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  • PROTEIN  (7)
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  • 1
    Keywords: CANCER ; CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; CELL ; Germany ; KINASE ; THERAPY ; GENE ; GENE-EXPRESSION ; PROTEIN ; cell line ; TUMORS ; LINES ; DNA ; INFECTION ; REDUCTION ; CELL-LINES ; PHOSPHORYLATION ; treatment ; PARTICLES ; virus ; ISOFORM ; gene expression ; PROMOTER ; DECREASE ; ELEMENTS ; NUMBER ; CELL-LINE ; LINE ; TRANSFORMATION ; GLUCOSE ; FLUORESCENCE ; REGULATORY ELEMENTS ; adeno-associated virus ; ADENOASSOCIATED VIRUS ; VIRUS THYMIDINE KINASE ; TUMOR-CELL-LINES ; HIGH-LEVEL ; HaCaT ; Ras ; THYMIDINE KINASE ; SRC ONCOGENE ; ADENOASSOCIATED VIRUS VECTORS ; CYSTIC-FIBROSIS ; glucose transporter promoter,HSV thymidine kinase,suicide gene,AAV
    Abstract: In order to achieve tumor-specific targeting of adeno-associated virus (AAV)-mediated gene expression, the promoter of the glucose transporter isoform 1 (GLUT1) gene was cloned upstream of the enhanced green fluorescence protein (EGFP) and the herpes simplex virus thymidine kinase (HSVtk) gene. FACS analysis performed at 48 h after transient infection with rAAV/cytomegalovirus (CMV)egfp viral particles revealed an increase of fluorescence in all the cell lines tested. However, EGFP expression under control of the GLUT1 promoter element (rAAV/GTI-1.3egfp) was limited to the tumor cells and oncogene-transformed cells. Evidence for phosphorylation of the HSVtk substrates ganciclovir (GCV) and I-125-deoxycytidine was found in all transfected tumor cell lines compared to noninfected controls (HCT116: 111%; MH3924A: 130%; HaCaT-RT3: 257% increase), but not in HaCaT and HUVEC cells. Furthermore, tumor cells and the oncogene-transformed (ras) cell line HaCaT-RT3 showed a GCV-induced reduction in cell number (HCT116:-71%; MH3924A:-43% and HaCaT-RT3:-31%). No statistically relevant cytotoxic effect was observed in HaCaT (6% decrease) and HUVEC cells (2% decrease). Furthermore, a reduction of H-3-thymidine incorporation into the DNA was seen after treatment with GCV (HCT116: 38%; MH3924A: 33% and HaCaT-RT3: 37% decrease). In a therapy study of HSVtk-expressing tumors with GCV, we achieved total tumor remission
    Type of Publication: Journal article published
    PubMed ID: 14681725
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  • 2
    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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  • 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: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; TUMOR-CELLS ; carcinoma ; Germany ; MICROSCOPY ; THERAPY ; VITRO ; DISEASE ; GENE ; GENES ; PROTEIN ; LINES ; gene transfer ; GENE-TRANSFER ; INFECTION ; ANTIGEN ; BINDING ; CELL-LINES ; MOLECULE ; antibodies ; antibody ; virus ; leukemia ; LINE ; DELIVERY ; VACCINE ; FLUORESCENCE ; cell lines ; ADENOVIRUS ; FUSION PROTEIN ; LEUKEMIA-CELLS ; targeting ; RE ; targeted ; NEWCASTLE-DISEASE-VIRUS ; SINGLE-CHAIN ANTIBODY ; bispecific ; CLONED CDNA ; enhanced green fluorescent protein ; FOREIGN GENE ; Newcastle disease virus ; RNA VIRUSES
    Abstract: We developed a novel strategy to target recombinant Newcastle disease virus (NDV) to tumor cells for gene therapy. Modifying the virus with a bispecific fusion protein allowed virus receptor-independent tumor cell binding and gene transfer. The targeting molecule alphaHN-IL-2 contains an scFv antibody cloned from a neutralizing hemagglutinin-neuraminidase (HN)-specific hybridoma linked to the human cytokine IL-2. A recombinant NDV expressing the enhanced green fluorescent protein (NDFL-EGFP) was applied to show the expression of foreign genes in virus-infected tumor cells. At 24 hours after infection with the modified virus (NDFL-EGFP/alphaHN-IL-2), FACS analysis and fluorescence microscopy revealed neutralization of natural infection in IL-2 receptor-negative Jurkat leukemia cells, but targeted expression of EGFP in IL-2 receptor-positive human leukemia-derived MT-2 cells. The targeted gene delivery of NDFL-EGFP/alphaHN-IL-2 in MT-2 cells was blocked by the target ligand human IL-2. Selective virus entry to IL-2 receptor bearing tumor cells was also observed in a mixture of Jurkat and MT-2 cell lines. These results demonstrate that a recombinant NDV carrying a foreign gene can be successfully targeted to a specific tumor through a bispecific protein, which thereby increases the selectivity of gene transfer
    Type of Publication: Journal article published
    PubMed ID: 15605075
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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: APOPTOSIS ; CANCER ; CELLS ; tumor ; TUMOR-CELLS ; IN-VIVO ; THERAPY ; GENE ; PROTEIN ; TUMORS ; gene therapy ; RELEASE ; INFECTION ; animals ; DENDRITIC CELLS ; mechanisms ; TARGET ; VECTORS ; MELANOMA ; LYMPHOCYTES ; HUMAN-TUMOR-CELLS ; REPLICATION ; melanoma cells ; AUTONOMOUS PARVOVIRUSES ; autonomous parvovirus ; heat-shock protein ; tumor immunogenicity
    Abstract: Certain autonomous parvoviruses preferentially replicate in and kill in vitro-transformed cells and may reduce the incidence of spontaneous and implanted tumors in animals. Hence, these viruses and their derivatives are currently under evaluation as antitumor vectors. However, the mechanisms underlying their tumor-suppressing properties are not yet understood. We asked whether the lytic parvovirus H1 may enhance the immunogenicity of infected tumor cells. Out of human melanoma and gastrointestinal tumor cells, we selected the cell line SK29- Mel-1 being very susceptible to H1-induced apoptotic killing. Here, no upregulation of HLA class I and costimulatory molecules could be observed following H1 infection. However, a strong release of the immunogenic signal - the inducible heat- shock protein HSP72, but not constitutive HSP73 - was observed after H1 infection. The HSP72 release was higher and of longer duration than a conventional heat-shock treatment. We also explored H1 replication and cytotoxicity in human immune cells, as such cells may constitute targets for H1 virus replication. Long-term cultured lymphocytes, monocytes, immature and mature dendritic cells were not susceptible to H1 virus. Altogether, parvovirus-mediated cell killing may in vivo enhance tumor immunogenicity by HSP72 release and thus contribute to the antitumor effect of parvoviruses
    Type of Publication: Journal article published
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  • 7
    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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