膀胱组织特异性溶瘤腺病毒在动物体内的生物分布及安全性评价
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摘要
目的：膀胱癌是泌尿系统常见的肿瘤之一,其发病率呈逐年上升趋势且治疗后复发率较高。利用膀胱组织特异性溶瘤腺病毒的基因治疗是一种很有前景的治疗策略。对于溶瘤腺病毒,除了肯定的药效学外,其毒性和安全性的问题也至关重要。目前关于膀胱组织特异性溶瘤腺病毒的生物分布和安全性评价的报道还比较少。在临床前安全性评价中,获得腺病毒E1A基因在靶向器官组织以外的表达和分布的数据,对于评价利用溶瘤腺病毒进行基因治疗的风险十分关键。因此,本课题针对我们课题组构建的膀胱组织特异性溶瘤腺病毒Ad-PSCAE-UP Ⅱ-E1A (APU-E1A)和Ad-PSCAE-UP Ⅱ-E1A-AR (APU-E1A-AR),研究该系列病毒的扩增、纯化、鉴定,以及在裸鼠皮下移植瘤模型中的生物分布和近期安全性评价,为今后该溶瘤腺病毒进入临床试验治疗膀胱癌提供基本数据和理论依据。
方法：我们利用膀胱组织特异性启动子UPⅡ启动溶瘤腺病毒E1A基因及E1A与雄激素受体AR的融合基因E1A-AR的表达,并在上游插入前列腺抗原增强子PSCAE增强UPⅡ的作用,构建了膀胱组织特异性溶瘤腺病毒APU-E1A和APU-E1A-AR。为了方便检测病毒在动物体内的复制,我们还利用萤火虫荧光素酶基因(LUC)构建了检测病毒Ad-PSCAE-UP Ⅱ-LUC (APU-LUC),通过LUC的检测实时观察病毒的复制情况。将得到的重组腺病毒在人胚肾293细胞(HEK293)中扩增,用氯化铯试剂盒进行纯化,用PCR的方法分别对溶瘤腺病毒中E1A、UP Ⅱ、PSCAE、AR, UP Ⅱ-E1A和UP Ⅱ-LUC各基因片段的表达进行鉴定,最后用TCIDso(50%组织培养感染病毒的剂量)的方法确定病毒的滴度。在前期试验已证实这些溶瘤腺病毒有效的基础上,我们利用人膀胱癌EJ细胞建立了裸鼠皮下移植瘤模型,并用不同剂量(5×107pfu,5×108pfu,5×109pfu)溶瘤腺病毒APU-E1A、APU-E1A-AR和APU-LUC进行瘤内注射。我们通过动物体重的测量、大体健康状况和行为学观察、血液中淋巴细胞百分比、血小板(platelet)数量及肝脏谷丙转氨酶(ALT)、谷草转氨酶(AST)水平的测定、各组织器官脏器系数的改变、宏观观察和H&E染色、免疫组化染色等实验研究溶瘤腺病毒对各组织器官的毒性反应。我们还通过提取注射溶瘤腺病毒APU-E1A、APU-E1A-AR后各组织器官中的E1A RNA及蛋白,用实时荧光定量PCR(qRT-PCR)的方法和Western Blot方法分别检测E1A基因和蛋白的分布和表达,通过检测注射了APU-LUC的动物各主要器官中LUC的表达,检测病毒在动物各组织器官中的复制情况。
结果：溶瘤腺病毒(APU-E1A, APU-E1A-AR)感染HEK293细胞后,出现了明显的细胞病变效应(CPE),确定了腺病毒的扩增反应；病毒纯化后OD260/OD280为1.2-1.24, TCID50/VP为0.98%-1%,最高感染滴度为1.2×1012IU/mL;溶瘤腺病毒中E1A、UP Ⅱ、PSCAE、AR, UP Ⅱ-E1A和UP Ⅱ-LUC基因的表达稳定。与注射了PBS的对照组动物相比,注射溶瘤腺病毒组的动物体重呈逐步上升趋势,大体健康状况和行为学观察未发现明显异常改变。注射了5×107pfu、5×108pfu及更高剂量5×109pfu溶瘤腺病毒APU-E1A及APU-E1A-AR的动物组,其血液学中淋巴细胞百分比、血小板数量无明显改变；注射5×109pfu溶瘤腺病毒动物组的肝脏转氨酶(AST,ALT)有轻微升高。通过解剖和大体观察未发现注射了溶瘤腺病毒动物的主要脏器如心、肝、脾、肺、肾、脑、胃、睾丸、精囊腺、甲状腺、膀胱等器官有出血、坏死、肿大等异常现象,各组动物平均脏器系数与对照组相比统计没有显著性差异。动物主要脏器的H&E染色和针对腺病毒E1A的免疫组化染色结果表明溶瘤腺病毒APU-E1A、APU-E1A-AR只在膀胱移植瘤组织内复制和表达,在其他器官中没有复制和表达。qRT-PCR检测结果表明溶瘤腺病毒E1A基因主要在动物移植瘤组织中表达,在肝脏中有少量表达,在其他脏器中没有表达；Western Blot检测结果表明E1A蛋白只在动物移植瘤组织中表达,在其他组织脏器中未检测到明显表达；LUC在肿瘤组织中的活性较高,而在其他组织内较低,差异有统计学意义。
结论：我们构建的膀胱组织特异性溶瘤腺病毒APU-E1A-AR和APU-E1A在HEK293细胞中的扩增方法可行,纯度、滴度符合要求；扩增后的溶瘤病毒中E1A、UP Ⅱ、PSCAE、AR, UP Ⅱ-E1A和UP Ⅱ-LUC基因的表达稳定。溶瘤腺病毒APU-E1A、APU-E1A-AR具有膀胱组织特异性,在5×107pfu和5×108pfu剂量瘤内注射裸鼠后,在动物的一般健康状况及行为学表现、血液学中淋巴细胞百分比及血小板的数量、肝脏转氨酶(AST,ALT)水平、各主要脏器的脏器系数及病理学表现、溶瘤腺病毒E1A基因及蛋白的表达水平中,未观察到明显毒性作用,相对安全。
Background:Bladder cancer is one of the most common tumors in urinary systerm, it's mobidity is yearly rising and the recurrence rate after treating is comparably high. Gene therapy based on bladder-specific conditionally replication competent adenoviruses are attractive therapeutics for bladder cancer. For oncolytic adenoviruses, besides the specific efficacy, the toxicity and safety are equally important. The previous works about safety evaluation for constructed bladder tissue specific adenovirus are poorly documented. Collection of data from preclinical studies to access the spread of adenovirus E1A transgene expression outside tumor tissue is of the utmost importance in assessing the risks associated with gene therapy. Thus, we investigated the amplification, purification, identification, biodistribution and body toxicity of bladder specific oncolytic adenovirus Ad-PSCAE-UPⅡ-E1A (APU-E1A) and Ad-PSCAE-UPⅡ-E1A-AR (APU-E1A-AR), providing meaningful information prior to embarking on human clinical trials.
Materials and Method:Conditionally replicate recombinant adenoviruses (CRADs) APU-E1A, APU-EIA-AR were constructed with bladder tissue specific Uroplakin Ⅱ (UP Ⅱ) promoter to induce the expression of Ad5E1A gene and E1A-AR fusing gene, and PSCAE was inserted at upstream of promoter to enhance the function of promoter. To examine adenovirus replication and distribution in mice, we also constructed the detection adenovirus Ad-PSCAE-UPⅡ-LUC (APU-LUC). These adenoviruses were propagated in HEK293cells and purified by cesium chloride gradient centrifugation. E1A, UP Ⅱ, PSCAE, PSCAE, AR, UPⅡ-El A and UP Ⅱ-LUC gene fragments in adenoviruses were indentified with PCR, and the viral titer was determined by TCID50(50%Tissue Culture Infective Dose) method. Based on the cytopathic and anti-tumor effect of bladder cancer, subcutaneous xenografts tumor in nude mice were made by human bladder cancer cell line EJ injection, then different doses (5×107pfu,5×108pfu,5×109pfu) of oncolytic adenoviruses (APU-E1A, APU-E1A-AR and APU-LUC) were intratumorally injected into xenografts. We then determined the toxicity through animal's body weight, general health and behavioral assessment, hematological (percentage of lymphocytes in white blood cell and platelets) and hepatic (Aspartate aminotransferase, AST and Alanine aminotransferase, ALT) toxicity evaluation, organ coefficient, macroscopic and microscopic postmortem analyses (H&E and immunohistochemical staining). The spread of the transgene E1A of adenoviruses were detected with qRT-PCR and Western blot. Virus replication and distribution were examined with APU-LUC administration and Luciferase Assay.
Results:After HEK293were transfected with oncolytic adenoviruses APU-E1A and APU-E1A-AR, the HEK293cells showed significant cytopathic effect (CPE), which confirmed the propagated reaction. After the adenoviruses were purified, OD260/OD280of viruses were1.2-1.24, TCID50/VP were0.98%-1%, and the higest infection unit was1.2×1012IU/ml. The expressions of gene E1A, UP Ⅱ, PSCAE, AR, UP Ⅱ-E1A and UP Ⅱ-LUC fragment were stable. Comparing with the control group, animal's body weight of groups which were injected with APU-E1A and APU-E1A-AR were rising stably, and general assessment did not reveal any alteration in general behavior. The hematological alterations (percentage of lymphocytes in white blood cell and platelets) of groups which were injected with5×107、5×10pfu or higher dose (5×109pfu) of APU-E1A and APU-E1A-AR showed no difference in comparison with PBS group, and only slight increased transaminases (AST and ALT) in contrast to PBS group at5×109pfu of APU-E1A and APU-E1A-AR were observed. After adenoviruses injection, through dissection and general observations, the major organs of animals such as heart, liver, spleen, lung, kidney, brain, stomach, testicles, seminal vesicle, thyroid, bladder and urethra were not observed any abnormal phenomena such as hemorrhage, necrosis and swelling. Statistics of average organ coefficient of animals had no significant difference compared with control group. H&E staining and immunohistochemical staining for adenovirus E1A gene showed that the oncolytic adenoviruses APU-E1A, APU-E1A-AR did not replicate and express outside of xenograft tumor tissue. E1A transgene were detected highly expressed in tumor and slightly expressed in liver tissue, and E1A protein did not disseminate to organs outside of xenograft tumor. Expression of LUC was much higher in xenograft tumor tissue comparing with other organs, which had significant statistical difference.
Conclusions:Our study showed that the recombinant oncolytic adenoviruses APU-E1A-AR and APU-E1A could be amplified in HEK293cells, the purity and titer of adenoviruses could meet the demand. The expressions of gene fragment E1A, UPⅡ, PSCAE, AR, UPⅡ-E1A and UP Ⅱ-LUC were stable after amplification and purification. APU-E1A-AR and APU-EIA had bladder cancer tissue specificity and appeared safe with5×107pfu and5×108 pfu intratumorally injection in mice, without any discernable effects on general health and behavior, hematological (percentage of lymphocytes in white blood cell and platelets) and hepatic (AST and ALT) evaluation, organ coefficient, macroscopic and microscopic postmortem analyses, as well as the E1A transgene and protein expression.
方法：我们利用膀胱组织特异性启动子UPⅡ启动溶瘤腺病毒E1A基因及E1A与雄激素受体AR的融合基因E1A-AR的表达,并在上游插入前列腺抗原增强子PSCAE增强UPⅡ的作用,构建了膀胱组织特异性溶瘤腺病毒APU-E1A和APU-E1A-AR。为了方便检测病毒在动物体内的复制,我们还利用萤火虫荧光素酶基因(LUC)构建了检测病毒Ad-PSCAE-UP Ⅱ-LUC (APU-LUC),通过LUC的检测实时观察病毒的复制情况。将得到的重组腺病毒在人胚肾293细胞(HEK293)中扩增,用氯化铯试剂盒进行纯化,用PCR的方法分别对溶瘤腺病毒中E1A、UP Ⅱ、PSCAE、AR, UP Ⅱ-E1A和UP Ⅱ-LUC各基因片段的表达进行鉴定,最后用TCIDso(50%组织培养感染病毒的剂量)的方法确定病毒的滴度。在前期试验已证实这些溶瘤腺病毒有效的基础上,我们利用人膀胱癌EJ细胞建立了裸鼠皮下移植瘤模型,并用不同剂量(5×107pfu,5×108pfu,5×109pfu)溶瘤腺病毒APU-E1A、APU-E1A-AR和APU-LUC进行瘤内注射。我们通过动物体重的测量、大体健康状况和行为学观察、血液中淋巴细胞百分比、血小板(platelet)数量及肝脏谷丙转氨酶(ALT)、谷草转氨酶(AST)水平的测定、各组织器官脏器系数的改变、宏观观察和H&E染色、免疫组化染色等实验研究溶瘤腺病毒对各组织器官的毒性反应。我们还通过提取注射溶瘤腺病毒APU-E1A、APU-E1A-AR后各组织器官中的E1A RNA及蛋白,用实时荧光定量PCR(qRT-PCR)的方法和Western Blot方法分别检测E1A基因和蛋白的分布和表达,通过检测注射了APU-LUC的动物各主要器官中LUC的表达,检测病毒在动物各组织器官中的复制情况。
结果：溶瘤腺病毒(APU-E1A, APU-E1A-AR)感染HEK293细胞后,出现了明显的细胞病变效应(CPE),确定了腺病毒的扩增反应；病毒纯化后OD260/OD280为1.2-1.24, TCID50/VP为0.98%-1%,最高感染滴度为1.2×1012IU/mL;溶瘤腺病毒中E1A、UP Ⅱ、PSCAE、AR, UP Ⅱ-E1A和UP Ⅱ-LUC基因的表达稳定。与注射了PBS的对照组动物相比,注射溶瘤腺病毒组的动物体重呈逐步上升趋势,大体健康状况和行为学观察未发现明显异常改变。注射了5×107pfu、5×108pfu及更高剂量5×109pfu溶瘤腺病毒APU-E1A及APU-E1A-AR的动物组,其血液学中淋巴细胞百分比、血小板数量无明显改变；注射5×109pfu溶瘤腺病毒动物组的肝脏转氨酶(AST,ALT)有轻微升高。通过解剖和大体观察未发现注射了溶瘤腺病毒动物的主要脏器如心、肝、脾、肺、肾、脑、胃、睾丸、精囊腺、甲状腺、膀胱等器官有出血、坏死、肿大等异常现象,各组动物平均脏器系数与对照组相比统计没有显著性差异。动物主要脏器的H&E染色和针对腺病毒E1A的免疫组化染色结果表明溶瘤腺病毒APU-E1A、APU-E1A-AR只在膀胱移植瘤组织内复制和表达,在其他器官中没有复制和表达。qRT-PCR检测结果表明溶瘤腺病毒E1A基因主要在动物移植瘤组织中表达,在肝脏中有少量表达,在其他脏器中没有表达；Western Blot检测结果表明E1A蛋白只在动物移植瘤组织中表达,在其他组织脏器中未检测到明显表达；LUC在肿瘤组织中的活性较高,而在其他组织内较低,差异有统计学意义。
结论：我们构建的膀胱组织特异性溶瘤腺病毒APU-E1A-AR和APU-E1A在HEK293细胞中的扩增方法可行,纯度、滴度符合要求；扩增后的溶瘤病毒中E1A、UP Ⅱ、PSCAE、AR, UP Ⅱ-E1A和UP Ⅱ-LUC基因的表达稳定。溶瘤腺病毒APU-E1A、APU-E1A-AR具有膀胱组织特异性,在5×107pfu和5×108pfu剂量瘤内注射裸鼠后,在动物的一般健康状况及行为学表现、血液学中淋巴细胞百分比及血小板的数量、肝脏转氨酶(AST,ALT)水平、各主要脏器的脏器系数及病理学表现、溶瘤腺病毒E1A基因及蛋白的表达水平中,未观察到明显毒性作用,相对安全。
Background:Bladder cancer is one of the most common tumors in urinary systerm, it's mobidity is yearly rising and the recurrence rate after treating is comparably high. Gene therapy based on bladder-specific conditionally replication competent adenoviruses are attractive therapeutics for bladder cancer. For oncolytic adenoviruses, besides the specific efficacy, the toxicity and safety are equally important. The previous works about safety evaluation for constructed bladder tissue specific adenovirus are poorly documented. Collection of data from preclinical studies to access the spread of adenovirus E1A transgene expression outside tumor tissue is of the utmost importance in assessing the risks associated with gene therapy. Thus, we investigated the amplification, purification, identification, biodistribution and body toxicity of bladder specific oncolytic adenovirus Ad-PSCAE-UPⅡ-E1A (APU-E1A) and Ad-PSCAE-UPⅡ-E1A-AR (APU-E1A-AR), providing meaningful information prior to embarking on human clinical trials.
Materials and Method:Conditionally replicate recombinant adenoviruses (CRADs) APU-E1A, APU-EIA-AR were constructed with bladder tissue specific Uroplakin Ⅱ (UP Ⅱ) promoter to induce the expression of Ad5E1A gene and E1A-AR fusing gene, and PSCAE was inserted at upstream of promoter to enhance the function of promoter. To examine adenovirus replication and distribution in mice, we also constructed the detection adenovirus Ad-PSCAE-UPⅡ-LUC (APU-LUC). These adenoviruses were propagated in HEK293cells and purified by cesium chloride gradient centrifugation. E1A, UP Ⅱ, PSCAE, PSCAE, AR, UPⅡ-El A and UP Ⅱ-LUC gene fragments in adenoviruses were indentified with PCR, and the viral titer was determined by TCID50(50%Tissue Culture Infective Dose) method. Based on the cytopathic and anti-tumor effect of bladder cancer, subcutaneous xenografts tumor in nude mice were made by human bladder cancer cell line EJ injection, then different doses (5×107pfu,5×108pfu,5×109pfu) of oncolytic adenoviruses (APU-E1A, APU-E1A-AR and APU-LUC) were intratumorally injected into xenografts. We then determined the toxicity through animal's body weight, general health and behavioral assessment, hematological (percentage of lymphocytes in white blood cell and platelets) and hepatic (Aspartate aminotransferase, AST and Alanine aminotransferase, ALT) toxicity evaluation, organ coefficient, macroscopic and microscopic postmortem analyses (H&E and immunohistochemical staining). The spread of the transgene E1A of adenoviruses were detected with qRT-PCR and Western blot. Virus replication and distribution were examined with APU-LUC administration and Luciferase Assay.
Results:After HEK293were transfected with oncolytic adenoviruses APU-E1A and APU-E1A-AR, the HEK293cells showed significant cytopathic effect (CPE), which confirmed the propagated reaction. After the adenoviruses were purified, OD260/OD280of viruses were1.2-1.24, TCID50/VP were0.98%-1%, and the higest infection unit was1.2×1012IU/ml. The expressions of gene E1A, UP Ⅱ, PSCAE, AR, UP Ⅱ-E1A and UP Ⅱ-LUC fragment were stable. Comparing with the control group, animal's body weight of groups which were injected with APU-E1A and APU-E1A-AR were rising stably, and general assessment did not reveal any alteration in general behavior. The hematological alterations (percentage of lymphocytes in white blood cell and platelets) of groups which were injected with5×107、5×10pfu or higher dose (5×109pfu) of APU-E1A and APU-E1A-AR showed no difference in comparison with PBS group, and only slight increased transaminases (AST and ALT) in contrast to PBS group at5×109pfu of APU-E1A and APU-E1A-AR were observed. After adenoviruses injection, through dissection and general observations, the major organs of animals such as heart, liver, spleen, lung, kidney, brain, stomach, testicles, seminal vesicle, thyroid, bladder and urethra were not observed any abnormal phenomena such as hemorrhage, necrosis and swelling. Statistics of average organ coefficient of animals had no significant difference compared with control group. H&E staining and immunohistochemical staining for adenovirus E1A gene showed that the oncolytic adenoviruses APU-E1A, APU-E1A-AR did not replicate and express outside of xenograft tumor tissue. E1A transgene were detected highly expressed in tumor and slightly expressed in liver tissue, and E1A protein did not disseminate to organs outside of xenograft tumor. Expression of LUC was much higher in xenograft tumor tissue comparing with other organs, which had significant statistical difference.
Conclusions:Our study showed that the recombinant oncolytic adenoviruses APU-E1A-AR and APU-E1A could be amplified in HEK293cells, the purity and titer of adenoviruses could meet the demand. The expressions of gene fragment E1A, UPⅡ, PSCAE, AR, UPⅡ-E1A and UP Ⅱ-LUC were stable after amplification and purification. APU-E1A-AR and APU-EIA had bladder cancer tissue specificity and appeared safe with5×107pfu and5×108 pfu intratumorally injection in mice, without any discernable effects on general health and behavior, hematological (percentage of lymphocytes in white blood cell and platelets) and hepatic (AST and ALT) evaluation, organ coefficient, macroscopic and microscopic postmortem analyses, as well as the E1A transgene and protein expression.
引文
[1]Jemal A, Siegel R, Ward E, et al. Cancer statistics,2008. CA Cancer J Clin,2008,58(2): 71-96.
[2]温登瑰,单保恩,张思维,et al.2003—2007年中国肿瘤登记地区膀胱癌的发病与死亡分析.T U M O R,2012,32(4):256-262.
[3]Zieger K, Dyrskjot L, Wiuf C, et al. Role of activating fibroblast growth factor receptor 3 mutations in the development of bladder tumors. Clin Cancer Res,2005,11(21): 7709-7719.
[4]Chan KS, Espinosa I, Chao M, et al. Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Proc Natl Acad Sci U S A,2009,106(33):14016-14021.
[5]Babjuk M, Oosterlinck W, Sylvester R, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update. Eur Urol,2011,59(6):997-1008.
[6]Liu TC, Kirn D. Gene therapy progress and prospects cancer:oncolytic viruses. Gene Ther,2008,15(12):877-884.
[7]Mahller YY, Williams JP, Baird WH, et al. Neuroblastoma cell lines contain pluripotent tumor initiating cells that are susceptible to a targeted oncolytic virus. PLoS One,2009, 4(1):e4235.
[8]Kelly E, Russell SJ. History of oncolytic viruses:genesis to genetic engineering. Mol Ther,2007,15(4):651-659.
[9]Kanerva A, Hemminki A. Adenoviruses for treatment of cancer. Ann Med,2005,37(1): 33-43.
[10]Power AT, Bell JC. Cell-based delivery of oncolytic viruses:a new strategic alliance for a biological strike against cancer. Mol Ther,2007,15(4):660-665.
[11]Raki M, Rein DT, Kanerva A, et al. Gene transfer approaches for gynecological diseases. Mol Ther,2006,14(2):154-163.
[12]Kanerva A, Raki M, Hemminki A. Gene therapy of gynaecological diseases. Expert Opin Biol Ther,2007,7(9):1347-1361.
[13]Russell WC. Update on adenovirus and its vectors. J Gen Virol,2000,81(Pt 11): 2573-2604.
[14]Wickham TJ, Mathias P, Cheresh DA, et al. Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalization but not virus attachment. Cell,1993,73(2):309-319.
[15]Fueyo J, Gomez-Manzano C, Alemany R, et al. A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo. Oncogene,2000,19(1):2-12.
[16]Heise C, Hermiston T, Johnson L, et al. An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy. Nat Med,2000,6(10):1134-1139.
[17]Wang H, Satoh M, Abe H, et al. Oncolytic viral therapy by bladder instillation using an E1A, E1B double-restricted adenovirus in an orthotopic bladder cancer model. Urology, 2006,68(3):674-681.
[18]Sherr CJ. Cancer cell cycles. Science,1996,274(5293):1672-1677.
[19]Hsieh JL, Wu CL, Lee CH, et al. Hepatitis B virus X protein sensitizes hepatocellular carcinoma cells to cytolysis induced by E1B-deleted adenovirus through the disruption of p53 function. Clin Cancer Res,2003,9(1):338-345.
[20]Hsieh JL, Wu CL, Lai MD, et al. Gene therapy for bladder cancer using E1B-55 kD-deleted adenovirus in combination with adenoviral vector encoding plasminogen kringles 1-5. Br J Cancer,2003,88(9):1492-1499.
[21]Nakashima H, Kaur B, Chiocca EA. Directing systemic oncolytic viral delivery to tumors via carrier cells. Cytokine Growth Factor Rev,2010,21(2-3):119-126.
[22]Saukkonen K, Hemminki A. Tissue-specific promoters for cancer gene therapy. Expert Opin Biol Ther,2004,4(5):683-696.
[23]Wang D, Wang Z, Tian J, et al. Prostate stem cell antigen enhancer and uroplakin Ⅱ promoter based bladder cancer targeted tissue-specific vector. Urol Oncol,2010,28(2): 164-169.
[24]Terao S, Shirakawa T, Kubo S, et al. Midkine promoter-based conditionally replicative adenovirus for targeting midkine-expressing human bladder cancer model. Urology, 2007,70(5):1009-1013.
[25]Shirakawa T, Hamada K, Zhang Z, et al. A cox-2 promoter-based replication-selective adenoviral vector to target the cox-2-expressing human bladder cancer cells. Clin Cancer Res,2004,10(13):4342-4348.
[26]Melquist JJ, Kacka M, Li Y, et al. Conditionally replicating adenovirus-mediated gene therapy in bladder cancer:an orthotopic in vivo model. Urol Oncol,2006,24(4): 362-371.
[27]Zhang J, Ramesh N, Chen Y, et al. Identification of human uroplakin Ⅱ promoter and its use in the construction of CG8840, a urothelium-specific adenovirus variant that eliminates established bladder tumors in combination with docetaxel. Cancer Res,2002, 62(13):3743-3750.
[28]He XD, Wang ZP, Wei HY, et al. Construction of urothelium-specific recombinant adenovirus and its inhibition in bladder cancer cell. Urol Int,2009,82(2):209-213.
[29]Lanson NA, Jr., Friedlander PL, Schwarzenberger P, et al. Replication of an adenoviral vector controlled by the human telomerase reverse transcriptase promoter causes tumor-selective tumor lysis. Cancer Res,2003,63(22):7936-7941.
[30]Gidekel S, Pizov G, Bergman Y, et al. Oct-3/4 is a dose-dependent oncogenic fate determinant. Cancer Cell,2003,4(5):361-370.
[31]Atlasi Y, Mowla SJ, Ziaee SA, et al. OCT-4, an embryonic stem cell marker, is highly expressed in bladder cancer. Int J Cancer,2007,120(7):1598-1602.
[32]Wu CL, Shieh GS, Chang CC, et al. Tumor-selective replication of an oncolytic adenovirus carrying oct-3/4 response elements in murine metastatic bladder cancer models. Clin Cancer Res,2008,14(4):1228-1238.
[33]Ramesh N, Ge Y, Ennist DL, et al. CG0070, a conditionally replicating granulocyte macrophage colony-stimulating factor--armed oncolytic adenovirus for the treatment of bladder cancer. Clin Cancer Res,2006,12(1):305-313.
[34]Hu J, Xuan X, Han C, et al. Anti-tumor function of double-promoter regulated adenovirus carrying SEA gene, in the treatment of bladder cancer. Cell Biochem Biophys,2012,62(2):353-359.
[35]李怀富.表达金黄色葡萄球菌肠毒素A基因的高靶向、双调控溶瘤腺病毒载体的构建、鉴定及其抗膀胱肿瘤作用.中华实验外科杂志,2009,26(8)：1052-1054.
[36]Bauerschmitz GJ, Guse K, Kanerva A, et al. Triple-targeted oncolytic adenoviruses featuring the cox2 promoter, E1A transcomplementation, and serotype chimerism for enhanced selectivity for ovarian cancer cells. Mol Ther,2006,14(2):164-174.
[37]Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer,2005, 5(4):275-284.
[38]Rich JN. Cancer stem cells in radiation resistance. Cancer Res,2007,67(19): 8980-8984.
[39]Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature,2006,444(7120):756-760.
[40]Fukazawa T, Matsuoka J, Yamatsuji T, et al. Adenovirus-mediated cancer gene therapy and virotherapy (Review). Int J Mol Med,2010,25(1):3-10.
[41]Alonso MM, Jiang H, Gomez-Manzano C, et al. Targeting brain tumor stem cells with oncolytic adenoviruses. Methods Mol Biol,2012,797(111-125.
[42]Hoti N, Chowdhury WH, Mustafa S, et al. Armoring CRAds with p21/Waf-1 shRNAs: the next generation of oncolytic adenoviruses. Cancer Gene Ther,2010,17(8):585-597.
[43]Khuri 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(8):879-885.
[44]Vasey PA, Shulman LN, Campos S, et al. Phase Ⅰ trial of intraperitoneal injection of the E1B-55-kd-gene-deleted adenovirus ONYX-015 (d11520) given on days 1 through 5 every 3 weeks in patients with recurrent/refractory epithelial ovarian cancer. J Clin Oncol,2002,20(6):1562-1569.
[45]Reid T, Galanis E, Abbruzzese J, et al. Hepatic arterial infusion of a replication-selective oncolytic adenovirus (d11520):phase Ⅱ viral, immunologic, and clinical endpoints. Cancer Res,2002,62(21):6070-6079.
[46]Nemunaitis J, Senzer N, Sarmiento S, et al. A phase Ⅰ trial of intravenous infusion of ONYX-015 and enbrel in solid tumor patients. Cancer Gene Ther,2007,14(11): 885-893.
[47]Demers GW, Johnson DE, Tsai V, et al. Pharmacologic indicators of antitumor efficacy for oncolytic virotherapy. Cancer Res,2003,63(14):4003-4008.
[48]Kumar S, Gao L, Yeagy B, et al. Virus combinations and chemotherapy for the treatment of human cancers. Curr Opin Mol Ther,2008,10(4):371-379.
[49]Hemminki A. From molecular changes to customised therapy. Eur J Cancer,2002,38(3): 333-338.
[50]Burke J. Virus therapy for bladder cancer. Cytokine Growth Factor Rev,2010,21(2-3): 99-102.
[51]Ganly I, Kirn D, Eckhardt G, et al. A phase I study of Onyx-015, an E1B attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer. Clin Cancer Res,2000,6(3):798-806.
[52]Jiang H, Gomez-Manzano C, Lang FF, et al. Oncolytic adenovirus:preclinical and clinical studies in patients with human malignant gliomas. Curr Gene Ther,2009,9(5): 422-427.
[53]Freytag SO, Stricker H, Peabody J, et al. Five-year follow-up of trial of replication-competent adenovirus-mediated suicide gene therapy for treatment of prostate cancer. Mol Ther,2007,15(3):636-642.
[54]Freytag SO, Khil M, Stricker 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(17):4968-4976.
[55]Small EJ, Carducci MA, Burke JM, et al. A phase I trial of intravenous CG7870, a replication-selective, prostate-specific antigen-targeted oncolytic adenovirus, for the treatment of hormone-refractory, metastatic prostate cancer. Mol Ther,2006,14(1): 107-117.
[56]DeWeese TL, van der Poel H, Li S, et al. A phase I trial of CV706, a replication-competent, PSA selective oncolytic adenovirus, for the treatment of locally recurrent prostate cancer following radiation therapy. Cancer Res,2001,61(20): 7464-7472.
[57]Page JG, Tian B, Schweikart K, et al. Identifying the safety profile of a novel infectivity-enhanced conditionally replicative adenovirus, Ad5-delta24-RGD, in anticipation of a phase I trial for recurrent ovarian cancer. Am J Obstet Gynecol,2007, 196(4):389 e381-389; discussion 389 e389-310.
[58]Dobbelstein M. Replicating adenoviruses in cancer therapy. Curr Top Microbiol Immunol,2004,273(8):291-334.
[59]Chiocca EA, Abbed KM, Tatter S, et al. A phase I open-label, dose-escalation, multi-institutional trial of injection with an EIB-Attenuated adenovirus, ONYX-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting. Mol Ther,2004,10(5):958-966.
[60]Ries S, Korn WM. ONYX-015:mechanisms of action and clinical potential of a replication-selective adenovirus. Br J Cancer,2002,86(1):5-11.
[61]Mulvihill S, Warren R, Venook A, et al. Safety and feasibility of injection with an E1B-55 kDa gene-deleted, replication-selective adenovirus (ONYX-015) into primary carcinomas of the pancreas:a phase I trial. Gene Ther,2001,8(4):308-315.
[62]Nemunaitis J, Cunningham C, Tong A, et al. Pilot trial of intravenous infusion of a replication-selective adenovirus (ONYX-015) in combination with chemotherapy or IL-2 treatment in refractory cancer patients. Cancer Gene Ther,2003,10(5):341-352.
[63]Burke JM, Lamm DL, Meng MV, et al. A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer. J Urol,2012,188(6):2391-2397.
[64]Chang J, Zhao X, Wu X, et al. A Phase I study of KH901, a conditionally replicating granulocyte-macrophage colony-stimulating factor:armed oncolytic adenovirus for the treatment of head and neck cancers. Cancer Biol Ther,2009,8(8):676-682.
[65]Pesonen S, Diaconu I, Kangasniemi L, et al. Oncolytic immunotherapy of advanced solid tumors with a CD40L-expressing replicating adenovirus:assessment of safety and immunologic responses in patients. Cancer Res,2012,72(7):1621-1631.
[66]Kimball KJ, Preuss MA, Barnes MN, et al. A phase I study of a tropism-modified conditionally replicative adenovirus for recurrent malignant gynecologic diseases. Clin Cancer Res,2010,16(21):5277-5287.
[67]Yuan ZY, Zhang L, Li S, et al. Safety of an E1B deleted adenovirus administered intratumorally to patients with cancer. Ai Zheng,2003,22(3):310-313.
[68]Lu W, Zheng S, Li XF, et al. Intra-tumor injection of H101, a recombinant adenovirus, in combination with chemotherapy in patients with advanced cancers:a pilot phase Ⅱ clinical trial. World J Gastroenterol,2004,10(24):3634-3638.
[69]Yu W, Fang H. Clinical trials with oncolytic adenovirus in China. Curr Cancer Drug Targets,2007,7(2):141-148.
[70]Xu RH, Yuan ZY, Guan ZZ, et al. Phase Ⅱ clinical study of intratumoral H101, an E1B deleted adenovirus, in combination with chemotherapy in patients with cancer. Ai Zheng, 2003,22(12):1307-1310.
[71]Xia ZJ, Chang JH, Zhang L, et al. Phase Ⅲ randomized clinical trial of intratumoral injection of E1B gene-deleted adenovirus (H101) combined with cisplatin-based chemotherapy in treating squamous cell cancer of head and neck or esophagus. Ai Zheng,2004,23(12):1666-1670.
[72]胡永超.溶瘤腺病毒治疗实体瘤安全性及临床疗效的初步评价.中华临床医师杂志(电子版),2011,5(9)：2537-2542.
[73]Breitbach CJ, Burke J, Jonker D, et al. Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans. Nature,2011,477(7362):99-102.
[74]Chang JY, Xia W, Shao R, et al. Inhibition of intratracheal lung cancer development by systemic delivery of E1A. Oncogene,1996,13(7):1405-1412.
[75]Shao R, Karunagaran D, Zhou BP, et al. Inhibition of nuclear factor-kappaB activity is involved in E1A-mediated sensitization of radiation-induced apoptosis. J Biol Chem, 1997,272(52):32739-32742.
[76]Zhu H, Zhang ZA, Xu C, et al. Targeting gene expression of the mouse uroplakin II promoter to human bladder cells. Urol Res,2003,31(1):17-21.
[77]Latham JP, Searle PF, Mautner V, et al. Prostate-specific antigen promoter/enhancer driven gene therapy for prostate cancer:construction and testing of a tissue-specific adenovirus vector. Cancer Res,2000,60(2):334-341.
[78]Jain A, Lam A, Vivanco I, et al. Identification of an androgen-dependent enhancer within the prostate stem cell antigen gene. Mol Endocrinol,2002,16(10):2323-2337.
[79]Hoti N, Li Y, Chen CL, et al. Androgen receptor attenuation of Ad5 replication: implications for the development of conditionally replication competent adenoviruses. Mol Ther,2007,15(8):1495-1503.
[80]Zhai Z, Wang Z, Fu S, et al. Antitumor effects of bladder cancer-specific adenovirus carrying E1A-androgen receptor in bladder cancer. Gene Ther,2012,19(11):1065-1074.
[81]Kanegae Y, Makimura M, Saito I. A simple and efficient method for purification of infectious recombinant adenovirus. Jpn J Med Sci Biol,1994,47(3):157-166.
[82]Vail DM, MacEwen EG. Spontaneously occurring tumors of companion animals as models for human cancer. Cancer Invest,2000,18(8):781-792.
[83]Knapp DW, Waters DJ. Naturally occurring cancer in pet dogs:important models for developing improved cancer therapy for humans. Mol Med Today,1997,3(1):8-11.
[84]Yamamoto S, Tatematsu M, Yamamoto M, et al. Clonal analysis of urothelial carcinomas in C3H/HeN<-->BALB/c chimeric mice treated with N-butyl-N-(4-hydroxybutyl)nitrosamine. Carcinogenesis,1998,19(5):855-860.
[85]Steinberg GD, Brendler CB, Ichikawa T, et al. Characterization of an N-methyl-N-nitrosourea-induced autochthonous rat bladder cancer model. Cancer Res, 1990,50(20):6668-6674.
[86]Jiang F, Zhou XM. A model of orthotopic murine bladder (MBT-2) tumor implants. Urol Res,1997,25(3):179-182.
[87]Vandepitte J, Maes J, Van Cleynenbreugel B, et al. An improved orthotopic rat bladder tumor model using Dil-loaded fluorescent AY-27 cells. Cancer Biol Ther,9(12): 986-993.
[88]李凌.一种新的高转移膀胱癌动物模型的建立.中华实验外科杂志,2002,19(1)：78-79.
[89]Li F, Ye Z, Yang W. Evaluation of tumor formation of three bladder cancer cell lines in nude mice. J Huazhong Univ Sci Technolog Med Sci,2011,31(2):210-214.
[90]Hadaschik BA, Black PC, Sea JC, et al. A validated mouse model for orthotopic bladder cancer using transurethral tumour inoculation and bioluminescence imaging. BJU Int, 2007,100(6):1377-1384.
[91]Engler H, Machemer T, Philopena J, et al. Acute hepatotoxicity of oncolytic adenoviruses in mouse models is associated with expression of wild-type Ela and induction of TNF-alpha. Virology,2004,328(1):52-61.
[92]Shayakhmetov DM, Gaggar A, Ni S, et al. Adenovirus binding to blood factors results in liver cell infection and hepatotoxicity. J Virol,2005,79(12):7478-7491.
[93]Cascallo M, Alonso MM, Rojas JJ, et al. Systemic toxicity-efficacy profile of ICOVIR-5, a potent and selective oncolytic adenovirus based on the pRB pathway. Mol Ther,2007, 15(9):1607-1615.
[94]Tsukuda K, Wiewrodt R, Molnar-Kimber K, et al. An E2F-responsive replication-selective adenovirus targeted to the defective cell cycle in cancer cells: potent antitumoral efficacy but no toxicity to normal cell. Cancer Res,2002,62(12): 3438-3447.
[95]Lovatt A. Applications of quantitative PCR in the biosafety and genetic stability assessment of biotechnology products. J Biotechnol,2002,82(3):279-300.
[96]Carney BJ, Shah K. Migration and fate of therapeutic stem cells in different brain disease models. Neuroscience,2011,197(10):37-47.
[97]Dmitriev I, Krasnykh V, Miller CR, et al. An adenovirus vector with genetically modified fibers demonstrates expanded tropism via utilization of a coxsackievirus and adenovirus receptor-independent cell entry mechanism. J Virol,1998,72(12): 9706-9713.
[98]Li Y, Pong RC, Bergelson JM, et al. Loss of adenoviral receptor expression in human bladder cancer cells:a potential impact on the efficacy of gene therapy. Cancer Res, 1999,59(2):325-330.
[99]Sachs MD, Rauen KA, Ramamurthy M, et al. Integrin alpha(v) and coxsackie adenovirus receptor expression in clinical bladder cancer. Urology,2002,60(3): 531-536.
[100]Havenga MJ, Lemckert AA, Ophorst OJ, et al. Exploiting the natural diversity in adenovirus tropism for therapy and prevention of disease. J Virol,2002,76(9): 4612-4620.
[101]Iguchi K, Sakurai F, Tomita K, et al. Efficient antitumor effects of carrier cells loaded with a fiber-substituted conditionally replicating adenovirus on CAR-negative tumor cells. Cancer Gene Ther,2012,19(2):118-125.
[102]Wakayama M, Abei M, Kawashima R, et al. E1A, E1B double-restricted adenovirus with RGD-fiber modification exhibits enhanced oncolysis for CAR-deficient biliary cancers. Clin Cancer Res,2007,13(10):3043-3050.
[103]Dehari H, Ito Y, Nakamura T, et al. Enhanced antitumor effect of RGD fiber-modified adenovirus for gene therapy of oral cancer. Cancer Gene Ther,2003,10(1):75-85.
[104]Suzuki K, Fueyo J, Krasnykh V, et al. A conditionally replicative adenovirus with enhanced infectivity shows improved oncolytic potency. Clin Cancer Res,2001,7(1): 120-126.
[105]Lavilla-Alonso S, Bauerschmitz G, Abo-Ramadan U, et al. Adenoviruses with an alphavbeta integrin targeting moiety in the fiber shaft or the HI-loop increase tumor specificity without compromising antitumor efficacy in magnetic resonance imaging of colorectal cancer metastases. J Transl Med,2010,8(2):80-87.
[106]Ranki T, Kanerva A, Ristimaki A, et al. A heparan sulfate-targeted conditionally replicative adenovirus, Ad5.pk7-Delta24, for the treatment of advanced breast cancer. Gene Ther,2007,14(1):58-67.
[107]van der Poel HG, Molenaar B, van Beusechem VW, et al. Epidermal growth factor receptor targeting of replication competent adenovirus enhances cytotoxicity in bladder cancer. J Urol,2002,168(1):266-272.
[108]Mizuguchi H, Sasaki T, Kawabata K, et al. Fiber-modified adenovirus vectors mediate efficient gene transfer into undifferentiated and adipogenic-differentiated human mesenchymal stem cells. Biochem Biophys Res Commun,2005,332(4):1101-1106.
[109]Hakkarainen T, Sarkioja M, Lehenkari P, et al. Human mesenchymal stem cells lack tumor tropism but enhance the antitumor activity of oncolytic adenoviruses in orthotopic lung and breast tumors. Hum Gene Ther,2007,18(7):627-641.
[110]Zhao Y, Li Y, Wang Q, et al. Increased antitumor capability of fiber-modified adenoviral vector armed with TRAIL against bladder cancers. Mol Cell Biochem,2011,353(1-2): 93-99.
[111]Shieh GS, Shiau AL, Yo YT, et al. Low-dose etoposide enhances telomerase-dependent adenovirus-mediated cytosine deaminase gene therapy through augmentation of adenoviral infection and transgene expression in a syngeneic bladder tumor model. Cancer Res,2006,66(20):9957-9966.
[112]Okegawa T, Nutahara K, Pong RC, et al. Enhanced transgene expression in urothelial cancer gene therapy with histone deacetylase inhibitor. J Urol,2005,174(2):747-752.
[113]Lupold SE, Kudrolli TA, Chowdhury WH, et al. A novel method for generating and screening peptides and libraries displayed on adenovirus fiber. Nucleic Acids Res,2007, 35(20):e138.
[114]Lilly JD, Parsons CL. Bladder surface glycosaminoglycans is a human epithelial permeability barrier. Surg Gynecol Obstet,1990,171(6):493-496.
[115]Ratliff TL. Identification of pretreatment agents to enhance adenovirus infection of bladder epithelium. J Urol,2005,173(6):2198-2199.
[116]Ranki T, Sarkioja M, Hakkarainen T, et al. Systemic efficacy of oncolytic adenoviruses in imagable orthotopic models of hormone refractory metastatic breast cancer. Int J Cancer,2007,121(1):165-174.
[117]Kanerva A, Zinn KR, Chaudhuri TR, et al. Enhanced therapeutic efficacy for ovarian cancer with a serotype 3 receptor-targeted oncolytic adenovirus. Mol Ther,2003,8(3): 449-458.
[1]Dean M,Fojo T,Bates S.Tumour stem cells and drug resistance[J].Nat Rev Cancer,2005,5(4):275-284.
[2]Liu TC,Kirn D.Gene therapy progress and prospects cancer:oncolytic viruses[J].Gene Ther, 2008,15(12):877-884.
[3]Mahller YY.Williams JP,Baird WH,et al.Neuroblastoma cell lines contain pluripotent tumor initiating cells that are susceptible to a targeted oncolytic virus[J].PLoS One,2009,4(1):e4235.
[4]Jordan CT.Cancer stem cells:controversial or just misunderstood?[J].Cell Stem Cell,2009,4(3):203-205.
[5]Bonnet D,Dick JE.Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell[J].Nat Med,1997,3(7):730-737.
[6]Al-Hajj M,Wicha MS,Benito-Hernandez A,et al.Prospective identification of tumorigenic breast cancer cells[J].Proc Natl Acad Sci U S A,2003,100(7):3983-3988.
[7]Ponti D,Costa A,Zaffaroni N,et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties[J].Cancer Res,2005,65(13):5506-5511.
[8]Singh SK,Hawkins C,Clarke ID,et al.Identification of human brain tumour initiating cells[J].Nature,2004,432(7015):396-401.
[9]Gibbs CP,Kukekov VG,Reith JD,et al.Stem-like cells in bone sarcomas:implications for tumorigenesis[J].Neoplasia,2005,7(11):967-976.
[10]O'Brien CA,Pollett A,Gallinger S,et al.A human colon cancer cell capable of initiating tumour growth in immunodeficient mice[J].Nature,2007,445(7123):106-110.
[11]Dalerba P,Dylla SJ,Park IK,et al.Phenotypic characterization of human colorectal cancer stem cells[J].Proc Natl Acad Sci U S A,2007,104(24):10158-10163.
[12]Prince ME.Sivanandan R,Kaczorowski A,et al.Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma[J].Proc Natl Acad Sci U S A,2007,104(3):973-978.
[13]Ma S,Chan KW,Hu L,et al.Identification and characterization of tumorigenic liver cancer stem/progenitor cells[J].Gastroenterology,2007,132(7):2542-2556.
[14]Ma S,Chan KW,Lee TK,et al.Aldehyde dehydrogenase discriminates the CD 133 liver cancer stem cell populations[J].Mol Cancer Res,2008,6(7):1146-1153.
[15]Kim CF,Jackson EL,Woolfenden AE,et al.Identification of bronchioalveolar stem cells in normal lung and lung cancer[J].Cell,2005,121(6):823-835.
[16]Li C,Lee CJ,Simeone DM.Identification of human pancreatic cancer stem cells[J].Methods Mol Biol,2009,568:161-173.
[17]Xin L,Lawson DA,Witte ON.The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis[J].Proc Natl Acad Sci U S A,2005,102(19):6942-6947.
[18]Chan KS,Espinosa I,Chao M,et al.Identification,molecular characterization,clinical prognosis,and therapeutic targeting of human bladder tumor-initiating cells[J].Proc Natl Acad Sci US A,2009,106(33):14016-14021.
[19]Bisson I.Prowse DM.WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics[J].Cell Res,2009,19(6):683-697.
[20]Rich JN.Cancer stem cells in radiation resistance[J].Cancer Res,2007,67(19):8980-8984.
[21]Bao S,Wu Q,McLendon RE,et al.Glioma stem cells promote radioresistance by preferential activation of the DNA damage response[J].Nature,2006,444(7120):756-760.
[22]Kelly E,Russell SJ.History of oncolytic viruses:genesis to genetic engineering[J].Mol Ther, 2007,15(4):651-659.
[23]Kanerva A,Raki M,Hemminki A.Gene therapy of gynaecological diseases[J].Expert Opin Biol Ther, 2007,7(9):1347-1361.
[24]Nakashima H,Kaur B,Chiocca EA.Directing systemic oncolytic viral delivery to tumors via carrier cells[J].Cytokine Growth Factor Rev,2010,21(2-3):119-126.
[25]Fukazawa T,Matsuoka J,Yamatsuji T,et al.Adenovirus-mediated cancer gene therapy and virotherapy (Review)[J].Int J Mol Med,2010,25(1):3-10.
[26]Alonso MM,Jiang H,Gomez-Manzano C,et al.Targeting brain tumor stem cells with oncolytic adenoviruses[J].Methods Mol Biol 2012,797:111-125.
[27]Hoti N.Chowdhury WH,Mustafa S,et al.Armoring CRAds with p21/Waf-1 shRNAs:the next generation of oncolytic adenoviruses[J].Cancer Gene Ther,2010,17(8):585-597.
[28]Eriksson M,Guse K,Bauerschmitz G,et al.Oncolytic adenoviruses kill breast cancer initiating CD44+CD24-/low cells[J].Mol Ther,2007,15(12):2088-2093.
[29]Ranki T,Kanerva A,Ristimaki A,et al.A heparan sulfate-targeted conditionally replicative adenovirus,Ad5.pk7-Delta24,for the treatment of advanced breast cancer[J].Gene Ther,2007,14(1):58-67.
[30]Ranki T,Sarkioja M,Hakkarainen T,et al.Systemic efficacy of oncolytic adenoviruses in imagable orthotopic models of hormone refractory metastatic breast cancer[J].Int J Cancer,2007,121(1):165-174.
[31]Rein DT,Volkmer A,Beyer IM,et al.Treatment of chemotherapy resistant ovarian cancer with a MDR1 targeted oncolytic adenovirus [J].Gynecol Oncol,2011,123(1):138-146.
[32]Pesonen S,Nokisalmi P,Escutenaire S,et al.Prolonged systemic circulation of chimeric oncolytic adenovirus Ad5/3-Cox2L-D24 in patients with metastatic and refractory solid tumors[J].Gene Ther, 2011,17(7):892-904.
[33]Doloff JC,Jounaidi Y,Waxman DJ.Dual E1A oncolytic adenovirus:targeting tumor heterogeneity with two independent cancer-specific promoter elements,DF3/MUC1 and hTERT[J].Cancer Gene Ther,2011,18(3):153-166.
[34]Skog J,Edlund K,Bergenheim AT,et al.Adenoviruses 16 and CV23 efficiently transduce human low-passage brain tumor and cancer stem cells[J].Mol Ther 2007,15(12):2140-2145.
[35]Jiang H,Gomez-Manzano C,Aoki H,et al.Examination of the therapeutic potential of Delta-24-RGD in brain tumor stem cells:role of autophagic cell death[J].J Natl Cancer Inst 2007,99(8):1410-1414.
[36]Carney BJ,Shah K.Migration and fate of therapeutic stem cells in different brain disease models[J].Neuroscience,2011,197:37-47.
[2]温登瑰,单保恩,张思维,et al.2003—2007年中国肿瘤登记地区膀胱癌的发病与死亡分析.T U M O R,2012,32(4):256-262.
[3]Zieger K, Dyrskjot L, Wiuf C, et al. Role of activating fibroblast growth factor receptor 3 mutations in the development of bladder tumors. Clin Cancer Res,2005,11(21): 7709-7719.
[4]Chan KS, Espinosa I, Chao M, et al. Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Proc Natl Acad Sci U S A,2009,106(33):14016-14021.
[5]Babjuk M, Oosterlinck W, Sylvester R, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update. Eur Urol,2011,59(6):997-1008.
[6]Liu TC, Kirn D. Gene therapy progress and prospects cancer:oncolytic viruses. Gene Ther,2008,15(12):877-884.
[7]Mahller YY, Williams JP, Baird WH, et al. Neuroblastoma cell lines contain pluripotent tumor initiating cells that are susceptible to a targeted oncolytic virus. PLoS One,2009, 4(1):e4235.
[8]Kelly E, Russell SJ. History of oncolytic viruses:genesis to genetic engineering. Mol Ther,2007,15(4):651-659.
[9]Kanerva A, Hemminki A. Adenoviruses for treatment of cancer. Ann Med,2005,37(1): 33-43.
[10]Power AT, Bell JC. Cell-based delivery of oncolytic viruses:a new strategic alliance for a biological strike against cancer. Mol Ther,2007,15(4):660-665.
[11]Raki M, Rein DT, Kanerva A, et al. Gene transfer approaches for gynecological diseases. Mol Ther,2006,14(2):154-163.
[12]Kanerva A, Raki M, Hemminki A. Gene therapy of gynaecological diseases. Expert Opin Biol Ther,2007,7(9):1347-1361.
[13]Russell WC. Update on adenovirus and its vectors. J Gen Virol,2000,81(Pt 11): 2573-2604.
[14]Wickham TJ, Mathias P, Cheresh DA, et al. Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalization but not virus attachment. Cell,1993,73(2):309-319.
[15]Fueyo J, Gomez-Manzano C, Alemany R, et al. A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo. Oncogene,2000,19(1):2-12.
[16]Heise C, Hermiston T, Johnson L, et al. An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy. Nat Med,2000,6(10):1134-1139.
[17]Wang H, Satoh M, Abe H, et al. Oncolytic viral therapy by bladder instillation using an E1A, E1B double-restricted adenovirus in an orthotopic bladder cancer model. Urology, 2006,68(3):674-681.
[18]Sherr CJ. Cancer cell cycles. Science,1996,274(5293):1672-1677.
[19]Hsieh JL, Wu CL, Lee CH, et al. Hepatitis B virus X protein sensitizes hepatocellular carcinoma cells to cytolysis induced by E1B-deleted adenovirus through the disruption of p53 function. Clin Cancer Res,2003,9(1):338-345.
[20]Hsieh JL, Wu CL, Lai MD, et al. Gene therapy for bladder cancer using E1B-55 kD-deleted adenovirus in combination with adenoviral vector encoding plasminogen kringles 1-5. Br J Cancer,2003,88(9):1492-1499.
[21]Nakashima H, Kaur B, Chiocca EA. Directing systemic oncolytic viral delivery to tumors via carrier cells. Cytokine Growth Factor Rev,2010,21(2-3):119-126.
[22]Saukkonen K, Hemminki A. Tissue-specific promoters for cancer gene therapy. Expert Opin Biol Ther,2004,4(5):683-696.
[23]Wang D, Wang Z, Tian J, et al. Prostate stem cell antigen enhancer and uroplakin Ⅱ promoter based bladder cancer targeted tissue-specific vector. Urol Oncol,2010,28(2): 164-169.
[24]Terao S, Shirakawa T, Kubo S, et al. Midkine promoter-based conditionally replicative adenovirus for targeting midkine-expressing human bladder cancer model. Urology, 2007,70(5):1009-1013.
[25]Shirakawa T, Hamada K, Zhang Z, et al. A cox-2 promoter-based replication-selective adenoviral vector to target the cox-2-expressing human bladder cancer cells. Clin Cancer Res,2004,10(13):4342-4348.
[26]Melquist JJ, Kacka M, Li Y, et al. Conditionally replicating adenovirus-mediated gene therapy in bladder cancer:an orthotopic in vivo model. Urol Oncol,2006,24(4): 362-371.
[27]Zhang J, Ramesh N, Chen Y, et al. Identification of human uroplakin Ⅱ promoter and its use in the construction of CG8840, a urothelium-specific adenovirus variant that eliminates established bladder tumors in combination with docetaxel. Cancer Res,2002, 62(13):3743-3750.
[28]He XD, Wang ZP, Wei HY, et al. Construction of urothelium-specific recombinant adenovirus and its inhibition in bladder cancer cell. Urol Int,2009,82(2):209-213.
[29]Lanson NA, Jr., Friedlander PL, Schwarzenberger P, et al. Replication of an adenoviral vector controlled by the human telomerase reverse transcriptase promoter causes tumor-selective tumor lysis. Cancer Res,2003,63(22):7936-7941.
[30]Gidekel S, Pizov G, Bergman Y, et al. Oct-3/4 is a dose-dependent oncogenic fate determinant. Cancer Cell,2003,4(5):361-370.
[31]Atlasi Y, Mowla SJ, Ziaee SA, et al. OCT-4, an embryonic stem cell marker, is highly expressed in bladder cancer. Int J Cancer,2007,120(7):1598-1602.
[32]Wu CL, Shieh GS, Chang CC, et al. Tumor-selective replication of an oncolytic adenovirus carrying oct-3/4 response elements in murine metastatic bladder cancer models. Clin Cancer Res,2008,14(4):1228-1238.
[33]Ramesh N, Ge Y, Ennist DL, et al. CG0070, a conditionally replicating granulocyte macrophage colony-stimulating factor--armed oncolytic adenovirus for the treatment of bladder cancer. Clin Cancer Res,2006,12(1):305-313.
[34]Hu J, Xuan X, Han C, et al. Anti-tumor function of double-promoter regulated adenovirus carrying SEA gene, in the treatment of bladder cancer. Cell Biochem Biophys,2012,62(2):353-359.
[35]李怀富.表达金黄色葡萄球菌肠毒素A基因的高靶向、双调控溶瘤腺病毒载体的构建、鉴定及其抗膀胱肿瘤作用.中华实验外科杂志,2009,26(8)：1052-1054.
[36]Bauerschmitz GJ, Guse K, Kanerva A, et al. Triple-targeted oncolytic adenoviruses featuring the cox2 promoter, E1A transcomplementation, and serotype chimerism for enhanced selectivity for ovarian cancer cells. Mol Ther,2006,14(2):164-174.
[37]Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer,2005, 5(4):275-284.
[38]Rich JN. Cancer stem cells in radiation resistance. Cancer Res,2007,67(19): 8980-8984.
[39]Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature,2006,444(7120):756-760.
[40]Fukazawa T, Matsuoka J, Yamatsuji T, et al. Adenovirus-mediated cancer gene therapy and virotherapy (Review). Int J Mol Med,2010,25(1):3-10.
[41]Alonso MM, Jiang H, Gomez-Manzano C, et al. Targeting brain tumor stem cells with oncolytic adenoviruses. Methods Mol Biol,2012,797(111-125.
[42]Hoti N, Chowdhury WH, Mustafa S, et al. Armoring CRAds with p21/Waf-1 shRNAs: the next generation of oncolytic adenoviruses. Cancer Gene Ther,2010,17(8):585-597.
[43]Khuri 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(8):879-885.
[44]Vasey PA, Shulman LN, Campos S, et al. Phase Ⅰ trial of intraperitoneal injection of the E1B-55-kd-gene-deleted adenovirus ONYX-015 (d11520) given on days 1 through 5 every 3 weeks in patients with recurrent/refractory epithelial ovarian cancer. J Clin Oncol,2002,20(6):1562-1569.
[45]Reid T, Galanis E, Abbruzzese J, et al. Hepatic arterial infusion of a replication-selective oncolytic adenovirus (d11520):phase Ⅱ viral, immunologic, and clinical endpoints. Cancer Res,2002,62(21):6070-6079.
[46]Nemunaitis J, Senzer N, Sarmiento S, et al. A phase Ⅰ trial of intravenous infusion of ONYX-015 and enbrel in solid tumor patients. Cancer Gene Ther,2007,14(11): 885-893.
[47]Demers GW, Johnson DE, Tsai V, et al. Pharmacologic indicators of antitumor efficacy for oncolytic virotherapy. Cancer Res,2003,63(14):4003-4008.
[48]Kumar S, Gao L, Yeagy B, et al. Virus combinations and chemotherapy for the treatment of human cancers. Curr Opin Mol Ther,2008,10(4):371-379.
[49]Hemminki A. From molecular changes to customised therapy. Eur J Cancer,2002,38(3): 333-338.
[50]Burke J. Virus therapy for bladder cancer. Cytokine Growth Factor Rev,2010,21(2-3): 99-102.
[51]Ganly I, Kirn D, Eckhardt G, et al. A phase I study of Onyx-015, an E1B attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer. Clin Cancer Res,2000,6(3):798-806.
[52]Jiang H, Gomez-Manzano C, Lang FF, et al. Oncolytic adenovirus:preclinical and clinical studies in patients with human malignant gliomas. Curr Gene Ther,2009,9(5): 422-427.
[53]Freytag SO, Stricker H, Peabody J, et al. Five-year follow-up of trial of replication-competent adenovirus-mediated suicide gene therapy for treatment of prostate cancer. Mol Ther,2007,15(3):636-642.
[54]Freytag SO, Khil M, Stricker 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(17):4968-4976.
[55]Small EJ, Carducci MA, Burke JM, et al. A phase I trial of intravenous CG7870, a replication-selective, prostate-specific antigen-targeted oncolytic adenovirus, for the treatment of hormone-refractory, metastatic prostate cancer. Mol Ther,2006,14(1): 107-117.
[56]DeWeese TL, van der Poel H, Li S, et al. A phase I trial of CV706, a replication-competent, PSA selective oncolytic adenovirus, for the treatment of locally recurrent prostate cancer following radiation therapy. Cancer Res,2001,61(20): 7464-7472.
[57]Page JG, Tian B, Schweikart K, et al. Identifying the safety profile of a novel infectivity-enhanced conditionally replicative adenovirus, Ad5-delta24-RGD, in anticipation of a phase I trial for recurrent ovarian cancer. Am J Obstet Gynecol,2007, 196(4):389 e381-389; discussion 389 e389-310.
[58]Dobbelstein M. Replicating adenoviruses in cancer therapy. Curr Top Microbiol Immunol,2004,273(8):291-334.
[59]Chiocca EA, Abbed KM, Tatter S, et al. A phase I open-label, dose-escalation, multi-institutional trial of injection with an EIB-Attenuated adenovirus, ONYX-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting. Mol Ther,2004,10(5):958-966.
[60]Ries S, Korn WM. ONYX-015:mechanisms of action and clinical potential of a replication-selective adenovirus. Br J Cancer,2002,86(1):5-11.
[61]Mulvihill S, Warren R, Venook A, et al. Safety and feasibility of injection with an E1B-55 kDa gene-deleted, replication-selective adenovirus (ONYX-015) into primary carcinomas of the pancreas:a phase I trial. Gene Ther,2001,8(4):308-315.
[62]Nemunaitis J, Cunningham C, Tong A, et al. Pilot trial of intravenous infusion of a replication-selective adenovirus (ONYX-015) in combination with chemotherapy or IL-2 treatment in refractory cancer patients. Cancer Gene Ther,2003,10(5):341-352.
[63]Burke JM, Lamm DL, Meng MV, et al. A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer. J Urol,2012,188(6):2391-2397.
[64]Chang J, Zhao X, Wu X, et al. A Phase I study of KH901, a conditionally replicating granulocyte-macrophage colony-stimulating factor:armed oncolytic adenovirus for the treatment of head and neck cancers. Cancer Biol Ther,2009,8(8):676-682.
[65]Pesonen S, Diaconu I, Kangasniemi L, et al. Oncolytic immunotherapy of advanced solid tumors with a CD40L-expressing replicating adenovirus:assessment of safety and immunologic responses in patients. Cancer Res,2012,72(7):1621-1631.
[66]Kimball KJ, Preuss MA, Barnes MN, et al. A phase I study of a tropism-modified conditionally replicative adenovirus for recurrent malignant gynecologic diseases. Clin Cancer Res,2010,16(21):5277-5287.
[67]Yuan ZY, Zhang L, Li S, et al. Safety of an E1B deleted adenovirus administered intratumorally to patients with cancer. Ai Zheng,2003,22(3):310-313.
[68]Lu W, Zheng S, Li XF, et al. Intra-tumor injection of H101, a recombinant adenovirus, in combination with chemotherapy in patients with advanced cancers:a pilot phase Ⅱ clinical trial. World J Gastroenterol,2004,10(24):3634-3638.
[69]Yu W, Fang H. Clinical trials with oncolytic adenovirus in China. Curr Cancer Drug Targets,2007,7(2):141-148.
[70]Xu RH, Yuan ZY, Guan ZZ, et al. Phase Ⅱ clinical study of intratumoral H101, an E1B deleted adenovirus, in combination with chemotherapy in patients with cancer. Ai Zheng, 2003,22(12):1307-1310.
[71]Xia ZJ, Chang JH, Zhang L, et al. Phase Ⅲ randomized clinical trial of intratumoral injection of E1B gene-deleted adenovirus (H101) combined with cisplatin-based chemotherapy in treating squamous cell cancer of head and neck or esophagus. Ai Zheng,2004,23(12):1666-1670.
[72]胡永超.溶瘤腺病毒治疗实体瘤安全性及临床疗效的初步评价.中华临床医师杂志(电子版),2011,5(9)：2537-2542.
[73]Breitbach CJ, Burke J, Jonker D, et al. Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans. Nature,2011,477(7362):99-102.
[74]Chang JY, Xia W, Shao R, et al. Inhibition of intratracheal lung cancer development by systemic delivery of E1A. Oncogene,1996,13(7):1405-1412.
[75]Shao R, Karunagaran D, Zhou BP, et al. Inhibition of nuclear factor-kappaB activity is involved in E1A-mediated sensitization of radiation-induced apoptosis. J Biol Chem, 1997,272(52):32739-32742.
[76]Zhu H, Zhang ZA, Xu C, et al. Targeting gene expression of the mouse uroplakin II promoter to human bladder cells. Urol Res,2003,31(1):17-21.
[77]Latham JP, Searle PF, Mautner V, et al. Prostate-specific antigen promoter/enhancer driven gene therapy for prostate cancer:construction and testing of a tissue-specific adenovirus vector. Cancer Res,2000,60(2):334-341.
[78]Jain A, Lam A, Vivanco I, et al. Identification of an androgen-dependent enhancer within the prostate stem cell antigen gene. Mol Endocrinol,2002,16(10):2323-2337.
[79]Hoti N, Li Y, Chen CL, et al. Androgen receptor attenuation of Ad5 replication: implications for the development of conditionally replication competent adenoviruses. Mol Ther,2007,15(8):1495-1503.
[80]Zhai Z, Wang Z, Fu S, et al. Antitumor effects of bladder cancer-specific adenovirus carrying E1A-androgen receptor in bladder cancer. Gene Ther,2012,19(11):1065-1074.
[81]Kanegae Y, Makimura M, Saito I. A simple and efficient method for purification of infectious recombinant adenovirus. Jpn J Med Sci Biol,1994,47(3):157-166.
[82]Vail DM, MacEwen EG. Spontaneously occurring tumors of companion animals as models for human cancer. Cancer Invest,2000,18(8):781-792.
[83]Knapp DW, Waters DJ. Naturally occurring cancer in pet dogs:important models for developing improved cancer therapy for humans. Mol Med Today,1997,3(1):8-11.
[84]Yamamoto S, Tatematsu M, Yamamoto M, et al. Clonal analysis of urothelial carcinomas in C3H/HeN<-->BALB/c chimeric mice treated with N-butyl-N-(4-hydroxybutyl)nitrosamine. Carcinogenesis,1998,19(5):855-860.
[85]Steinberg GD, Brendler CB, Ichikawa T, et al. Characterization of an N-methyl-N-nitrosourea-induced autochthonous rat bladder cancer model. Cancer Res, 1990,50(20):6668-6674.
[86]Jiang F, Zhou XM. A model of orthotopic murine bladder (MBT-2) tumor implants. Urol Res,1997,25(3):179-182.
[87]Vandepitte J, Maes J, Van Cleynenbreugel B, et al. An improved orthotopic rat bladder tumor model using Dil-loaded fluorescent AY-27 cells. Cancer Biol Ther,9(12): 986-993.
[88]李凌.一种新的高转移膀胱癌动物模型的建立.中华实验外科杂志,2002,19(1)：78-79.
[89]Li F, Ye Z, Yang W. Evaluation of tumor formation of three bladder cancer cell lines in nude mice. J Huazhong Univ Sci Technolog Med Sci,2011,31(2):210-214.
[90]Hadaschik BA, Black PC, Sea JC, et al. A validated mouse model for orthotopic bladder cancer using transurethral tumour inoculation and bioluminescence imaging. BJU Int, 2007,100(6):1377-1384.
[91]Engler H, Machemer T, Philopena J, et al. Acute hepatotoxicity of oncolytic adenoviruses in mouse models is associated with expression of wild-type Ela and induction of TNF-alpha. Virology,2004,328(1):52-61.
[92]Shayakhmetov DM, Gaggar A, Ni S, et al. Adenovirus binding to blood factors results in liver cell infection and hepatotoxicity. J Virol,2005,79(12):7478-7491.
[93]Cascallo M, Alonso MM, Rojas JJ, et al. Systemic toxicity-efficacy profile of ICOVIR-5, a potent and selective oncolytic adenovirus based on the pRB pathway. Mol Ther,2007, 15(9):1607-1615.
[94]Tsukuda K, Wiewrodt R, Molnar-Kimber K, et al. An E2F-responsive replication-selective adenovirus targeted to the defective cell cycle in cancer cells: potent antitumoral efficacy but no toxicity to normal cell. Cancer Res,2002,62(12): 3438-3447.
[95]Lovatt A. Applications of quantitative PCR in the biosafety and genetic stability assessment of biotechnology products. J Biotechnol,2002,82(3):279-300.
[96]Carney BJ, Shah K. Migration and fate of therapeutic stem cells in different brain disease models. Neuroscience,2011,197(10):37-47.
[97]Dmitriev I, Krasnykh V, Miller CR, et al. An adenovirus vector with genetically modified fibers demonstrates expanded tropism via utilization of a coxsackievirus and adenovirus receptor-independent cell entry mechanism. J Virol,1998,72(12): 9706-9713.
[98]Li Y, Pong RC, Bergelson JM, et al. Loss of adenoviral receptor expression in human bladder cancer cells:a potential impact on the efficacy of gene therapy. Cancer Res, 1999,59(2):325-330.
[99]Sachs MD, Rauen KA, Ramamurthy M, et al. Integrin alpha(v) and coxsackie adenovirus receptor expression in clinical bladder cancer. Urology,2002,60(3): 531-536.
[100]Havenga MJ, Lemckert AA, Ophorst OJ, et al. Exploiting the natural diversity in adenovirus tropism for therapy and prevention of disease. J Virol,2002,76(9): 4612-4620.
[101]Iguchi K, Sakurai F, Tomita K, et al. Efficient antitumor effects of carrier cells loaded with a fiber-substituted conditionally replicating adenovirus on CAR-negative tumor cells. Cancer Gene Ther,2012,19(2):118-125.
[102]Wakayama M, Abei M, Kawashima R, et al. E1A, E1B double-restricted adenovirus with RGD-fiber modification exhibits enhanced oncolysis for CAR-deficient biliary cancers. Clin Cancer Res,2007,13(10):3043-3050.
[103]Dehari H, Ito Y, Nakamura T, et al. Enhanced antitumor effect of RGD fiber-modified adenovirus for gene therapy of oral cancer. Cancer Gene Ther,2003,10(1):75-85.
[104]Suzuki K, Fueyo J, Krasnykh V, et al. A conditionally replicative adenovirus with enhanced infectivity shows improved oncolytic potency. Clin Cancer Res,2001,7(1): 120-126.
[105]Lavilla-Alonso S, Bauerschmitz G, Abo-Ramadan U, et al. Adenoviruses with an alphavbeta integrin targeting moiety in the fiber shaft or the HI-loop increase tumor specificity without compromising antitumor efficacy in magnetic resonance imaging of colorectal cancer metastases. J Transl Med,2010,8(2):80-87.
[106]Ranki T, Kanerva A, Ristimaki A, et al. A heparan sulfate-targeted conditionally replicative adenovirus, Ad5.pk7-Delta24, for the treatment of advanced breast cancer. Gene Ther,2007,14(1):58-67.
[107]van der Poel HG, Molenaar B, van Beusechem VW, et al. Epidermal growth factor receptor targeting of replication competent adenovirus enhances cytotoxicity in bladder cancer. J Urol,2002,168(1):266-272.
[108]Mizuguchi H, Sasaki T, Kawabata K, et al. Fiber-modified adenovirus vectors mediate efficient gene transfer into undifferentiated and adipogenic-differentiated human mesenchymal stem cells. Biochem Biophys Res Commun,2005,332(4):1101-1106.
[109]Hakkarainen T, Sarkioja M, Lehenkari P, et al. Human mesenchymal stem cells lack tumor tropism but enhance the antitumor activity of oncolytic adenoviruses in orthotopic lung and breast tumors. Hum Gene Ther,2007,18(7):627-641.
[110]Zhao Y, Li Y, Wang Q, et al. Increased antitumor capability of fiber-modified adenoviral vector armed with TRAIL against bladder cancers. Mol Cell Biochem,2011,353(1-2): 93-99.
[111]Shieh GS, Shiau AL, Yo YT, et al. Low-dose etoposide enhances telomerase-dependent adenovirus-mediated cytosine deaminase gene therapy through augmentation of adenoviral infection and transgene expression in a syngeneic bladder tumor model. Cancer Res,2006,66(20):9957-9966.
[112]Okegawa T, Nutahara K, Pong RC, et al. Enhanced transgene expression in urothelial cancer gene therapy with histone deacetylase inhibitor. J Urol,2005,174(2):747-752.
[113]Lupold SE, Kudrolli TA, Chowdhury WH, et al. A novel method for generating and screening peptides and libraries displayed on adenovirus fiber. Nucleic Acids Res,2007, 35(20):e138.
[114]Lilly JD, Parsons CL. Bladder surface glycosaminoglycans is a human epithelial permeability barrier. Surg Gynecol Obstet,1990,171(6):493-496.
[115]Ratliff TL. Identification of pretreatment agents to enhance adenovirus infection of bladder epithelium. J Urol,2005,173(6):2198-2199.
[116]Ranki T, Sarkioja M, Hakkarainen T, et al. Systemic efficacy of oncolytic adenoviruses in imagable orthotopic models of hormone refractory metastatic breast cancer. Int J Cancer,2007,121(1):165-174.
[117]Kanerva A, Zinn KR, Chaudhuri TR, et al. Enhanced therapeutic efficacy for ovarian cancer with a serotype 3 receptor-targeted oncolytic adenovirus. Mol Ther,2003,8(3): 449-458.
[1]Dean M,Fojo T,Bates S.Tumour stem cells and drug resistance[J].Nat Rev Cancer,2005,5(4):275-284.
[2]Liu TC,Kirn D.Gene therapy progress and prospects cancer:oncolytic viruses[J].Gene Ther, 2008,15(12):877-884.
[3]Mahller YY.Williams JP,Baird WH,et al.Neuroblastoma cell lines contain pluripotent tumor initiating cells that are susceptible to a targeted oncolytic virus[J].PLoS One,2009,4(1):e4235.
[4]Jordan CT.Cancer stem cells:controversial or just misunderstood?[J].Cell Stem Cell,2009,4(3):203-205.
[5]Bonnet D,Dick JE.Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell[J].Nat Med,1997,3(7):730-737.
[6]Al-Hajj M,Wicha MS,Benito-Hernandez A,et al.Prospective identification of tumorigenic breast cancer cells[J].Proc Natl Acad Sci U S A,2003,100(7):3983-3988.
[7]Ponti D,Costa A,Zaffaroni N,et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties[J].Cancer Res,2005,65(13):5506-5511.
[8]Singh SK,Hawkins C,Clarke ID,et al.Identification of human brain tumour initiating cells[J].Nature,2004,432(7015):396-401.
[9]Gibbs CP,Kukekov VG,Reith JD,et al.Stem-like cells in bone sarcomas:implications for tumorigenesis[J].Neoplasia,2005,7(11):967-976.
[10]O'Brien CA,Pollett A,Gallinger S,et al.A human colon cancer cell capable of initiating tumour growth in immunodeficient mice[J].Nature,2007,445(7123):106-110.
[11]Dalerba P,Dylla SJ,Park IK,et al.Phenotypic characterization of human colorectal cancer stem cells[J].Proc Natl Acad Sci U S A,2007,104(24):10158-10163.
[12]Prince ME.Sivanandan R,Kaczorowski A,et al.Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma[J].Proc Natl Acad Sci U S A,2007,104(3):973-978.
[13]Ma S,Chan KW,Hu L,et al.Identification and characterization of tumorigenic liver cancer stem/progenitor cells[J].Gastroenterology,2007,132(7):2542-2556.
[14]Ma S,Chan KW,Lee TK,et al.Aldehyde dehydrogenase discriminates the CD 133 liver cancer stem cell populations[J].Mol Cancer Res,2008,6(7):1146-1153.
[15]Kim CF,Jackson EL,Woolfenden AE,et al.Identification of bronchioalveolar stem cells in normal lung and lung cancer[J].Cell,2005,121(6):823-835.
[16]Li C,Lee CJ,Simeone DM.Identification of human pancreatic cancer stem cells[J].Methods Mol Biol,2009,568:161-173.
[17]Xin L,Lawson DA,Witte ON.The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis[J].Proc Natl Acad Sci U S A,2005,102(19):6942-6947.
[18]Chan KS,Espinosa I,Chao M,et al.Identification,molecular characterization,clinical prognosis,and therapeutic targeting of human bladder tumor-initiating cells[J].Proc Natl Acad Sci US A,2009,106(33):14016-14021.
[19]Bisson I.Prowse DM.WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics[J].Cell Res,2009,19(6):683-697.
[20]Rich JN.Cancer stem cells in radiation resistance[J].Cancer Res,2007,67(19):8980-8984.
[21]Bao S,Wu Q,McLendon RE,et al.Glioma stem cells promote radioresistance by preferential activation of the DNA damage response[J].Nature,2006,444(7120):756-760.
[22]Kelly E,Russell SJ.History of oncolytic viruses:genesis to genetic engineering[J].Mol Ther, 2007,15(4):651-659.
[23]Kanerva A,Raki M,Hemminki A.Gene therapy of gynaecological diseases[J].Expert Opin Biol Ther, 2007,7(9):1347-1361.
[24]Nakashima H,Kaur B,Chiocca EA.Directing systemic oncolytic viral delivery to tumors via carrier cells[J].Cytokine Growth Factor Rev,2010,21(2-3):119-126.
[25]Fukazawa T,Matsuoka J,Yamatsuji T,et al.Adenovirus-mediated cancer gene therapy and virotherapy (Review)[J].Int J Mol Med,2010,25(1):3-10.
[26]Alonso MM,Jiang H,Gomez-Manzano C,et al.Targeting brain tumor stem cells with oncolytic adenoviruses[J].Methods Mol Biol 2012,797:111-125.
[27]Hoti N.Chowdhury WH,Mustafa S,et al.Armoring CRAds with p21/Waf-1 shRNAs:the next generation of oncolytic adenoviruses[J].Cancer Gene Ther,2010,17(8):585-597.
[28]Eriksson M,Guse K,Bauerschmitz G,et al.Oncolytic adenoviruses kill breast cancer initiating CD44+CD24-/low cells[J].Mol Ther,2007,15(12):2088-2093.
[29]Ranki T,Kanerva A,Ristimaki A,et al.A heparan sulfate-targeted conditionally replicative adenovirus,Ad5.pk7-Delta24,for the treatment of advanced breast cancer[J].Gene Ther,2007,14(1):58-67.
[30]Ranki T,Sarkioja M,Hakkarainen T,et al.Systemic efficacy of oncolytic adenoviruses in imagable orthotopic models of hormone refractory metastatic breast cancer[J].Int J Cancer,2007,121(1):165-174.
[31]Rein DT,Volkmer A,Beyer IM,et al.Treatment of chemotherapy resistant ovarian cancer with a MDR1 targeted oncolytic adenovirus [J].Gynecol Oncol,2011,123(1):138-146.
[32]Pesonen S,Nokisalmi P,Escutenaire S,et al.Prolonged systemic circulation of chimeric oncolytic adenovirus Ad5/3-Cox2L-D24 in patients with metastatic and refractory solid tumors[J].Gene Ther, 2011,17(7):892-904.
[33]Doloff JC,Jounaidi Y,Waxman DJ.Dual E1A oncolytic adenovirus:targeting tumor heterogeneity with two independent cancer-specific promoter elements,DF3/MUC1 and hTERT[J].Cancer Gene Ther,2011,18(3):153-166.
[34]Skog J,Edlund K,Bergenheim AT,et al.Adenoviruses 16 and CV23 efficiently transduce human low-passage brain tumor and cancer stem cells[J].Mol Ther 2007,15(12):2140-2145.
[35]Jiang H,Gomez-Manzano C,Aoki H,et al.Examination of the therapeutic potential of Delta-24-RGD in brain tumor stem cells:role of autophagic cell death[J].J Natl Cancer Inst 2007,99(8):1410-1414.
[36]Carney BJ,Shah K.Migration and fate of therapeutic stem cells in different brain disease models[J].Neuroscience,2011,197:37-47.