瘤作用,肿瘤增长的抑制率达到90%。免疫组织化学分析显示,5-Fu能增强肿瘤组织中TRAIL受体DR5的表达。
此外,我们还观察到hTERT启动子驱动的TRAIL表达具有给药途径的选择性,即局部瘤内注射有效而系统给药(尾静脉注射和肌肉注射)则无效。
我们还对hTERT驱动的AAV.TRAIL进行了安全性检测。病理分析及转氨酶测定表明,无论是瘤内注射还是系统给药,重组病毒对动物正常组织器官尤其是肝脏没有影响,说明在hTERT启动子驱动下,重组病毒是安全的。
综上,我们的研究表明肿瘤特异启动子能特异性驱动外源基因在肿瘤细胞中的表达及效应。在肿瘤特异启动子驱动下,重组AAV病毒能使外源基因TRAIL安全有效的发挥作用,这为实现以重组AAV病毒为载体的肿瘤靶向性基因治疗提供了新的思路。
Gene therapy represents an attractive approach to treating cancers.For a good cancer gene therapy delivery system,an ideal vector is absolutely necessary for effective and safe therapeutic.Among quite a few viral vectors which have been tested in recent years,Adeno-associated virus(AAV) is considered to be the most promising vector due to its nonpathogenic property,wide tropisms,non immunogenecity to host and long-term transgene expression.Experimental and clinical trials using recombinant AAV(rAAV) as the delivery vehicles have been proved to be an effective way in gene therapy.However, in gene therapy,especially in treating tumors,the most concerned problem is how to limit the cytotoxic exogenous gene expression in the tumors without harm to normal cells.Since the wide host range infectivity of rAAV may become a disadvantage for its applications in cancer gene therapy,due to its nonselective tissue transduction,safety issue of rAAV as the vector of carrying exogenous genes,which are often toxic to both cancer and normal cells in treating tumors,must be considered.
Using tumor-specific promoters has been proved to be a potential way to control the exogenous genes in limited sites.Human telomerase reverse transcriptase(hTERT) is considered to be the most crucial unit in telomerase activity,which is present in a majority of human cancers.The hTERT promoter has been proved to be able to controlling the expression and effect of exogenous genes in tumors without implication of normal tissues.Survivin is the member of the inhibitors of apoptosis(IAP),which is expressed in various human cancers but not in normal adult human tissues.As its expression is activated transcriptionally,the promoter of survivin was used as a cancer-specific promoter in cancer gene therapy.
In recent years,TNF-related apoptosis-inducing ligand(TRAIL),as an inducer of tumor cell apoptosis,has been proven to be a promising agent for cancer treatment. However,the potential utility and safety of TRAIL has been questioned because its potential toxicity on normal human cells(e.g.hepatocytes) and the mechanism of the related toxicity still hangs in doubt.From a point of clinical view,safety is the most critical problem in developing a drug.Thus,how to control the effect of TRAIL specifically on tumor cells appears to be imperative.Several studies have proved the tumor-specific efficiency of TRAIL mediated by hTERT promoter using adenovirus or plasmids.However,the capability of rAAV-mediated TRAIL expression driven by hTERT promoter to lead tumor-specific killing effect is unknown.Therefore,in the present study,by using rAAV2 as the vector,we tested whether hTERT promoter and survivin promoter are promising candidates in rAAV-mediated tumor-specific therapy.
First all,we constructed the EGFP report gene and soluble TRAIL gene controlled by hTERT promoter(about 284bp) or survivin promoter(about 980bp) in rAAV2 vector, repectively.The specificity of EGFP or TRAIL expression driven by the two promoters was tested in human hepatocellular carcinoma(HCC) cells and primary human hepatocyte(PHH).It showed that hTERT and survivin promoter were both efficient in driving tumor-specific expression of EGFP gene in HCC cells and the activity of hTERT promoter seemed higher compared with that of survivin,but both the two promoters had no acitivity in PHH.The apoptosis of HCC induced by TRAIL expression under the control of tumor-specific promoters was proved that hTERT promoter was more efficient in driving the exogenous gene expression than that of survivin promoter.
The second,we tested the activity of hTERT promoter in immortal cell line HEK293 and various tumor cell lines,including human carcinoma of lung,breast,colon, cervix,and lymphoma etc.and human kidney proximal tubular cells(HKC).The result demonstrated that hTERT promoter was active in all the tumor cells although they were not same.Moreover,the AAV.hTERT.TRAIL leaded to apoptosis of various tumor cells, including A549,Hela,SMMC-7721,but not in PHH.
Thirdly,in vivo study was carried out and proved that hTERT promoter mediated the surppression of tumor formation and growth by apoptosis without toxic to normal tissues,suggesting it is a promising construct for cancer gene therapy.
Fatherly,we studied the effect of combination of AAV.hTERT.TRAIL and chemotherapeutic drugs 5-Fu in vivo.The result showed that the combination of the AAV.hTERT.TRAIL and 5-Fu suppressed the tumor growth more efficiently than either one agent,indicating a novel strategy of AAV-mediated gene threpay combined with chemotherapeutic drugs for cancer treatment.
引文
1. Anderson WF, Biases RM, Culver K et al: The ADA human gene therapy clinical protocol: points to consider response with clinical protocol. Hum Gene Ther, 1990,1: 331-362
2. Gottesman MM: Cancer gene therapy: an awkward adolescence. Cancer Gene Therapy, 2003, 10:501 -508
3. Yand Lu: Recombinant Adeno-associated virus as delivery vector for gene therapy. Stem Cells and Dev, 2004, 13: 133-145
4. Hildegard B, Markus BF, Michael H: Progress in the use of adeno-associated viral vectors for gene therapy. Cells Tissues Organs, 2004, 177:139-150
5. Oyeux BB, Denissenko M, Thomassin H et al: The c-jun Proto-oncogene Down-regulates the Rat-Fetoprotein Promoter in HepG2 Hepatoma Cells without Binding to DNA. J Bio Chem, 1995, 270: 10204-10211
6. Koch PE, Guo ZS, Kagawa S: Augmenting transgene expression from carcinoembryonic antigen (CEA) promoter via a GAL4 gene regulatory system. Mol Ther, 2001,3:278-83
7. Gu J, Fang BL: Telomerase promoter-driven cancer gene therapy. Can Bio & Ther, 2003, 2:s64-70
8. Takakura M, Kyo S, Kanaya T, Hirano H, Takeda J 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. Cancer Res, 1999, 59: 551-557
9. Cong YS, Wen J, Bacchetti S: The human telomerase catalytic subunit hTERT: organization of the gene and characterization of the promoter. Human Mol Genet, 1999, 8:137-142
10. Horikawa I, Cable PL, Afshari C et al: Cloning and characterization of the promoterregion of human telomerase reverse transcriptase gene. Cancer Res, 1999, 59: 826-830
11. Devereux TR, Hurikawa I, Anna CH et al: DNA methylation analysis of the promoter region of the human telomerase rverse transcriptase (hTERT) gene. Cancer Res, 1999, 59:6087-6090
12. Kyo S, Inoue M: Complex regulartory mechanisms of telomerase activity in normal and cancer cells: how can we apply them for cancer therapy? Oncogene, 2002, 21: 688-697
13. Ducrest AL, Szutorisz H, Lingner J et al: Regulation of the human telolerase reverse transcriptase gene. Oncogene, 2002, 21: 541-542
14. Gu J, Kagawa S, Takakura M, Kyo S, Inoue M, Roth JA, 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. Cancer Res 2000,60:5359-64
15. Koga S, Hirohata S, Kondo Y, Komata T, Takakura M, Inoue M, et al, A novel telomerase-specific gene therapy: gene transfer of caspase-8 utilizing the human telomerase catalytic subunit gene promoter. Human gene therapy 2000, 11: 1397-406
16. Liu J, Zou WG, Lang MF, et al: Cancer-specific killing by the CD suicide gene using the human telomerase reverse transcriptase promoter. Int J Oncol, 2002, 21: 661-666
17. Koga S, Hirohata S, Kondo Y, Komata T, Takakura M, Inoue M, 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. Anticancer Res, 2001, 21: 1937-1943
18. Komata T, Koga S, Hirohata S, Takakura M 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. Int J Oncol, 2001, 19: 1015-20.
19. Song JS, Kim HP, Yoon WS et al: Adenovirus-mediated suicide gene therapy using the human telomerase catalytic subunit (hTERT) gene promoter induced apoptosis of ovarian cancer cell line. Biosci Biotechnol Biochem. 2003, 67: 2344-50
20. 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. Oncogene, 2002, 21: 8020-8028
21. Deveraux QL, Reed JC: IAP family proteins—suppressors of apoptosis. Genes Dev, 1999, 13:239-252
22. Hoffman WH, Biade S, Zilfou JT et al: Transcriptional repression of the anti-apoptitic Survivin gene by wide type 53. J Biol Chem, 2002, 277: 3247-3257
23. Mesri M, Morales-Ruiz M, Ackermann EJ et al: Suppression of vascular endothelial growth factor-mediated endothelial cell protection by Survivin targeting. Am J Pathol, 2001, 158: 1757-1765
24. Konnikova L, Kotechi M, Kruger MM et al: Knockdown of STAT3 expressio by RNAi induces apoptosis in astrocytoma cells. BMC Cancer, 2003, 3: 23
25. Papaperropoulos AM, Fulton D, Mahboubi K et al: Angiopoietin-1 inhibits endothelial celll apoptosis via the Akt/survivin pathway. J Biol Chem, 2000, 275: 9102-9105
26. Fukuda S, Foster RG, Porter SB, Pelus LM: The antiapoptosis protein Survivin is associated with cell cycle entry of normal cord blood CD34+ cells and modulated cell cycle and proliferation of mouse hematopoietic progenitor cells. Blood, 2002, 100:2463-2471
27. Fukuda S, Pelus LM: Regulation of the inhibitor of apoptosis family member Survivin in normal cord blood and bone marrow CD34+ cells by hematopoietic growth factors: implication of Survivin expression in normal hematopoiesis. Blood, 2001,98:2091-2100
28. Lu B, Makhija SK, Nettelbeck DM et al: Evaluation of tumor-specific promoter activities in melanoma. Gene Ther, 2005, 330-338
29. Kamizono J, Nagano S, Murofushi Y et al: Survivin-responsive conditionally replicating adenovirus exhibits cancer-specific and efficient viral replication. Cancer Res, 2005, 65: 5284-91
30. Van Houdt WJ, Haviv YS, Lu B et al: The human Survivin promoter: a novel transcriptional targeting strategy for treatment of glioma. J Neurosurg, 2006, 104: 583-92
31. William H, Hoffman, Siham Biade: Transcriptional Repression of the Anti-apoptotic Survivin Gene by Wild Type p53. J Biol Chem, 2002, 277: 3247-3257
32. Rudi B, Denise Connolly CB, Murphy M: Activation of Cancer-Specific Gene Expression by the Survivin Promoter. J Nat Cancer Inst, 2002, 94: 522-528
33. Esteve PO, Chin HG, Pradhan S et al: Human maintenance DNA (cytosine-5)-methyltransferase and p53 modulate expressionof p53-repressed promoters. Proc Natl Acad Sci U S A, 2005, 102: 1000-1005
34. Li F, Altieri DC: Transcriptional analysis of human Survivin gene expression. Biochem J, 1999, 344: 305-311
35. Almasan A, Ashkenazi A: Apo2L/TRAIL: Apoptosis signaling, biology, and potential for cancer therapy. Cytokine Growth Fac Rev, 2003, 14: 337-348
36. Kim Y, Seol DW: TRAIL, a might apoptosis inducer. Mol Cells, 2003, 15: 283-293
37. Gazitt Y: TRAIL is a potent inducer of apoptosis in myeloma cells derived from multiple myeloma patients and is not cytotoxic to hematopoietic stem cells. Leukemia, 1999, 13: 1817-1824
38. Ashkenazi A, Pai R, Fong S, et al: Safety and anti-tumor activity of recombinant soluble Apo2 ligand. J Clin Invest, 1999: 104: 155-162
39. Pollack IF, Erff M, Ashkenazi A: Direct stimulation of apoptotic signaling by soluble Apo2L/tumor necrosis factor-related apoptosis-inducing ligand leads to selective killing of glioma cells. Clin Cancer Res, 2001, 7: 1362-1369
40. Mohr A, Henderson G, Dudus L et al: AAV-encoded expression of TRAIL in experimental human colorectal cancer leads to tumor regression. Gene Ther, 2004, 11:534-543
41. Lawrence D, Shahrokh Z, Marsters S, et al: Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nat Med, 2001, 7: 383-385
42. Kelley SK, Ashkenazi A. Targeting death receptors in cancer with Apo2L/TRAIL. Curr Opin Pharmacol, 2004, 4: 333-339
43. Minko T, Dharap SS, Pakunlu RI et al: Molecular targeting of drug delivery systems to cancer. Curr Drug Targets, 2004, 5: 389-406
44. Shi J, Zheng DX, Liu YX et al: Overexpression of soluble TRAIL induces apoptosis in human lung Adenocarcinoma and inhibits growth of tumor xenografts in nude mice. Cancer Res, 2005, 65: 1687-1692
45. Ma H, Liu Y, Liu S: Oral adeno-associated virus-sTRAIL gene therapy suppresses human hepatocellular carcinoma growth in mice. Hepatology, 2005, 42: 1355-63
46. Kaludov N, Brown KE, Walters RW et al: Adeno-associated virus serotype 4 (AAV4) and AAV5 both require sialic acid binding for hemagglutination and efficient transduction but differ in sialic acid linkage specificity. J Virol, 2001, 75: 6884-93
47. Gao GP, Alvira MR, Wang L et al: Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc Natl Acad Sci U S A, 2002, 99:11854-911859
48. Mori S, Wang L, Takeuchi T, Kanda T: Two novel adeno-associated viruses from cynomolgus monkey: pseudotyping characterization of capsid protein. Virology, 2004, 330: 375-383
49. Summerford C, Samulski RJ: Membrane-associated heparan sulfate proteoglycan is a receptor for adeno-associated virus type 2 virions. J Virol, 1998, 72: 1438-1445
50. Walters RW, Yi SM, Keshavjee S et al: Binding of adeno-associated virus type 5 to 2, 3-linked sialic acid is required for gene transfer. J Biol Chem, 2001, 276: 20610-20616
51. Di Pasquale G, Davidson BL, Stein CS et al: Identification of PDGFR as a receptor for AAV-5 transduction. Nat Med, 2003, 9: 1306-1312
52. Bartlett JS et al: Targeted adeno-associated virus vector transduction of nonpermissive cells mediated by a bispecific F(ab'γ)2 antibody. Nat Biotechnol, 1999, 17: 181-186
53. Shi W, Bartlett JS: RGD inclusion in VP3provides adeno-associated virus type 2 -based vectors with a heparin sulfate-independent cell entry mechanism. Mol Ther, 2003,7:515-525
54. Shi W, Arnold GS, Bartlett JS: Insertional mutagenesis of the adeno-associated virus type2 capsid gene and generation of AAV2 vectors targeted to alternative cell-surface receptors. Hum Gene Ther, 2001, 12: 1697-1711
55. Girod AM, Ried C, Wobus H: Genetic capsid modifications allow efficient retargeting of adeno-associated virus type 2. Nat Med, 1999, 5: 1052-1056
56. Cordier L et al: Muscle-specific promoters may be necessary for adeno-associated cirus-mediated gene transfer in the treatment of muscular dystrophies. Hum Gene Ther, 2001, 12:205-215
57. Rolling F: Recombinant AAV-mediated gene transfer to the retina: gene therapy perspecitives. Gene Ther, 2004, 11: s26-s32
58. Su H, Lu R, Chang JC et al: Tissue-specific expression of herpes simplex virus thymidine kinase gene delivered by adeno-associated virus inhibits the growth of human hepatocellular carcinoma in athymic mice. Proc Natl Acad Sci USA, 1997, 94: 3891-13896
59. Kim NW, Piatyszek MA, Prowse KR et al: Specific association of human telomerase activity with immortal cells and cancer. Science, 1994, 266: 2011-2015
60. Nakai H, Thomas CE, Storm TA, et al. A limited number of transducible hepatocytes restricts a wide-range linear vector dose response in recombinant adeno-associated virus-mediated liver transduction. J virol, 2002, 76: 11343-11349
61. Jacob D, Davis J, Zhang LD et al: Suppression of pancreatic tumor growth in the liver by systemic administration of the TRAIL gene driven by the hTERT promoter. Cancer gene ther, 2005, 12:109-115
62. Keane MM, Ettenberg SA, Nau MM et al: Chemotherapy augments TRAIL-induced apoptosis in breast cell lines. Cancer Res, 1999, 59: 734-741
63. Gliniak B, Le T: Tumor necrosis factor-related apoptosis-inducing ligand's antitumor activity in vivo is enhanced by the chemotherapeutic agent CPT-11. Cancer Res, 1999,59:6153-6158
64. Yamanaka T, Shiraki K, Sugimoto K et al: Chemotherapeutic agents augment TRAIL-induced apoptosis in human hepatocellular carcinoma cell lines. Hepatology, 2000,32: 482-490
65. Nagane, M, Pan G, Weddle JJ: Increased death receptor 5 expression by chemotherapeutic agents in human gliomas causes synergistic cytotoxicity with tumor necrosis factor-related apoptosis-inducing ligand in vitro and in vivo. Cancer Res, 2000, 60: 847-853
66. Goto H, Osaki T, Kijima T et al: Gene therapy utilizing the Cre/loxP system selectivity suppresses tumor growth of disseminated carcinoembryonic antigen-producing cancer cells. Int J Cancer, 2001, 94: 414-419
67. Koch PE, Guo ZS, Kagawa S et al: Augmenting transgene expression from carcinoembryonic antigen (CEA) promoter via a GAL4 gene regulatory system. Mol ther, 2001, 3: 278-283
1. Somia N and IM Verma: Gene therapy: trials and tribulations. Nature Rev Genet, 2000,1:91-99
2. Erles K, Sebokova P, Schlehofer JR: Update on the prevalence of serum antibodies to adeno-associated virus (AAV). J Med Virol, 1999, 59:406-411
3. Yand Lu: Recombinant Adeno-associated virus as delivery vector for gene therapy. Stem Cells and Dev, 2004, 13: 133-145
4. Mori S, Wang L, Takeuchi T, Kanda T: Two novel adeno-associated viruses from cynomolgus monkey: pseudotyping characterization of capsid protein. Virology, 2004, 330:375-83
5. Hildegard B, Markus BF, Michael H: Progress in the use of adeno-associated viral vectors for gene therapy. Cells tissues organs, 2004, 177:139-150
6. Seisenberger G, Ried MU, Endresss T, Buning H: Real-time single-molecule imaging of the infection pathway of an adeno-associated virus. Science, 2001, 294:1929-1932
7. Hauck B, Xiao WD: Characterization of tissue tropism determinants of adeno-associated virus type 1. J Virol, 2003, 77: 2768-2774
8. Gao GP et al. Novel adeno-associated virus from rhesus monkeys as vectors for human gene therapy. Proc Natl Acad Sci USA, 2002, 99:11854-11859
9. Russell, DW, Alecander IE, Miller AD: DNA synthesis and topoisomerase inhibitors increase transduction by adeno-associated virus vectors. Natl Acad Sci USA, 92: 5719-5723
10. Huttner NA, Girod A, Schnittger S, Schoch C: Analyses of site-specific transgene integration following co-transduction with recombinant adeno-associated virus and a rep encoding plasmid. J Gne Med, 2003, 5: 120-129
11. Nakai H, Thomas CE, Strom TA, Fuess S: A limited number of transducible hepatocytes restrict a wide-range linear vector dose response in recombinant adeno-associated virus-mediated liver transduction. J Viro, 2002, 76:11343-11349
12. Harper SQ Crawford RW, DelloRusso C: Spectrin-like repeats from dystrophin and alpha-actinin-2 are not functionally interchangeable. Hum Mol genet, 2002, 11:1807-1815
13. Watchko J et al: Adeno-associated virus vector-mediated minidystrophin gene therapy improves dystrophic muscle contractile function in mdx mice. Hum Gene Ther, 2002,13: 1451-1460
14. Cordier L et al: Muscle-specific promoters may be necessary for adeno-associated cirus-mediated gene transfer in the treatment of muscular dystrophies. Hum Gene Ther, 2001,12:205-215
15. Chenuaud P et al: Optimal design of a single recombinant adeno-associated virus derived from serotypesl and 2 to achieve more tightly regulated transgene expression from nonhuman primate muscle. Mol Ther 2004, 9: 410-418
16. Duan DS, Yue YP, Engelhardt JF: Expanding AAV pacaking capacity with tran-splicing or overlapping vectors: a quantitative comparison. Mol Ther, 2001, 4: 383-391
17. Svensson EC et al: Efficient and stable transduction of cardiomyocytes after intramyocardial injection or intra-coronary perfusion with recombinant adeno-associated virus vectors. Circulations, 1999, 99: 201-205
18. Vassalli G et al: Adeno-associated virus(AAV) vector achieve prolonged transgene expression in mouse myocardium and arteries in vivo. Int J Cardiol, 2003, 90:229-238
19. Blankinship MJ et al: Progress toward gene therapy of Duchenne muscular dystrophy using truncated four-repeated dystrophin and AAV6. J Neurol Sci, 2002, 199: 1-5
20. Ponnazhagan S et al. Adeno-associated virus 2-mediated gene transfer in vivo: organ-tropism and expression of transduced sequences in mice. Gene, 1997, 190: 203-210
21. Mori K et al: AAV-mediated gene transfer of pigment epithelium-derived factor inhibits choroidal neovascularization. Invest Ophthalmol Vis Sci, 2002, 43: 1994-2000
22. Lai YK et al: Potential long-term inhibition of ocular neovascularisation by recombinant adeno-associated virus mediated secretion gene therapy. Gent Therapy, 2002, 9: 804-813
23. Green ES et al: Two animal models of retinal degeneration are rescued by recombinant adeno-associated virus-mediated production of fgf-5 and fgf-18. Mol Ther, 2001,3:507-515
24. Narfstrom K et al: Functional and structural recovery of the retinal after gene therapy in the RPE65 null mutation dog. Invest Ophthalmol Vis Sci, 2003,44:1663-1672
25. Hengge UR et al: Adeno-associated virus expresses transgenes in hair follicles and epidermis. Mol Ther, 2: 188-194
26. Branu-Falco M: gene therapy concepts for promoting wound healing. Hautarzt, 2002, 53: 238-243
27. Deodato, B, Arsic N, Zentilin L: Recombinant AAV vector encoding human VEGF165 enhances wound healing. Gene Ther, 2002, 9: 777-785
28. Galeano M et al: Adeno-associated viral vector-mediated human vascular endothelial growth factor gene transfer stimulates angiogenesis and wound healing in the genetically diabetic mouse. Diabetologia, 2003, 46: 546-555
29. Duan D, Yue Y, Yan Z: A new dual-vector approach to enhance recombinant adeno-associated virus-mediated gene expression through intermolecular cis activation. Nat Med, 2000, 6:595-598
30. Rizzo, WB, Lin Z, Carney G: Fatty aldehyde dehydrogenase: genomic structure, expression and mutation analyses in sjOgren-larsson syndrome. Chem Biol Interact, 2002,130:297-307
31. Donahue, BA et al: Selective uptake and sustained expression of AAV vectors following subcutaneous delivery. J Gene Med, 1999, 1:31-42
32. Descamps V, Blumenfeld N, Beuzard Y: Keratinocytes as a target for gene therapy. Sustained production of erythropoietin in mice by human keratinocytes transduced with an adeno-associated virus vector. Arch Dermatol, 1996, 132:1207-1211
33. Bartlett JS et al: Targeted adeno-associated virus vector transduction of nonpermissive cells mediated by a bispecific F(ab'γ)2 antibody. Nat Biotechnol, 1999, 17: 181-186
34. Shi W, Bartlett JS: RGD inclusion in VP3provides adeno-associated virus type 2 -based vectors with a heparin sulfate-independent cell entry mechanism. Mol Ther, 2003, 7:515-525
35. Shi W, Arnold GS, Bartlett JS: Insertional mutagenesis of the adeno-associated virus type2 capsid gene and generation of AAV2 vectors targeted to alternative cell-surface receptors. Hum Gene Ther, 2001, 12: 1697-1711
36. Girod AM, Ried C, Wobus H: Genetic capsid modifications allow efficient retargeting of adeno-associated virus type 2. Nat Med, 1999, 5: 1052-1056
37. Ried MU, Girod K, Leike H: Adeno-associated virus capsids displaying immunoglobulin-binding domains permit antibody-mediated vector retargeting to specific cell surface receptors. J Virol, 2002, 76: 4559-4566
38. White SJ, Nicklin SA, Buning H: Targeted gene delivery to vascular tissue in vivo by tropism-modified adeno-associated virus vectors. Circulation, 2004, 109: 513-519
39. Perabo L, Buning H, Kofler DM: In vitro selection of viral vectors with modified tropism: the adeno-associated virus display. Mol Ther, 2003, 8: 151-157
1. Yee JK, Moores JC, Joly DJ et al: Gene expression from transcriptionally disabled retro viral vectors. Proc Natl Acad Sci USA, 1987, 84: 5197-5201
2. Yu SF, von Ruden T, Kantoff PW: Self-inactivating retroviral vectors designed for transfer of whole genes into mammalian cels. Proc Natl Acad Sci USA, 1986, 83: 3194-3198
3. Miller DG, Adam MA, Miller AD: Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection. Mol Cell Biol, 1990, 10: 4239:4242
4. Klatzmann D, Valery CA, Bensimon G et al: A phase I/II study of herpes simplex virus type 1 thymidine kinase 'suicide' gene therapy for recurrent glioblastoma. Study Group on gene therapy for glioblastma. Hum Gene Ther, 1998, 9: 2595-2604
5. Shand N, Weber F, Mariani L et al: A phase 1-2 clinical trial of gene therapy for recurrent glioblastoma multiforme by tumor transduction with the herpes simplex thymidine kinase gene followed by ganciclovir. GLI328 European-Canadian study group. Hum Gene Ther, 1999, 10: 2325-2335
6. Rainov NG. A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther, 2000, 11: 2389-2401
7. Takafuji ET, Gaydos JC, Allen RG et al: Simultaneous administration of live, enteric-coated adenovirus types-4, types-7 and bypes-21 vaccines- safety and immunofenicity. J Invest Dis, 1979,140: 48-53
8. Shenk TE: Adenoviridae: the viruses and their replication. In Fields Virology, 2001:2265-2300
9. Bergelson JM, Cunningham JA, Droguett G et al: Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science, 1997, 275: 1320-1323
10. Tomko RP, Xu RL, Philipson L: HCAR and MCAR: the human and mouse cellular receptors for subgroup C adenoviruses and group B Coxsackieviruses. Proc Natl Acad Sci U S A, 1997, 94:3352-3356
11. Bett AJ, Haddara W, Prevec L et al: An efficient and flexible system for construction of adenovirus vectors with insertions or deletions in early region-1 and region-3. Proc Natl Acad Sci U S A: 1994, 91: 8802-8806
12. Horwitz MS: Adenoviruses. In Fields Virology, 2001: 2301-2326
13. Graham FL, Smiley L, Russell WC et al: Characteristics of a human cell line transformed by DNA from human adenovirus type-5. J Gen Virol, 1977, 36: 59-72
14. Fallaux FJ, Kranenburg O, Cramer SJ et al: Characterization of 911: a new helper cell line for the titration and propagation of early region 1-deleted adenoviral vectors. Hum Gene Ther, 1996, 7: 215-222
15. Fallaux FJ, Bout A, Van der Velde I et al: New helper cells and matched early region 1-deleted adenovirus vectors prevent generation of replication-competent adenoviruses. Hum Gene Ther, 1998, 9:1909-1917
16. Young LS, Searle PF, Onion D et al: viral gene therapy strategies: from basic science to clinical application. J Path, 2006, 208: 299-318
17. Volpers C, Kochanek S: Adenoviral vectors for gene transfer and therapy. J Gene Med, 2004, 6: s163-s171
18. Lee TWR, Matthews DA, Blair GE: Novel molecular approaches to cystic fibrosis gene therapy. Biochem J, 2005, 387: 1-15
19. The BS, Ayala G, Aguilar L et al: Phase I-II trial evaluating combined intensity-modulated radiotherapy and in situ gene therapy with or without hormonal therapy in treatment of prostate cancer- interim report on PSA response and biopsy data. Int J Radiat Oncol Biol Phys, 2004, 58: 1520-1529
20. O'Shea CC, Johnson L, Bagus B et al: Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity. Cancer Cell, 2004, 6: 611-623
21. Khun FR, Nemunaitis J, Ganly I et al: A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med, 2000, 6: 879-885
22. Freytag SO, Khil M, Strieker H et al: Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer. Cancer Res, 2002, 62: 4968-4976
23. Market JM, Medlock MD, Rabkin SD et al: Conditionally replicating herpes simplex virus mutant, G207, for the treatment of malignant glioma: results of a phase I trial. Gene Ther, 2000, 7: 867-874
24. Liu P, Speck SH: Synergistic autoactivation of the Epstein-Barr virus immediate-early BRLFl promoter by Rta and Zta. Virology, 2003, 10: 199-206
25. Thorne SH, Hermiston T, Kirn D: Oncolytic virotherapy: approaches to tumor targeting and enhancing antitumor effects. Semi Oncol, 2005, 32: 537-548
26. Ramachandra M, Rahman A, Zou A: Re-engineering adenovirus regulatory pathways to enhance oncolytic specificity and efficacy. Nat Biotechnol, 2001, 19: 1035-1041
2. Gottesman MM: Cancer gene therapy: an awkward adolescence. Cancer Gene Therapy, 2003, 10:501 -508
3. Yand Lu: Recombinant Adeno-associated virus as delivery vector for gene therapy. Stem Cells and Dev, 2004, 13: 133-145
4. Hildegard B, Markus BF, Michael H: Progress in the use of adeno-associated viral vectors for gene therapy. Cells Tissues Organs, 2004, 177:139-150
5. Oyeux BB, Denissenko M, Thomassin H et al: The c-jun Proto-oncogene Down-regulates the Rat-Fetoprotein Promoter in HepG2 Hepatoma Cells without Binding to DNA. J Bio Chem, 1995, 270: 10204-10211
6. Koch PE, Guo ZS, Kagawa S: Augmenting transgene expression from carcinoembryonic antigen (CEA) promoter via a GAL4 gene regulatory system. Mol Ther, 2001,3:278-83
7. Gu J, Fang BL: Telomerase promoter-driven cancer gene therapy. Can Bio & Ther, 2003, 2:s64-70
8. Takakura M, Kyo S, Kanaya T, Hirano H, Takeda J 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. Cancer Res, 1999, 59: 551-557
9. Cong YS, Wen J, Bacchetti S: The human telomerase catalytic subunit hTERT: organization of the gene and characterization of the promoter. Human Mol Genet, 1999, 8:137-142
10. Horikawa I, Cable PL, Afshari C et al: Cloning and characterization of the promoterregion of human telomerase reverse transcriptase gene. Cancer Res, 1999, 59: 826-830
11. Devereux TR, Hurikawa I, Anna CH et al: DNA methylation analysis of the promoter region of the human telomerase rverse transcriptase (hTERT) gene. Cancer Res, 1999, 59:6087-6090
12. Kyo S, Inoue M: Complex regulartory mechanisms of telomerase activity in normal and cancer cells: how can we apply them for cancer therapy? Oncogene, 2002, 21: 688-697
13. Ducrest AL, Szutorisz H, Lingner J et al: Regulation of the human telolerase reverse transcriptase gene. Oncogene, 2002, 21: 541-542
14. Gu J, Kagawa S, Takakura M, Kyo S, Inoue M, Roth JA, 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. Cancer Res 2000,60:5359-64
15. Koga S, Hirohata S, Kondo Y, Komata T, Takakura M, Inoue M, et al, A novel telomerase-specific gene therapy: gene transfer of caspase-8 utilizing the human telomerase catalytic subunit gene promoter. Human gene therapy 2000, 11: 1397-406
16. Liu J, Zou WG, Lang MF, et al: Cancer-specific killing by the CD suicide gene using the human telomerase reverse transcriptase promoter. Int J Oncol, 2002, 21: 661-666
17. Koga S, Hirohata S, Kondo Y, Komata T, Takakura M, Inoue M, 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. Anticancer Res, 2001, 21: 1937-1943
18. Komata T, Koga S, Hirohata S, Takakura M 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. Int J Oncol, 2001, 19: 1015-20.
19. Song JS, Kim HP, Yoon WS et al: Adenovirus-mediated suicide gene therapy using the human telomerase catalytic subunit (hTERT) gene promoter induced apoptosis of ovarian cancer cell line. Biosci Biotechnol Biochem. 2003, 67: 2344-50
20. 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. Oncogene, 2002, 21: 8020-8028
21. Deveraux QL, Reed JC: IAP family proteins—suppressors of apoptosis. Genes Dev, 1999, 13:239-252
22. Hoffman WH, Biade S, Zilfou JT et al: Transcriptional repression of the anti-apoptitic Survivin gene by wide type 53. J Biol Chem, 2002, 277: 3247-3257
23. Mesri M, Morales-Ruiz M, Ackermann EJ et al: Suppression of vascular endothelial growth factor-mediated endothelial cell protection by Survivin targeting. Am J Pathol, 2001, 158: 1757-1765
24. Konnikova L, Kotechi M, Kruger MM et al: Knockdown of STAT3 expressio by RNAi induces apoptosis in astrocytoma cells. BMC Cancer, 2003, 3: 23
25. Papaperropoulos AM, Fulton D, Mahboubi K et al: Angiopoietin-1 inhibits endothelial celll apoptosis via the Akt/survivin pathway. J Biol Chem, 2000, 275: 9102-9105
26. Fukuda S, Foster RG, Porter SB, Pelus LM: The antiapoptosis protein Survivin is associated with cell cycle entry of normal cord blood CD34+ cells and modulated cell cycle and proliferation of mouse hematopoietic progenitor cells. Blood, 2002, 100:2463-2471
27. Fukuda S, Pelus LM: Regulation of the inhibitor of apoptosis family member Survivin in normal cord blood and bone marrow CD34+ cells by hematopoietic growth factors: implication of Survivin expression in normal hematopoiesis. Blood, 2001,98:2091-2100
28. Lu B, Makhija SK, Nettelbeck DM et al: Evaluation of tumor-specific promoter activities in melanoma. Gene Ther, 2005, 330-338
29. Kamizono J, Nagano S, Murofushi Y et al: Survivin-responsive conditionally replicating adenovirus exhibits cancer-specific and efficient viral replication. Cancer Res, 2005, 65: 5284-91
30. Van Houdt WJ, Haviv YS, Lu B et al: The human Survivin promoter: a novel transcriptional targeting strategy for treatment of glioma. J Neurosurg, 2006, 104: 583-92
31. William H, Hoffman, Siham Biade: Transcriptional Repression of the Anti-apoptotic Survivin Gene by Wild Type p53. J Biol Chem, 2002, 277: 3247-3257
32. Rudi B, Denise Connolly CB, Murphy M: Activation of Cancer-Specific Gene Expression by the Survivin Promoter. J Nat Cancer Inst, 2002, 94: 522-528
33. Esteve PO, Chin HG, Pradhan S et al: Human maintenance DNA (cytosine-5)-methyltransferase and p53 modulate expressionof p53-repressed promoters. Proc Natl Acad Sci U S A, 2005, 102: 1000-1005
34. Li F, Altieri DC: Transcriptional analysis of human Survivin gene expression. Biochem J, 1999, 344: 305-311
35. Almasan A, Ashkenazi A: Apo2L/TRAIL: Apoptosis signaling, biology, and potential for cancer therapy. Cytokine Growth Fac Rev, 2003, 14: 337-348
36. Kim Y, Seol DW: TRAIL, a might apoptosis inducer. Mol Cells, 2003, 15: 283-293
37. Gazitt Y: TRAIL is a potent inducer of apoptosis in myeloma cells derived from multiple myeloma patients and is not cytotoxic to hematopoietic stem cells. Leukemia, 1999, 13: 1817-1824
38. Ashkenazi A, Pai R, Fong S, et al: Safety and anti-tumor activity of recombinant soluble Apo2 ligand. J Clin Invest, 1999: 104: 155-162
39. Pollack IF, Erff M, Ashkenazi A: Direct stimulation of apoptotic signaling by soluble Apo2L/tumor necrosis factor-related apoptosis-inducing ligand leads to selective killing of glioma cells. Clin Cancer Res, 2001, 7: 1362-1369
40. Mohr A, Henderson G, Dudus L et al: AAV-encoded expression of TRAIL in experimental human colorectal cancer leads to tumor regression. Gene Ther, 2004, 11:534-543
41. Lawrence D, Shahrokh Z, Marsters S, et al: Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nat Med, 2001, 7: 383-385
42. Kelley SK, Ashkenazi A. Targeting death receptors in cancer with Apo2L/TRAIL. Curr Opin Pharmacol, 2004, 4: 333-339
43. Minko T, Dharap SS, Pakunlu RI et al: Molecular targeting of drug delivery systems to cancer. Curr Drug Targets, 2004, 5: 389-406
44. Shi J, Zheng DX, Liu YX et al: Overexpression of soluble TRAIL induces apoptosis in human lung Adenocarcinoma and inhibits growth of tumor xenografts in nude mice. Cancer Res, 2005, 65: 1687-1692
45. Ma H, Liu Y, Liu S: Oral adeno-associated virus-sTRAIL gene therapy suppresses human hepatocellular carcinoma growth in mice. Hepatology, 2005, 42: 1355-63
46. Kaludov N, Brown KE, Walters RW et al: Adeno-associated virus serotype 4 (AAV4) and AAV5 both require sialic acid binding for hemagglutination and efficient transduction but differ in sialic acid linkage specificity. J Virol, 2001, 75: 6884-93
47. Gao GP, Alvira MR, Wang L et al: Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc Natl Acad Sci U S A, 2002, 99:11854-911859
48. Mori S, Wang L, Takeuchi T, Kanda T: Two novel adeno-associated viruses from cynomolgus monkey: pseudotyping characterization of capsid protein. Virology, 2004, 330: 375-383
49. Summerford C, Samulski RJ: Membrane-associated heparan sulfate proteoglycan is a receptor for adeno-associated virus type 2 virions. J Virol, 1998, 72: 1438-1445
50. Walters RW, Yi SM, Keshavjee S et al: Binding of adeno-associated virus type 5 to 2, 3-linked sialic acid is required for gene transfer. J Biol Chem, 2001, 276: 20610-20616
51. Di Pasquale G, Davidson BL, Stein CS et al: Identification of PDGFR as a receptor for AAV-5 transduction. Nat Med, 2003, 9: 1306-1312
52. Bartlett JS et al: Targeted adeno-associated virus vector transduction of nonpermissive cells mediated by a bispecific F(ab'γ)2 antibody. Nat Biotechnol, 1999, 17: 181-186
53. Shi W, Bartlett JS: RGD inclusion in VP3provides adeno-associated virus type 2 -based vectors with a heparin sulfate-independent cell entry mechanism. Mol Ther, 2003,7:515-525
54. Shi W, Arnold GS, Bartlett JS: Insertional mutagenesis of the adeno-associated virus type2 capsid gene and generation of AAV2 vectors targeted to alternative cell-surface receptors. Hum Gene Ther, 2001, 12: 1697-1711
55. Girod AM, Ried C, Wobus H: Genetic capsid modifications allow efficient retargeting of adeno-associated virus type 2. Nat Med, 1999, 5: 1052-1056
56. Cordier L et al: Muscle-specific promoters may be necessary for adeno-associated cirus-mediated gene transfer in the treatment of muscular dystrophies. Hum Gene Ther, 2001, 12:205-215
57. Rolling F: Recombinant AAV-mediated gene transfer to the retina: gene therapy perspecitives. Gene Ther, 2004, 11: s26-s32
58. Su H, Lu R, Chang JC et al: Tissue-specific expression of herpes simplex virus thymidine kinase gene delivered by adeno-associated virus inhibits the growth of human hepatocellular carcinoma in athymic mice. Proc Natl Acad Sci USA, 1997, 94: 3891-13896
59. Kim NW, Piatyszek MA, Prowse KR et al: Specific association of human telomerase activity with immortal cells and cancer. Science, 1994, 266: 2011-2015
60. Nakai H, Thomas CE, Storm TA, et al. A limited number of transducible hepatocytes restricts a wide-range linear vector dose response in recombinant adeno-associated virus-mediated liver transduction. J virol, 2002, 76: 11343-11349
61. Jacob D, Davis J, Zhang LD et al: Suppression of pancreatic tumor growth in the liver by systemic administration of the TRAIL gene driven by the hTERT promoter. Cancer gene ther, 2005, 12:109-115
62. Keane MM, Ettenberg SA, Nau MM et al: Chemotherapy augments TRAIL-induced apoptosis in breast cell lines. Cancer Res, 1999, 59: 734-741
63. Gliniak B, Le T: Tumor necrosis factor-related apoptosis-inducing ligand's antitumor activity in vivo is enhanced by the chemotherapeutic agent CPT-11. Cancer Res, 1999,59:6153-6158
64. Yamanaka T, Shiraki K, Sugimoto K et al: Chemotherapeutic agents augment TRAIL-induced apoptosis in human hepatocellular carcinoma cell lines. Hepatology, 2000,32: 482-490
65. Nagane, M, Pan G, Weddle JJ: Increased death receptor 5 expression by chemotherapeutic agents in human gliomas causes synergistic cytotoxicity with tumor necrosis factor-related apoptosis-inducing ligand in vitro and in vivo. Cancer Res, 2000, 60: 847-853
66. Goto H, Osaki T, Kijima T et al: Gene therapy utilizing the Cre/loxP system selectivity suppresses tumor growth of disseminated carcinoembryonic antigen-producing cancer cells. Int J Cancer, 2001, 94: 414-419
67. Koch PE, Guo ZS, Kagawa S et al: Augmenting transgene expression from carcinoembryonic antigen (CEA) promoter via a GAL4 gene regulatory system. Mol ther, 2001, 3: 278-283
1. Somia N and IM Verma: Gene therapy: trials and tribulations. Nature Rev Genet, 2000,1:91-99
2. Erles K, Sebokova P, Schlehofer JR: Update on the prevalence of serum antibodies to adeno-associated virus (AAV). J Med Virol, 1999, 59:406-411
3. Yand Lu: Recombinant Adeno-associated virus as delivery vector for gene therapy. Stem Cells and Dev, 2004, 13: 133-145
4. Mori S, Wang L, Takeuchi T, Kanda T: Two novel adeno-associated viruses from cynomolgus monkey: pseudotyping characterization of capsid protein. Virology, 2004, 330:375-83
5. Hildegard B, Markus BF, Michael H: Progress in the use of adeno-associated viral vectors for gene therapy. Cells tissues organs, 2004, 177:139-150
6. Seisenberger G, Ried MU, Endresss T, Buning H: Real-time single-molecule imaging of the infection pathway of an adeno-associated virus. Science, 2001, 294:1929-1932
7. Hauck B, Xiao WD: Characterization of tissue tropism determinants of adeno-associated virus type 1. J Virol, 2003, 77: 2768-2774
8. Gao GP et al. Novel adeno-associated virus from rhesus monkeys as vectors for human gene therapy. Proc Natl Acad Sci USA, 2002, 99:11854-11859
9. Russell, DW, Alecander IE, Miller AD: DNA synthesis and topoisomerase inhibitors increase transduction by adeno-associated virus vectors. Natl Acad Sci USA, 92: 5719-5723
10. Huttner NA, Girod A, Schnittger S, Schoch C: Analyses of site-specific transgene integration following co-transduction with recombinant adeno-associated virus and a rep encoding plasmid. J Gne Med, 2003, 5: 120-129
11. Nakai H, Thomas CE, Strom TA, Fuess S: A limited number of transducible hepatocytes restrict a wide-range linear vector dose response in recombinant adeno-associated virus-mediated liver transduction. J Viro, 2002, 76:11343-11349
12. Harper SQ Crawford RW, DelloRusso C: Spectrin-like repeats from dystrophin and alpha-actinin-2 are not functionally interchangeable. Hum Mol genet, 2002, 11:1807-1815
13. Watchko J et al: Adeno-associated virus vector-mediated minidystrophin gene therapy improves dystrophic muscle contractile function in mdx mice. Hum Gene Ther, 2002,13: 1451-1460
14. Cordier L et al: Muscle-specific promoters may be necessary for adeno-associated cirus-mediated gene transfer in the treatment of muscular dystrophies. Hum Gene Ther, 2001,12:205-215
15. Chenuaud P et al: Optimal design of a single recombinant adeno-associated virus derived from serotypesl and 2 to achieve more tightly regulated transgene expression from nonhuman primate muscle. Mol Ther 2004, 9: 410-418
16. Duan DS, Yue YP, Engelhardt JF: Expanding AAV pacaking capacity with tran-splicing or overlapping vectors: a quantitative comparison. Mol Ther, 2001, 4: 383-391
17. Svensson EC et al: Efficient and stable transduction of cardiomyocytes after intramyocardial injection or intra-coronary perfusion with recombinant adeno-associated virus vectors. Circulations, 1999, 99: 201-205
18. Vassalli G et al: Adeno-associated virus(AAV) vector achieve prolonged transgene expression in mouse myocardium and arteries in vivo. Int J Cardiol, 2003, 90:229-238
19. Blankinship MJ et al: Progress toward gene therapy of Duchenne muscular dystrophy using truncated four-repeated dystrophin and AAV6. J Neurol Sci, 2002, 199: 1-5
20. Ponnazhagan S et al. Adeno-associated virus 2-mediated gene transfer in vivo: organ-tropism and expression of transduced sequences in mice. Gene, 1997, 190: 203-210
21. Mori K et al: AAV-mediated gene transfer of pigment epithelium-derived factor inhibits choroidal neovascularization. Invest Ophthalmol Vis Sci, 2002, 43: 1994-2000
22. Lai YK et al: Potential long-term inhibition of ocular neovascularisation by recombinant adeno-associated virus mediated secretion gene therapy. Gent Therapy, 2002, 9: 804-813
23. Green ES et al: Two animal models of retinal degeneration are rescued by recombinant adeno-associated virus-mediated production of fgf-5 and fgf-18. Mol Ther, 2001,3:507-515
24. Narfstrom K et al: Functional and structural recovery of the retinal after gene therapy in the RPE65 null mutation dog. Invest Ophthalmol Vis Sci, 2003,44:1663-1672
25. Hengge UR et al: Adeno-associated virus expresses transgenes in hair follicles and epidermis. Mol Ther, 2: 188-194
26. Branu-Falco M: gene therapy concepts for promoting wound healing. Hautarzt, 2002, 53: 238-243
27. Deodato, B, Arsic N, Zentilin L: Recombinant AAV vector encoding human VEGF165 enhances wound healing. Gene Ther, 2002, 9: 777-785
28. Galeano M et al: Adeno-associated viral vector-mediated human vascular endothelial growth factor gene transfer stimulates angiogenesis and wound healing in the genetically diabetic mouse. Diabetologia, 2003, 46: 546-555
29. Duan D, Yue Y, Yan Z: A new dual-vector approach to enhance recombinant adeno-associated virus-mediated gene expression through intermolecular cis activation. Nat Med, 2000, 6:595-598
30. Rizzo, WB, Lin Z, Carney G: Fatty aldehyde dehydrogenase: genomic structure, expression and mutation analyses in sjOgren-larsson syndrome. Chem Biol Interact, 2002,130:297-307
31. Donahue, BA et al: Selective uptake and sustained expression of AAV vectors following subcutaneous delivery. J Gene Med, 1999, 1:31-42
32. Descamps V, Blumenfeld N, Beuzard Y: Keratinocytes as a target for gene therapy. Sustained production of erythropoietin in mice by human keratinocytes transduced with an adeno-associated virus vector. Arch Dermatol, 1996, 132:1207-1211
33. Bartlett JS et al: Targeted adeno-associated virus vector transduction of nonpermissive cells mediated by a bispecific F(ab'γ)2 antibody. Nat Biotechnol, 1999, 17: 181-186
34. Shi W, Bartlett JS: RGD inclusion in VP3provides adeno-associated virus type 2 -based vectors with a heparin sulfate-independent cell entry mechanism. Mol Ther, 2003, 7:515-525
35. Shi W, Arnold GS, Bartlett JS: Insertional mutagenesis of the adeno-associated virus type2 capsid gene and generation of AAV2 vectors targeted to alternative cell-surface receptors. Hum Gene Ther, 2001, 12: 1697-1711
36. Girod AM, Ried C, Wobus H: Genetic capsid modifications allow efficient retargeting of adeno-associated virus type 2. Nat Med, 1999, 5: 1052-1056
37. Ried MU, Girod K, Leike H: Adeno-associated virus capsids displaying immunoglobulin-binding domains permit antibody-mediated vector retargeting to specific cell surface receptors. J Virol, 2002, 76: 4559-4566
38. White SJ, Nicklin SA, Buning H: Targeted gene delivery to vascular tissue in vivo by tropism-modified adeno-associated virus vectors. Circulation, 2004, 109: 513-519
39. Perabo L, Buning H, Kofler DM: In vitro selection of viral vectors with modified tropism: the adeno-associated virus display. Mol Ther, 2003, 8: 151-157
1. Yee JK, Moores JC, Joly DJ et al: Gene expression from transcriptionally disabled retro viral vectors. Proc Natl Acad Sci USA, 1987, 84: 5197-5201
2. Yu SF, von Ruden T, Kantoff PW: Self-inactivating retroviral vectors designed for transfer of whole genes into mammalian cels. Proc Natl Acad Sci USA, 1986, 83: 3194-3198
3. Miller DG, Adam MA, Miller AD: Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection. Mol Cell Biol, 1990, 10: 4239:4242
4. Klatzmann D, Valery CA, Bensimon G et al: A phase I/II study of herpes simplex virus type 1 thymidine kinase 'suicide' gene therapy for recurrent glioblastoma. Study Group on gene therapy for glioblastma. Hum Gene Ther, 1998, 9: 2595-2604
5. Shand N, Weber F, Mariani L et al: A phase 1-2 clinical trial of gene therapy for recurrent glioblastoma multiforme by tumor transduction with the herpes simplex thymidine kinase gene followed by ganciclovir. GLI328 European-Canadian study group. Hum Gene Ther, 1999, 10: 2325-2335
6. Rainov NG. A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther, 2000, 11: 2389-2401
7. Takafuji ET, Gaydos JC, Allen RG et al: Simultaneous administration of live, enteric-coated adenovirus types-4, types-7 and bypes-21 vaccines- safety and immunofenicity. J Invest Dis, 1979,140: 48-53
8. Shenk TE: Adenoviridae: the viruses and their replication. In Fields Virology, 2001:2265-2300
9. Bergelson JM, Cunningham JA, Droguett G et al: Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science, 1997, 275: 1320-1323
10. Tomko RP, Xu RL, Philipson L: HCAR and MCAR: the human and mouse cellular receptors for subgroup C adenoviruses and group B Coxsackieviruses. Proc Natl Acad Sci U S A, 1997, 94:3352-3356
11. Bett AJ, Haddara W, Prevec L et al: An efficient and flexible system for construction of adenovirus vectors with insertions or deletions in early region-1 and region-3. Proc Natl Acad Sci U S A: 1994, 91: 8802-8806
12. Horwitz MS: Adenoviruses. In Fields Virology, 2001: 2301-2326
13. Graham FL, Smiley L, Russell WC et al: Characteristics of a human cell line transformed by DNA from human adenovirus type-5. J Gen Virol, 1977, 36: 59-72
14. Fallaux FJ, Kranenburg O, Cramer SJ et al: Characterization of 911: a new helper cell line for the titration and propagation of early region 1-deleted adenoviral vectors. Hum Gene Ther, 1996, 7: 215-222
15. Fallaux FJ, Bout A, Van der Velde I et al: New helper cells and matched early region 1-deleted adenovirus vectors prevent generation of replication-competent adenoviruses. Hum Gene Ther, 1998, 9:1909-1917
16. Young LS, Searle PF, Onion D et al: viral gene therapy strategies: from basic science to clinical application. J Path, 2006, 208: 299-318
17. Volpers C, Kochanek S: Adenoviral vectors for gene transfer and therapy. J Gene Med, 2004, 6: s163-s171
18. Lee TWR, Matthews DA, Blair GE: Novel molecular approaches to cystic fibrosis gene therapy. Biochem J, 2005, 387: 1-15
19. The BS, Ayala G, Aguilar L et al: Phase I-II trial evaluating combined intensity-modulated radiotherapy and in situ gene therapy with or without hormonal therapy in treatment of prostate cancer- interim report on PSA response and biopsy data. Int J Radiat Oncol Biol Phys, 2004, 58: 1520-1529
20. O'Shea CC, Johnson L, Bagus B et al: Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity. Cancer Cell, 2004, 6: 611-623
21. Khun FR, Nemunaitis J, Ganly I et al: A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med, 2000, 6: 879-885
22. Freytag SO, Khil M, Strieker H et al: Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer. Cancer Res, 2002, 62: 4968-4976
23. Market JM, Medlock MD, Rabkin SD et al: Conditionally replicating herpes simplex virus mutant, G207, for the treatment of malignant glioma: results of a phase I trial. Gene Ther, 2000, 7: 867-874
24. Liu P, Speck SH: Synergistic autoactivation of the Epstein-Barr virus immediate-early BRLFl promoter by Rta and Zta. Virology, 2003, 10: 199-206
25. Thorne SH, Hermiston T, Kirn D: Oncolytic virotherapy: approaches to tumor targeting and enhancing antitumor effects. Semi Oncol, 2005, 32: 537-548
26. Ramachandra M, Rahman A, Zou A: Re-engineering adenovirus regulatory pathways to enhance oncolytic specificity and efficacy. Nat Biotechnol, 2001, 19: 1035-1041