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  • MICE  (8)
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  • 1
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; tumor ; TUMOR-CELLS ; CELL ; Germany ; human ; KINASE ; MODEL ; MODELS ; THERAPY ; VITRO ; EXPOSURE ; GENE ; PROTEIN ; EFFICIENCY ; cell line ; TISSUE ; TUMORS ; gene therapy ; LINES ; MICE ; TRANSDUCTION ; MR ; CELL-LINES ; treatment ; SUSCEPTIBILITY ; NOD/Scid mice ; virus ; VECTORS ; PROMOTER ; IMMUNODEFICIENT MICE ; CELL-LINE ; chemotherapy ; FUSION ; LINE ; CANCER-CELLS ; STRATEGIES ; GENE-THERAPY ; RECOMBINANT ADENOASSOCIATED VIRUS ; SARCOMA ; GREEN FLUORESCENT PROTEIN ; adeno-associated virus ; ADENOASSOCIATED VIRUS ; THYMIDINE KINASE ; adeno-associated virus 2 ; GANCICLOVIR ; suicide gene therapy ; TRANSGENE EXPRESSION
    Abstract: Soft-tissue sarcomas are mesenchymal tumors that respond poorly to systemic chemotherapy. Suicide gene therapy may be an alternative treatment strategy. Here we show a high susceptibility of human sarcoma cell lines for recombinant adeno-associated virus 2 (rAAV-2) suicide vectors: connective tissue sarcoma (HS-1), fibrosarcoma (HT-1080), Ewing sarcoma (RD-ES), Askin tumor (SK-N-MC), rhabdomyosarcoma (A-204) and soft-tissue sarcoma (WSKL-1). Several vectors containing the thymidine kinase (TK) gene under the control of either the cytomegalovirus promoter or the elongation-factor 1 alpha (EF1alpha) promoter were cloned and tested. Higher expression levels of the transgene were observed in the sarcoma lines when using the EF1alpha-suicide gene-containing vectors. A complete eradication of rAAV-2-EF1alpha-TK/eGFP (TK/enhanced green fluorescent protein fusion gene)-transduced tumor cells was shown following exposure to ganciclovir (2.5 mug/ml) in vitro, while at this dose level 〉 90% of mock-transduced tumor cells survived. Xenotransplantation tumor models ( intraperitoneal, subcutaneous) for the human sarcoma cell line HS-1 were established in nonobese diabetic/severe-combined immunodeficient mice. Mice transplanted with rAAV-2-EF1alpha-TK/eGFP-transduced and ganciclovir-exposed tumor cells survived 〉5 months while in the nontransduced group all mice had died approximately 1 month after inoculation. These data hold promise for further development of rAAV-2-based suicide gene therapy of sarcomas
    Type of Publication: Journal article published
    PubMed ID: 15280909
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  • 2
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; CELL ; SYSTEM ; transcription ; MICE ; TRANSDUCTION ; DNA ; MINUTE VIRUS ; REPLICATION ; ADENOVIRUS ; AUTONOMOUS PARVOVIRUSES ; RECOMBINANT PARVOVIRUS ; ADENOASSOCIATED VIRUS VECTORS ; pXX6 ; virus helper ; virus production
    Abstract: Preclinical studies using various cell culture and animal systems highlight the potential of recombinant rodent parvoviruses (recPVs) for cancer therapy. Production of these viruses is, however, not efficient and this hampers the clinical applications of these agents. In this study, we show that the adenovirus genes E2a, E4(orf6) and VA RNA increase the production of recPVs by more than 10-fold and reduce the time of production from 3 to 2 days in HEK293T cells. The helper effects of these genes can be observed with different recPVs, regardless of the nature and size of the inserted transgene. Furthermore, we generated a recombinant Adenovirus 5 carrying the parvovirus VP transcription unit. This helper, named Ad-VP, allows recPVs to be efficiently produced through a protocol based only on cell infection, making possible to use cell lines, such as NB324K, which are good producers of parvoviruses but are hardly transfectable. Hence, we could further improve viral titers and reduce time and costs of production. This Ad-VP helper-based protocol could be scaled up to a bioreactor format for the generation of the large amounts of recPVs needed for future clinical applications.
    Type of Publication: Journal article published
    PubMed ID: 21102423
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  • 3
    Keywords: CANCER ; CANCER CELLS ; CELLS ; INHIBITION ; PATHWAY ; TOXICITY ; SITE ; SITES ; GENE ; GENES ; PROTEIN ; PROTEINS ; transcription ; MICE ; ACTIVATION ; DNA ; INFECTION ; FAMILY ; TRANSCRIPTION FACTOR ; colon ; BINDING ; CYCLE ; virus ; TRANSCRIPTION FACTORS ; PROMOTER ; NUMBER ; CAPSID PROTEIN ; CANCER-CELLS ; COLON-CANCER ; MUTATIONS ; MINUTE VIRUS ; REPLICATION ; beta-catenin ; CONSTITUTIVE ACTIVATION ; autonomous parvovirus ; WNT SIGNALING PATHWAY ; signaling ; colon cancer ; INCREASE ; cancer therapy ; HUMAN-FIBROBLASTS ; oncolytic virus ; VIRUS-INFECTION ; H-1 PARVOVIRUS ; function ; Wnt signaling ; H1 ; SIMIAN VIRUS-40
    Abstract: The Wnt signaling pathway is activated by mutations in the adenomatous polyposis coli (APC) or beta-catenin genes in most colon cancers, leading to the transactivation of promoters containing binding sites for the Tcf/LEF family of transcription factors. We have previously shown that it is possible to confer colon cancer specificity on autonomous parvoviruses by inserting Tcf sites into the viral P4 promoter. The mutant Tcf promoters were responsive to activation of the Wnt pathway but the viruses replicated poorly. We show here that reduction of the number of Tcf sites from four to two leads to an increase in the efficiency of replication and toxicity of the viruses in Co115 colon cancer cells, with only a small reduction in selectivity for cells with an active Wnt signaling pathway. Despite this improvement, virus production by most colon cancer cells remained low. Analysis of parental phH1 virus infection of SW480 colon cancer cells showed that the nonstructural and capsid proteins were expressed, but single stranded DNA and progeny virus were not produced. This defect reflects the dependence of autonomous parvoviruses on host functions for many steps in their replication cycle and represents a major limitation to the use of selectively replicating parvoviruses for colon cancer therapy
    Type of Publication: Journal article published
    PubMed ID: 16151476
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  • 4
    Keywords: CANCER ; CANCER CELLS ; CELLS ; tumor ; CELL ; COMBINATION ; Germany ; IN-VIVO ; MICROSCOPY ; THERAPY ; VOLUME ; GENE ; gene therapy ; MICE ; ACTIVATION ; prognosis ; colon ; INJECTION ; treatment ; BREAST-CANCER ; PROMOTER ; genetics ; colorectal cancer ; COLORECTAL-CANCER ; chemotherapy ; CANCER-CELLS ; COLON-CANCER ; FLUORESCENCE ; GENE-THERAPY ; GREEN FLUORESCENT PROTEIN ; heredity ; CYP2B1 ; ifosfamide ; ACTIVATING CYTOCHROME-P450 ; cytochrome P450 ; ONCOLOGY ; colon cancer ; QUALITY-OF-LIFE ; ENZYME ; SULFATE ; HISTOLOGY ; COMPOUND ; CANCER-TREATMENT ; animal ; viability ; cytomegalovirus ; FORMULATION ; INTRAPERITONEAL HYPERTHERMIC CHEMOTHERAPY ; ISOPHOSPHORAMIDE MUSTARD ; LAPAROSCOPIC FLUORESCENCE DIAGNOSIS ; peritoneal carcinomatosis ; TARGETED CHEMOTHERAPY
    Abstract: The prognosis of peritoneal spread from gastrointestinal cancer and subsequent malignant ascites is poor, and current medical treatments available are mostly ineffective. Targeted chemotherapy with intraperitoneal prodrug activation may be a beneficial new approach. L293 cells were genetically modified to express the cytochrome P450 enzyme 2B1 under the control of a cytomegalovirus immediate early promoter. This CYP2B1 enzyme converts ifosfamide to its active cytotoxic compounds. The cells are encapsulated in a cellulose sulfate formulation (Capcell(TM)). Adult Balb/c mice were inoculated intraperitoneally with 1 x 10(6) colon 26 cancer cells, previously transfected with GFP to emit a stable green fluorescence, by injection into the left lower abdominal quadrant. Two or five day's later animals were randomly subjected to either i.p. treatment with ifosfamide alone or ifosfamide combined with microencapsulated CYP2B1-expressing cells. Peritoneal tumor volume and tumor viability were assessed 10 days after tumor inoculation by means of fluorescence microscopy, spectroscopy and histology. Early i.p. treatment with ifosfamide and CYP2B1 cells resulted in a complete response. Treatment starting on day 5 and single-drug treatment with ifosfamide resulted in a partial response. These results suggest that targeted i.p. chemotherapy using a combination of a prodrug and its converting enzyme may be a successful treatment strategy for peritoneal spread from colorectal cancer
    Type of Publication: Journal article published
    PubMed ID: 16096652
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  • 5
    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; tumor ; TUMOR-CELLS ; CELL ; Germany ; human ; IN-VIVO ; LUNG ; VITRO ; VIVO ; lung cancer ; LUNG-CANCER ; DEATH ; PROTEIN ; EFFICIENCY ; TISSUE ; TUMORS ; MICE ; TRANSDUCTION ; ACTIVATION ; LIGAND ; INDUCTION ; T-CELLS ; SUPPRESSION ; PARTICLES ; virus ; VECTOR ; CELL-DEATH ; COLORECTAL-CANCER ; NUDE-MICE ; EFFICIENT ; CANCER-CELLS ; NORMAL TISSUE ; RETROVIRAL VECTORS ; CONSTRUCTION ; VIRAL VECTORS ; TUMOR CELLS ; TRAIL ; TRANSDUCTION EFFICIENCY ; APOPTOSIS-INDUCING LIGAND ; INTEGRATION ; RECOMBINANT ; RE ; TUMOR-GROWTH ; EX-VIVO ; LENTIVIRAL VECTOR ; analysis ; TUMOR-CELL ; TRANSFORMED-CELLS ; EVALUATE ; in vivo ; EXTENT ; NECROSIS ; APO2L/TRAIL ; anticancer agent ; translational research ; CANCER GENE-THERAPY ; gene therapy for solid tumors
    Abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, which selectively induces apoptosis in many transformed cells without apparent toxic side effects in normal tissue. We recently described the construction and characterization of a lentiviral vector for expression of TRAIL. In this report, we evaluate its suitability for therapeutic application. In vitro, we observed specific induction of apoptosis upon transduction in human lung cancer cells. Cell death was partially dependent on successful integration and TRAIL expression by the vectors, but was to some extent mediated by protein carryover, as we found TRAIL protein associated with virus particles. Transduction of subcutaneously growing lung tumors on nude mice with lentiviral TRAIL mediated a transient suppression of tumor growth. Analysis of tumor sections revealed that transduction efficiency of lentiviral control vector but not of lentiviral TRAIL vector was high. This was because of the direct cytotoxic activity of recombinant TRAIL present in viral particles, which prevented efficient tumor transduction. These data therefore suggest that enveloped viral vectors constitutively expressing TRAIL are well suited for ex vivo applications, such as the transduction of tumor-homing cells, but may have a lower effect when used directly for the transduction of tumor cells in vivo
    Type of Publication: Journal article published
    PubMed ID: 17186015
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  • 6
    Keywords: CANCER ; CELLS ; ENDOTHELIAL-CELLS ; GROWTH ; IN-VITRO ; CELL ; FACTOR RECEPTOR ; IN-VIVO ; INHIBITION ; MODEL ; THERAPY ; GENE ; MICE ; TUMOR-NECROSIS-FACTOR ; DENDRITIC CELLS ; genetics ; CENTRAL-NERVOUS-SYSTEM ; GENE-THERAPY ; INTERFERON-GAMMA ; CYTOKINE ; GLIOMA ; T-CELL-ACTIVATION ; IP-10/CXCL10 ; MEDIATED DELIVERY ; parvoviral vector
    Abstract: Interferon-gamma-inducible protein 10 is a potent chemoattractant for natural killer cells and activated T lymphocytes. It also displays angiostatic properties and some antitumor activity. Tumor necrosis factor-alpha (TNF-alpha) is a powerful immunomodulating cytokine with demonstrated tumoricidal activity in various tumor models and the ability to induce strong immune responses. This prompted us to evaluate the antitumor effects of recombinant parvoviruses designed to deliver IP-10 or TNF-alpha into a glioblastoma. When Gl261 murine glioma cells were infected in vitro with an IP-10- or TNF-alpha-transducing parvoviral vector and were subcutaneously implanted in mice, tumor growth was significantly delayed. Complete tumor regression was observed when the glioma cells were coinfected with both the vectors, demonstrating synergistic antitumor activity. In an established in vivo glioma model, however, repeated simultaneous peritumoral injection of the IP-10- and TNF-alpha-delivering parvoviruses failed to improve the therapeutic effect as compared with the use of a single cytokine-delivering vector. In this tumor model, cytokine-mediated immunostimulation, rather than inhibition of vascularization, is likely responsible for the therapeutic efficacy
    Type of Publication: Journal article published
    PubMed ID: 18670452
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  • 7
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; tumor ; carcinoma ; CELL ; Germany ; human ; IN-VIVO ; INHIBITION ; THERAPY ; VIVO ; SYSTEM ; TOOL ; HEPATOCELLULAR-CARCINOMA ; GENE ; GENE-EXPRESSION ; EFFICIENCY ; cell line ; TUMORS ; gene therapy ; MICE ; TRANSDUCTION ; gene transfer ; GENE-TRANSFER ; INFECTION ; murine ; treatment ; PARTICLES ; virus ; ELEMENT ; TRANSGENIC MICE ; gene expression ; VECTORS ; VECTOR ; PROMOTER ; ELEMENTS ; REQUIRES ; NUDE-MICE ; CELL-LINE ; LINE ; EFFICIENT ; MELANOMA ; GROWTH-INHIBITION ; Jun ; MALIGNANT-MELANOMA ; malignant melanoma ; GENE-THERAPY ; RECOMBINANT ADENOASSOCIATED VIRUS ; THYMIDINE KINASE GENE ; REGULATORY ELEMENTS ; adeno-associated virus ; ADENOASSOCIATED VIRUS ; nude mice ; HIGH-LEVEL ; TISSUE-SPECIFIC EXPRESSION ; growth inhibition ; CYTOTOXICITY ; F ; ENHANCER ; RECOMBINANT ; GANCICLOVIR ; suicide gene therapy ; HUMAN-MELANOMA ; THERAPIES ; GLIOMA-CELLS ; MELANOMA-CELLS ; ADENOASSOCIATED VIRUS VECTORS ; REPORTER GENE ; NONDIVIDING CELLS ; human melanoma ; herpes simplex virus thymidine kinase ; melanoma inhibitory activity
    Abstract: Suicide gene therapy of malignant melanoma essentially requires efficient gene transfer and highly selective therapeutic gene expression. To achieve this, recombinant adeno-associated virus (rAAV) particles were constructed containing the tissue-specific promoter of the human melanoma inhibitory activity (hMIA) gene combined with four copies of the enhancer element of the murine tyrosinase gene. Three melanoma and one cervix carcinoma cell line were infected with rAAV particles carrying a reporter gene under control of the enhancer/hMIA promoter in order to determine transcriptional activity and specificity of this system. Viral particles containing the enhancer/hMIA promoter mediated reporter gene activity only in melanoma cells, whereas infection with a cytomegalovirus (CMV)-based promoter construct induced unspecific gene expression. Correspondingly, transient transduction with viral particles bearing the HSVtk gene under the control of the enhancer/MIA promoter elements followed by treatment with ganciclovir (GCV) resulted in growth inhibition only in melanoma cells, whereas the CMV promoter-based construct induced unspecific cytotoxicity. In vivo experiments in nude mice demonstrated that tumors originating from human melanoma cells disappeared after stable, but not transient transduction with vectors bearing the HSVtk gene under the control of the enhancer/hMIA promoter in response to GCV application. In face of higher transduction efficiency, these rAAV particles might therefore be a useful tool for suicide gene therapy of malignant melanoma
    Type of Publication: Journal article published
    PubMed ID: 15118759
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  • 8
    Keywords: CANCER ; CELLS ; GROWTH ; IN-VITRO ; tumor ; CELL ; Germany ; human ; LUNG ; THERAPY ; TOOL ; liver ; POPULATION ; GENE ; GENES ; PROTEIN ; DIFFERENTIATION ; gene therapy ; MICE ; TRANSDUCTION ; gene transfer ; GENE-TRANSFER ; kidney ; BONE-MARROW ; MOUSE ; NUMBER ; genetics ; NUDE-MICE ; FUSION ; MIGRATION ; STEM-CELLS ; PROGENITOR CELLS ; SELECTION ; GENE-THERAPY ; RETROVIRAL VECTORS ; pancreatic cancer ; heredity ; VELOCITY ; ONCOLOGY ; homing ; XENOGRAFTS ; THERAPIES ; EX-VIVO ; HUMAN BONE-MARROW ; stem cells ; BONE ; EXTENT ; microbiology ; ENGLAND ; STEM ; UMBILICAL-CORD BLOOD ; MEDICINE ; biotechnology ; modification ; mesenchymal stem cells ; DELIVERY VEHICLES ; INDUCIBLE RNA INTERFERENCE ; lentiviral transduction ; TARGETED-DELIVERY
    Abstract: Genetic modification of human bone marrow mesenchymal stem cells ( MSC) is highly valuable for their exploitation in basic science and therapeutic applications, for example in cancer. We present here a new, fast and easy-to-use method to enrich a functional population of lentiviral (LV)-transduced MSC expressing enhanced green fluorescent protein (eGFP). We replaced the eGFP gene by a fusion gene of puromycin acetyltransferase and eGFP. Upon LV gene transfer and puromycin selection, we quickly obtained a pure transduced MSC population, in which growth, differentiation capacity and migration preferences were not compromised. Furthermore, we are the first to report the migration velocity of MSC among which 30% were moving and velocity of about 15 mu mh(-1) was not altered by LV transduction. Manipulated MSC underwent senescence one passage earlier than non-transduced cells, suggesting the use for therapeutic intervention in early passage numbers. Upon tail vein application in nude mice, the majority of LV-transduced MSC could be detected in human orthotopic pancreatic tumor xenografts and to a minor extent in mouse liver, kidney and lung. Together, LV transduction of genes to MSC followed by puromycin selection is a powerful tool for basic research and improves the therapeutic prospects of MSC as vehicles in gene therapy
    Type of Publication: Journal article published
    PubMed ID: 18202717
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