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hTERT-targeted E.coli purine nucleoside phosphorylase gene/ 6-methylpurine deoxyribose therapy for pancreatic cancer

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Chinese Medical Journal 2007年第15期120卷 1348-1352页

作者： ZHOU Jia-hua TANG Bo LIU Xun-liang HE Dao-wei YANG De-tong Department of Biliary-Pancreatic Surgery First Affiliated Hospital of Nanjing Medical University Nanjing 210029 China National Key Opening Laboratory of Biology and Medicine and Pharmacology Technology Nanjing University Nanjing 210008 China Clinical Medicine School of Southeast University Nanjing 210009 China Department of Biliary-Pancreatic Surgery Zhongda Hospital of Southeast University Nanjing 210009 China

Background Pancreatic cancer is one of the most common tumors and has a 5-year survival for all stages of less than 5%. Most patients with pancreatic cancer are diagnosed at an advanced stage and therefore are not candidates for surgical resection. In recent years, investigation into alternative treatment strategies for this aggressive disease has led to advances in the field of gene therapy for pancreatic cancer. E. coil purine nucleoside phosphorylase/6-methylpurine deoxyribose （ePNP/MePdR） is a suicide gene/prodrug system where PNP enzyme cleaves nontoxic MePdR into cytotoxic membrane-permeable compounds 6-methylpurine （MeP） with high bystander activity, hTERT is expressed in cell lines and tissues for telomerase activity. In this study we examined the efficacy of ePNP under the control of hTERT promoter sequences and assessed the selective killing effects of the ePNP/prodrug MePdR system on pancreatic tumors. Methods Recombinant pET-PNP was established. The protein of E. coil PNPase was expressed and an antibody to E. coil PNPase was prepared. Transcriptional activities of hTERT promoter sequences were analyzed using a luciferase reporter gene. A recombinant phTERT-ePNP vector was constructed. The ePNP/MePdR system affects SW1990 human pancreatic cancer cell lines in vitro. Results The hTERT promoter had high transcriptional activity and conferred specificity on cancer cell lines. The antibody to E. coil PNPase was demonstrated to be specific for the ePNP protein. The MePdR treatment induced a high in vitro cytotoxicity on the sole hTERT-ePNP-producing cell lines and affected SW1990 cells in a dose-dependent manner. Conclusions The hTERT promoter control of the ePNP/MePdR system can provide a beneficial anti-tumor treatment in pancreatic cancer cell lines including a good bystander killing effect.

关键词： hTERT promoter Escherichia coli purinenucleoside phosphorylase pancreatic cancer gene therapy

Current status of gene therapy for motor neuron disease

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Neural Regeneration Research 2006年第5期1卷 458-461页

作者： Xingkai An Rong Peng Shanshan Zhao Department of Neurology West China Hospital Sichuan University Chengdu 610041 Sichuan Province China Department of Pediatncs Second West China Hospital Sichuan University Chengdu 610041 Sichuan Province. China

OBJECTIVE： Although the etiology and pathogenesis of motor neuron disease is still unknown, there are many hypotheses on motor neuron mitochondrion, cytoskeleton structure and functional injuries. Thus, gene therapy of motor neuron disease has become a hot topic to apply in viral vectors, gene delivery and basic gene techniques. DATA SOURCES： The related articles published between January 2000 and October 2006 were searched in Medline database and ISI database by computer using the keywords ＂motor neuron disease, gene therapy＂, and the language is limited to English, Meanwhile, the related references of review were also searched by handiwork.STUDY SELECTION ： Original articles and referred articles in review were chosen after first hearing, then the full text which had new ideas were found, and when refer to the similar study in the recent years were considered first. DATA EXTRACTION ： Among the 92 related articles, 40 ones were accepted, and 52 were excluded because of repetitive study or reviews. DATA SYNTHESIS ： The viral vectors of gene therapy for motor neuron disease include adenoviral, adeno-associated viral vectors, herpes simplex virus type 1 vectors and lentiviral vectors. The delivery of them can be achieved by direct injection into the brain, or by remote delivery after injection vectors into muscle or peripheral nerves, or by ex vivo gene transfer. The viral vectors of gene therapy for motor neuron disease have been successfully developed, but the gene delivery of them is hampered by some difficulties. The RNA interference and neuroprotection are the main technologies for gene-based therapy in motor neuron disease. CONCLUSION ： The RNA interference for motor neuron disease has succeeded in animal models, and the neuroprotection also does. But, there are still a lot of questions for gene therapy in the clinical treatment of motor neuron disease.

关键词： gene therapy RNA interference gene delivery clinical treatment peripheral nerves direct injection gene transfer animal models hot topic

EXPERIMENTAL STUDY ON THE gene therapy OF MALIGNANT GLIOMA WITH ANTISENSE VEGF RNA

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Chinese Journal of Cancer Research 2003年第4期15卷 300-304页

作者：浦佩玉王建桢黄强张敬张云亭 Department of Neurosurgery Tianjin Medical University General Hospital Tianjing 300052

Objective: To study the effect of antisense VEGF RNA on rat C6 gliomas in vivo and find out the feasibility ofantiangiogenesis therapy with antisense VEGF RNA formalignant gliomas. Methods: Parental rat C6 glioma cells and C6 cells transfected with antisense VEGF cDNA were implanted intracerebrally and subcutaneously into SD rats as control and transfected group. Rats bearing cerebral and subcutaneous C6 gliomas were treated with antisenseVEGF cDNA as treated group and sense VEGF cDNA and empty vector as control of treated group. The generalmanifestation, survival time, MRI and histopathologicalchanges of all rats were observed. The volume ofsubcutaneously implanted tumors was determinedregularly. In situ hybridization and immunohistochemicalstaining were used for detection of VEGF gene expression of gliomas while PCNA immunostaining and TUNELmethod for examination of proliferation activity andapoptosis of gliomas, respectively. Results: The survival of the rats in transfected and treated group was prolonged.There were two rats surviving over 90 d in the treatedgroup and their tumors disappeared. The VEGF geneexpression, the number of microvessels and theproliferation activity were decreased and a large amount of apoptotic cells could be found in cerebral and subcutaneous gliomas in treated and transfected groups. Conclusion:VEGF is one of the candidate genes for gene therapy ofmalignant gliomas. Antisense VEGF RNA combined with other therapies should be studied further for enhancing the therapeutic effect of malignant gliomas.

关键词： Rat C6 glioma Antisense VEGF RNA gene therapy

HSVTK gene therapy for CarcinoembryonicAntigen-Producing Human Lung Cancer Cells

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Wuhan University Journal of Natural Sciences 1999年第3期4卷 367-371页

作者： Xiao Geng-fu Qi Yi-peng Cheng Xuan-hong Li Ling-yun

The long-term success of gene therapy for cancer relies heavily on the development of effective targeting systems. We investigate the possibility of targeted gene therapy using promoter of carcinoembryonic antigen (CEA) gene. By using luciferase reporter gene, we found that CEA promoter exhibit 16 times high activity in CEA-producing lung cancer cells, A549 than in nonproducing cells, Hela. We also constructed a recombinant expression plasmid pCEATK, in which CEA promoter drives the effector gene, thymidine kinase gene of Herpes Simplex Virus (HSVTK). A549 cells transfected with pCEATK became 865 times more sensitive to ganciclovir (GCV) than the control cells. However, Hela cells transfected with this plasmid remained resistant to GCV. These data indicate the potential for targeted gene therapy using the CEA promoter against CEA-producing tumor cells, such as lung cancer cells.

关键词： carcinoembryonic antigen Herpes Simplex Virus thymidine kinase gene gene therapy

Investigation of gene therapy of adenovirus in immune suppression

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Frontiers of Medicine 2008年第4期2卷 386-390页

作者： Xi XIA Beibei WANG Li CAO Gang CHEN Peng WU Yunping LU Jianfeng ZHOU Ding MA Molecular Cancer Center Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China

The aim of this paper is to investigate the safety of reconstructed adenovirus in immunosuppressive ther-apeutics and to explore the role of ciclosporin A in ant-agonizing the elimination of the vector.Several rats were given retroperitoneal injection of purified ADV-TK in order to obtain models.After 14 days’treatment of ciclos-porin A,samples of different periods were obtained,then stained with hematoxylin-eosin(HE)to detect inflam-mation reactions.Immunohistochemistry was used to examine the expression of adenovirus in organs.The results are as follows:(1)In HE stained sections of the organs,some transitory and reversible inflammation was detected.(2)In immunohistochemistry assay,recon-structed adenovirus decreased gradually as time went by in the control group,while it did not happen in the experi-mental group in which the adenovirus showed a relative increase compared with their counterparts(P,0.05).(3)The distributions of adenovirus in the liver,spleen and lung were higher than those in the other organs detected.Reconstructed adenovirus as a vector is definitely safe in immunosuppressive therapeutics,and ciclosporin A,to some extent,is able to consequently inhibit the immune response of the rats and prolong the existing period of adenovirus.

关键词： adenovirus gene therapy immunosuppres-sive therapeutics

Effects on the STAT3-shRNA in Non-Small-Cell Lung Cancer therapy: Design, Induction of Apoptosis, and Conjugation with Chitosan-Based gene Vectors

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Journal of Ocean University of China 2021年第5期20卷 1097-1108页

作者： ZHANG Wangwang ZHANG Yan JIANG Zhiwen SUN Le WANG Litong GU Zhiyang LI Wenya GUO Lili CHEN Xiaotong ZHANG Haibin HAN Baoqin CHANG Jing College of Marine Life Science Ocean University of ChinaQingdao 266003China Laboratory for Marine Drugs and Bioproducts Pilot National Laboratory for Marine Science and Technology(Qingdao)Qingdao 266235China

STAT3 plays a particularly important role in several cancer-related signal transduction pathways.Silencing STAT3 via RNA interference or small molecule inhibitors induces the apoptosis of tumor cells,thereby inhibiting the growth of the tumors.In this study,short-hairpin RNA sequences targeting the STAT3 genes were designed,synthesized,and then connected to pGPU6/GFP/Neo plasmids as the shRNA-expression vectors.The expression of STAT3-shRNA was analyzed by real-time PCR,western blotting,and cell apoptosis assay to study the growth and apoptosis of the cells.Then,the effect of STAT3 knockdown on the NCI-H1650 cells was studied in a tumor mouse model.The results revealed that,after an in vitro transfection,the proliferation of NCI-H1650 cells was inhibited,and the cells were induced to apoptosis.The mRNA and protein expression levels of STAT3 were downregulated in the STAT3-shRNA group.In vivo,the tumor mass and volume in the STAT3-shRNA group were significantly lower than in the other two groups.Both the in vivo and in vitro results demonstrated a long-period inhibiting effect on NSCLC,especially in vivo,when the tumor inhibition rate could reach 50%in the STAT3-shRNA group,which is an exciting outcome.Moreover,the study of the conjugation of STAT3-shRNA and chitosan-based vectors revealed that they could be combined steadily with good cytocompati-bility and transfection efficiency.These results together provide convincing evidence for the application of STAT3-shRNA used in the treatment of non-small lung cancer,which could be a promoting prospect for the development of gene therapy.

关键词： signal transducer and activator of transcription 3 short-hairpin RNA target downregulation chitosan-based vectors gene therapy

Experimental study of gene therapy with angiostatin gene in pancreatic cancer

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Hepatobiliary & Pancreatic Diseases International 2002年第3期1卷 452-457页

作者： Sheng-Li Nie Shi-Zhen Yuan the Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Medical College, Sun Yat-Sen University, Guangzhou 510120, China Department of Gastroenterology Sun Yat-Sen Memorial Hospital Sun Yat-Sen University Guangzhou 510120 China

Objective: To study the effects of angiostatin (AS) gene mediated by liposome on human pancreatic cancer cell line SW1990. Methods: Angiostatin gene was cloned into the eu- karyotic expression vector pRC/CMV. The recombi- nant of pRC/CMV-AS was introduced into the pan- creatic cancer cell line, SW1990. The mechanism of anti-tumor was studied and tested. Results: The eukaryotic expression vector pRC/ CMV-AS was identified by the restriction digest. pRC/CMV-AS was stably integrated into the target cells and expressed by Western blot and drug-sensi- tivity tests, and inhibited the vascular endothelial cells proliferation in vitro. In addition, the effects of the angiostatin vector on reducing the volume of tumors implanted in nude mouse models were also noted. Conclusion: This study demonstrated that the recom- binant pRC/CMV-AS mediated by liposome may play a potential role in the treatment of pancreatic cancer in the future.

关键词： angiostatin gene therapy pancreatic cancer vector angiogenesis liposome antiangiogenesis dormancy therapy

Augmentation of antitumor effect of adenovirus-mediated CD suicide gene therapy by cotransfer of interleukin 2 gene in melanoma-bearing mice

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Chinese Medical Journal 1999年第2期 67-70页

作者：鞠佃文曹雪涛陶群王宝梅陈国友于益芝

Objective To investigate the antitumor effect of combined adenovirus encoding E. coli cytosine deaminase (AdCD) and adenovirus encoding murine interleukin 2 (AdIL 2) on murine melanoma. Methods C57BL/6 mice were inoculated s.***.with B16F10 melanoma cells and 3 days later received injections of AdCD and/or AdIL 2 at the site of tumor inoculation followed by administration of 5 flurocytosine (5FC) 300 mg/kg per day for 10 days. Results Mice receiving AdCD/5FC/AdIL2 therapy developed tumors more slowly and survived much longer when compared with mice treated with AdCD/5FC, AdIL2, AdlacZ/5FC, or PBS. Immunological analysis illustrated that combined treatment could enhance NK activity and CTL activity. Flow cytometry demonstrated that AdCD/5FC/AdIL2 therapy increased the expression of MHC I and CD80 molecules on freshly isolated tumor cells. The CD4 + and CD8 + T cell infiltration in the tumor increased significantly after the combined therapy. Conclusions Our data showed that combined transfer of CD suicide gene and IL 2 gene could inhibit the tumor growth more significantly. The increased specific and non specific antitumor immunity might be responsible for the enhanced therapeutic effect.

关键词： gene therapy cytosine deaminase 5 fluorocytosine interleukin 2 adenovirus antitumor immunity

gene therapy for genetic Disease

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Progress in Natural Science:Materials International 1994年第5期 61-69页

作者：邱信芳薛京伦 Fudan University PRC Shanghai 200433 State Key Laboratory of genetic Engineering

There are more than 4700 kinds of genetic diseases and millions of sufferers worldwide. The deficient genes not only cause suffering to the patients, but bring tragedy to their descendants through heredity.People have been trying to use gene therapy strategy to cure hereditary diseases. With the development of technology, the laboratorial somatic cell gene therapy is moving towards clinical bed and has shown promising prospect. Hemophilia B is one of the several kinds of diseases that are suitable for somatic cell gene therapy owing to its small pathogenic gene and clear genetic

关键词： clotting factor IX gene therapy gene transfer hemophilia B.