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溶瘤腺病毒是一种改造过的能够选择性地在肿瘤细胞中复制,并能够杀死肿瘤细胞的腺病毒,目前已经应用于肿瘤治疗中。但是因为肿瘤的复杂性以及高突变性,所以提高溶瘤腺病毒对肿瘤的有效性,选择性和安全性成为了主要的研究方向。能够在体内正常表达shRNA、细胞因子、自杀基因、基质修饰蛋白等治疗性基因的溶瘤腺病毒具有比单纯的溶瘤腺病毒更强的抗肿瘤活性。而具有肿瘤特异性启动子,尤其是双调控启动子的溶瘤腺病毒对肿瘤细胞具有更强的选择性杀伤作用。另外用脂质体、PEG聚合物、纳米颗粒、多肽等包裹的溶瘤腺病毒能够减少病毒的免疫原性以及对肝脏的毒性,增强了全身给药途径的抗肿瘤活性。特别是用PEG连上抗体、小肽、细胞因子和配体,能显著提高溶瘤腺病毒的选择性。因此,整合病毒载体与非病毒载体的优点并与免疫治疗相结合,是一个很有希望的提高病毒靶向治疗效果的策略。 相似文献
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溶瘤腺病毒是通过遗传工程改造的腺病毒,具有溶细胞复制周期的特性和特异靶向肿瘤细胞和裂解肿瘤细胞的功能。溶瘤腺病毒通过复制、释放子代病毒感染邻近肿瘤细胞。现在对腺病毒生活周期的认识水平,可以对其基因组进行改造从而使其特异性裂解肿瘤细胞而不杀伤正常细胞,并且构建了多种溶瘤腺病毒。本文主要概述了溶瘤腺病毒的三种构建策略:剔除腺病毒在正常细胞中复制所必需而在肿瘤细胞中不需要的某些基因;利用肿瘤特异性启动子控制病毒复制所必需的基因;对腺病毒衣壳蛋白进行基因修饰,达到特异性结合肿瘤细胞的目的。 相似文献
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胶质瘤是颅内常见的恶性肿瘤之一,其发病率呈现逐年上升趋势.当前,胶质瘤的治疗仍以手术为主,结合放疗和化疗等,但这些传统的治疗方法均存在某些局限性,临床上迫切需要研究更新型的方法,例如肿瘤基因治疗.溶瘤腺病毒是一类经过基因工程改造的病毒,能够特异性感染并杀伤肿瘤细胞,而不影响正常细胞功能.溶瘤腺病毒治疗具有肿瘤特异性和安... 相似文献
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嵌合型E1B 55-kDa蛋白缺陷型腺病毒载体治疗肿瘤的评价 总被引:3,自引:0,他引:3
ONYX-015和H101为可复制E1B 55-kDa蛋白缺陷的C族腺病毒,它们正作为抗癌药物进行临床研究. 然而它们在癌症基因治疗中的应用却受到了C族腺病毒天然特性的制约,部分原因是由于在恶性肿瘤中C族腺病毒受体(coxsackievirus-adenovirus receptor,CAR) 的表达量较低. 构建了一个以H101为骨架的含有编码35型腺病毒鞭毛区域的基因,替代5型腺病毒鞭毛基因的嵌合型腺病毒载体. 这一改动使得腺病毒载体可以通过一种在肿瘤中高表达的膜蛋白CD46感染肿瘤细胞. 应用RT-PCR方法检测不同肿瘤细胞株中CAR和CD46表达量的区别. 在CAR受体低表达的细胞株中(MDA-MB-435和MCF-7),H101-F35表现出比H101和ONYX-015更强的细胞杀伤效果;在CAR受体高表达的细胞株中(A549,NCI-H446,Hep3B,LNCaP,ZR-75-30和Bcap-37),H101-F35、 H101和ONYX-015的细胞杀伤效果则相似. 在荷MDA-MB-435肿瘤的裸鼠模型中,注射H101-F35的抑瘤效果比注射H101的抑瘤效果更明显. 这些结果表明嵌合型溶瘤腺病毒载体H101-F35在肿瘤基因治疗中将有很好的应用前景. 相似文献
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应用分子克隆和同源重组技术构建双靶向溶瘤腺病毒MD55.分析MD55病毒在细胞中的复制能力,并用MTT和结晶紫方法检测MD55对肿瘤细胞和正常细胞生长的影响,West-ern印迹检测病毒感染后细胞中E1A蛋白和多聚ADP核糖聚合酶(PARP)片断的表达.结果显示,MD55能在MN/CA9阳性的肿瘤细胞SW620和OSRC-2中特异性表达E1A蛋白.并且在这些细胞中的复制能力和对这些细胞的杀伤性与对照病毒ZD55基本相同,而其在正常细胞中的复制能力很弱,对正常细胞的伤害很小;同时MD55可诱导肿瘤细胞SW620和OSRC-2的凋亡,而对正常细胞的凋亡无影响.实验结果表明双靶向溶瘤腺病毒MD55靶向性和安全性比单靶向病毒ZD55更高,有望成为一种很好的肿瘤靶向基因一病毒治疗载体. 相似文献
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《中国科学:生命科学》2017,(4)
溶瘤病毒治疗,是指利用具有复制能力的病毒选择性地感染和摧毁癌细胞,而对正常细胞或组织影响很少甚至没有影响的一种癌症治疗方法.痘苗病毒在肿瘤的基因治疗应用研究中以其独特的优势而备受关注.痘苗病毒感染细胞后具有产生病毒颗粒快、宿主范围广、基因组容量大、安全性高、传播高效等优点.尤为重要的是,基于溶瘤痘苗病毒的天然特性或遗传工程的改造,溶瘤痘苗病毒可以选择性地在肿瘤细胞中复制并对其产生杀伤效果.痘苗溶瘤病毒引起肿瘤细胞裂解和死亡是由多种不同的机制引起的.本文就近年来溶瘤痘苗病毒对细胞作用机制和相关信号通路的影响作一简要综述. 相似文献
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《中国生物工程杂志》2004,24(12):103
上海三维生物科技有限公司正在研制的H101(基因工程腺病毒注射液)抗癌药物目前已基本完成三期临床,即将获得SFDA新药证书。该药物上市后将成为我国第一个拥有全球知识产权的生物制剂。H101是该公司自1998年开始研制的一个项目,其率先开创了“溶瘤”技术来对抗肿瘤细胞。此技术可避免通常的施药方式将肿瘤细胞和有益细胞一同杀死的情况发生。 相似文献
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《中国细胞生物学学报》2017,(11)
溶瘤病毒(oncolytic viruses)可选择性地感染肿瘤细胞并在其中复制,使宿主细胞裂解并在体内产生强烈的免疫应答反应,从而抑制或者杀死肿瘤细胞。因其特有的溶瘤性和靶向性,溶瘤病毒成为肿瘤基因治疗的热门领域之一。基于Wnt信号的肿瘤特异性,本研究使用Wnt信号启动子TCF/LEF结合位点序列,调控腺病毒早期基因E1A,并删除E1A基因序列上能与Rb蛋白结合的24 bp片段。将抑癌基因TSLC1插入腺病毒的E3区,形成重组腺病毒Ad.wnt-E1A(Δ24)-TSLC1。通过双荧光素酶报告系统、Western blot实验、MTT法、结晶紫染色法、Hoechst染色实验分别检测Wnt信号活性、肿瘤细胞的存活率和凋亡的变化情况。结果发现,肿瘤细胞较正常肝细胞具有较高的Wnt通路活性和病毒敏感性,其中重组病毒处理Hep G2后杀伤效果显著,并可通过Caspase通路诱导细胞凋亡,为肝癌的临床治疗提供参考。 相似文献
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目的:探讨溶瘤腺病毒(ZD55-gene)作为载体携带外源抗癌基因(XAF1)抗肝癌移植瘤的生长及其安全性。方法:抽提溶瘤腺病毒ZD55-XAF1的基因组DNA,PCR扩增鉴定病毒;细菌平板培养和支原体检测试剂盒检测细胞有无细菌、支原体污染;通过荷瘤小鼠动物实验,观察溶瘤腺病毒ZD55-XAF1对肝癌移植瘤生长的抑制、小鼠的临床反应指标、血清肝毒性指标、各脏器组织中的病毒残留分布及病理切片观察。结果:细胞培养过程无细菌和支原体污染;较对照组,受试小鼠血清肝酶AST活性上升(P0.05),而ALT和ALP活性基本无变化(P0.05);PCR检测各脏器均有病毒基因组DNA存在;HE染色显示受试小鼠各脏器具有不同程度的损伤,病毒处理对肿瘤细胞具有明显的杀伤效果,而受试小鼠的临床反应并无明显异常。结论:溶瘤腺病毒ZD55-XAF1能够抑制肿瘤生长,杀死肿瘤细胞,对小鼠血清肝酶活性影响较小而对各脏器有不同程度的轻微损伤,作为癌症基因治疗载体有潜在的应用价值但其安全性还有待提高。 相似文献
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刘旭张东亮刘文虎 《现代生物医学进展》2011,11(7):1382-1384
溶瘤腺病毒是一组通过基因工程构建的腺病毒、能够选择性在肿瘤细胞中完成感染-复制周期,从而特异性地杀伤、溶解肿瘤而不伤及其他正常细胞、组织,其作用机制包括:通过基因的缺失突变、插入特异性启动子、以及通过病毒结构蛋白的修饰等方面,实现肿瘤靶向治疗作用。本文就相关研究及进展进行综述。 相似文献
11.
There is a need for more effective treatments for uveal melanoma. The recombinant oncolytic adenovirus H101 replicates specifically in p53-depleted tumor cells, and has been approved for use by the Chinese State Food and Drug Administration. However, this treatment is associated with subsequent remission. Transfection of uveal melanoma cells with a small interfering RNA against Notch1 (siNotch1) effectively suppressed Notch1 expression, resulting in significant cell growth inhibition when combined with H101 treatment. Combined treatment with siNotch1 and H101 (H101-Notch1-siRNA) greatly enhanced apoptosis and cell cycle arrest in vitro as compared to treatment with H101 or siNotch1 alone. For in vivo treatments, the combined treatment of siNotch1 and H101 showed remarkable tumor growth inhibition and prolonged mouse survival in the OCM1 xenograft model. We predict that Notch pathway deregulation could be a feature of uveal melanoma, and could be a therapeutic target, especially if p53 is concurrently targeted. 相似文献
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Weidan Huang Miao Ding Jing Xiao Dongmei Yang Huaguang Li Xin‐Yuan Liu Liang Chu 《Journal of cellular and molecular medicine》2015,19(5):915-923
Lung cancer stem cell (LCSC) is critical in cancer initiation, progression, drug resistance and relapse. Disadvantages showed in conventional lung cancer therapy probably because of its existence. In this study, lung cancer cell line A549 cells propagated as spheroid bodies (named as A549 sphere cells) in growth factors‐defined serum‐free medium. A549 sphere cells displayed CSC properties, including chemo‐resistance, increased proportion of G0/G1 cells, slower proliferation rate, ability of differentiation and enhanced tumour formation ability in vivo. Oncolytic adenovirus ZD55 carrying EGFP gene, ZD55‐EGFP, infected A549 sphere cells and inhibited cell growth. Tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL) armed oncolytic adenovirus, ZD55‐TRAIL, exhibited enhanced cytotoxicity and induced A549 sphere cells apoptosis through mitochondrial pathway. Moreover, small molecules embelin, LY294002 and resveratrol improved the cytotoxicity of ZD55‐TRAIL. In the A549 sphere cells xenograft models, ZD55‐TRAIL significantly inhibited tumour growth and improved survival status of mice. These results suggested that gene armed oncolytic adenovirus is a potential approach for lung cancer therapy through targeting LCSCs. 相似文献
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Roles of stem cell factor/c-Kit and effects of Glivec/STI571 in human uveal melanoma cell tumorigenesis 总被引:5,自引:0,他引:5
Lefevre G Glotin AL Calipel A Mouriaux F Tran T Kherrouche Z Maurage CA Auclair C Mascarelli F 《The Journal of biological chemistry》2004,279(30):31769-31779
The B-Raf(V599E)-mediated constitutive activation of ERK1/2 is involved in establishing the transformed phenotype of some uveal melanoma cells (Calipel, A., Lefevre, G., Pouponnot, C., Mouriaux, F., Eychene, A., and Mascarelli, F. (2003) J. Biol. Chem. 278, 42409-42418). We have shown that stem cell factor (SCF) is involved in the proliferation of normal uveal melanocytes and that c-Kit is expressed in 75% of primary uveal melanomas. This suggests that the acquisition of autonomous growth during melanoma progression may involve the SCF/c-Kit axis. We used six human uveal melanoma tumor-derived cell lines and normal uveal melanocytes to characterize the SCF/c-Kit system and to assess its specific role in transformation. We investigated the possible roles of activating mutations in c-KIT, the overexpression of this gene, and ligand-dependent c-Kit overactivation in uveal melanoma cell tumorigenesis. Four cell lines (92.1, SP6.5, Mel270, and TP31) expressed both SCF and c-Kit, and none harbored the c-KIT mutations in exons 9, 11, 13, and 17 that have been shown to induce SCF-independent c-Kit activation. Melanoma cell proliferation was strongly inhibited by small interfering RNA-mediated depletion of c-Kit in these cells, despite the presence of (V599E)B-Raf in SP6.5 and TP31 cells. We characterized the signaling pathways involved in SCF/c-Kit-mediated cell growth and survival in normal and tumoral melanocytes and found that constitutive ERK1/2 activation played a key role in both the SCF/c-Kit autocrine loop and the gain of function of (V599E)B-Raf for melanoma cell proliferation and transformation. We also provide the first evidence that Glivec/STI571, a c-Kit tyrosine kinase inhibitor, could be used to treat uveal melanomas. 相似文献
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Zhezhu Han Seungha Lee Suyeon Je Chi-Yong Eom Hye Jin Choi Jae J. Song Joo-Hang Kim 《Apoptosis : an international journal on programmed cell death》2016,21(3):351-364
In this study, we demonstrated that survivin downregulation with TRAIL expression greatly enhanced the cytotoxic death of pancreatic cancer cells after gemcitabine treatment. Using real-time RT-PCR, we analyzed five survivin shRNAs to identify the best target sequence for suppression of human survivin, with the goal of treating gemcitabine-resistant pancreatic cancer cells. Survivin shRNA 5, corresponding to target 5, showed the greatest reduction in survivin mRNA levels. Furthermore, combined treatment with survivin shRNA-expressing adenovirus with gemcitabine plus TRAIL decreased uncleaved PARP and increased consequent PARP cleavage, which was correlated with the greatest levels of survivin downregulation and cell death. These results indicate that survivin functions as a common mediator of gemcitabine- and TRAIL-induced cell death. Using a nude mouse model implanted with MiaPaCa-2 pancreatic cancer cells, we observed tumor regression induced by an oncolytic adenovirus expressing survivin shRNA and TRAIL plus gemcitabine. Together, our findings provide a strong rationale for treating pancreatic cancer patients with both gemcitabine and oncolytic adenovirus armed with survivin shRNA and TRAIL. 相似文献
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Lianli Xiao Xin Li Na Niu Jing Qian Guoliang Xie Yigang Wang 《Molecular and cellular biochemistry》2010,340(1-2):31-40
Dichloroacetate (DCA) is a metabolic modulator for the treatment of lactic acidosis and inherited mitochondrial diseases. A recent study showed that DCA treatment could induce apoptosis in many kinds of tumor cell lines via mitochondrial apoptotic pathway while sparing normal cells. ONYX-015 (dl 1520) is one of the oncolytic adenoviruses developed by the deletion of E1B-55kD gene of type 5 adenoviral DNA, and it replicates efficiently and selectively in tumor cells. ZD55-IL-24, an E1B-55kD deleted oncolytic adenovirus carrying interleukin-24 (IL-24, also called melanoma differentiation associated gene-7), had showed potent antitumor efficacy in a variety of tumor cells and exerted no apparent toxicity on normal cells. Given both the good therapeutic effect and low toxicity of these agents, here we investigated whether DCA in combination with ZD55-IL-24 or ONYX-015 could have more efficient antitumor activity in vitro experiments. Therefore, we tested the cytotoxicity of combination therapy in normal hepatic cells L-02 and QSG-7701 using the MTT assay. Our results showed that DCA combined with ONYX-015 or ZD55-IL-24 exhibited more potent antitumor activity than DCA or virus alone, and the combination treatment did not have superimposed toxicities in normal cells. Thus, a novel combination therapy associating oncolytic adenoviruses with relatively low toxic drug without severe side effects was proposed. 相似文献
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Calipel A Abonnet V Nicole O Mascarelli F Coupland SE Damato B Mouriaux F 《Molecular cancer research : MCR》2011,9(9):1187-1198
RASSF1A gene, found at the 3p21.3 locus, is a tumor suppressor gene frequently hypermethylated in human cancers. In this study, we report that compared with melanocytes in normal choroid, RASSF1A is downregulated in uveal melanoma samples and in uveal melanoma cell lines. LOH at 3p21.3 was detected in 50% of uveal melanoma. Moreover, methylation of the RASSF1A promoter was detected in 35 of 42 tumors (83%) and RASSF1A was also weakly expressed at the mRNA level. These data indicate that LOH at the RASSF1A locus or RASSF1A promoter methylation may partly account for the suppression of RASSF1A expression observed in uveal melanoma. Furthermore, following ectopic expression in three RASSF1A-deficient melanoma cell lines (OCM-1, Mel270, and 92.1), RASSF1A weakly reduces cell proliferation and anchorage-independent growth of uveal melanoma cells without effect on ERK1/2 activation, cyclin D1 and p27(Kip1) expression. This study explored biological functions and underlying mechanisms of RASSF1A in the ERK1/2 pathway in normal uveal melanocytes. We showed that siRNA-mediated depletion of RASSF1A increased ERK1/2 activation, cyclin D1 expression, and also decreased p27(Kip1) expression in normal uveal melanocytes. Moreover, that the depletion of RASSF1A induced senescence-associated β-galactosidase activity and increased p21(Cip1) expression suggests that RASSF1A plays a role in the escape of cellular senescence in normal uveal melanocytes. Interestingly, we found that RASSF1A was epigenetically inactivated in long-term culture of uveal melanocytes. Taken together, these data show that depletion of RASSF1A could be an early event observed during senescence of normal uveal melanocytes and that additional alterations are acquired during malignant transformation to uveal melanoma. 相似文献
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该文采用阳离子脂质体Lipofectamine介导的方法将microRNA-34a转染入体外培养的人葡萄膜黑色素瘤细胞M23和SP6.5。应用BrdU法、细胞平板克隆形成实验检测转染microRNA-34a后对细胞增殖的影响,发现M23和SP6.5细胞增殖明显被抑制(P<0.01);并利用流式细胞技术检测转染microRNA-34a后细胞周期的变化,发现细胞停滞于G_1期;同时检测转染microRNA-34a后细胞caspase-3/7酶的活性,发现无明显改变。另外,Real-time PCR检测表明阿霉素处理后M23、SP6.5细胞中microRNA-34a的表达量上调(P<0.01)。用阿霉素处理转染microRNA-34a的M23、SP6.5细胞,检测caspase-3/7酶活性的改变,发现caspase-3/7酶活性显著增加(P<0.01)。本研究表明microRNA-34a通过抑制细胞周期来抑制体外培养的人葡萄膜黑色素瘤细胞的增殖,能够增加细胞对阿霉素的敏感性,但不直接诱导细胞凋亡。 相似文献