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    Keywords: EXPRESSION ; Germany ; QUANTIFICATION ; TIME ; PATIENT ; treatment ; ALPHA ; ASSAY ; DECREASE ; POLYMERASE-CHAIN-REACTION ; INTERFERON
    Abstract: We developed a real-time quantitative polymerase chain reaction-based assay for quantification of PRV-1 mRNA. We found that the expression of PRV-1 in granulocytes of patients with polycythemia vera (PV) who were pretreated with phlebotomy or hydroxyurea was significantly higher than that in normal controls. Surprisingly, in PV patients who had received interferon-alpha (IFN) for five or more months no significant PRV-1 upregulation was found. Observation of four PV patients treated with IFN over six months revealed a uniform time- dependent decrease of initially upregulated PRV-1
    Type of Publication: Journal article published
    PubMed ID: 12651277
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  • 4
    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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  • 5
    Keywords: CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; IONIZING-RADIATION ; IRRADIATION ; PROTECTION ; radiotherapy ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; Germany ; human ; LUNG ; THERAPY ; SYSTEM ; SYSTEMS ; GENE ; GENES ; PROTEIN ; TISSUE ; TRANSDUCTION ; INDEX ; TISSUES ; MR ; SUSCEPTIBILITY ; virus ; NO ; VECTORS ; ASSAY ; resistance ; VECTOR ; DAMAGE ; CANCER-CELLS ; CARCINOMA-CELLS ; LOCALIZATION ; SAFETY ; NORMAL TISSUE ; OVEREXPRESSION ; mutagenesis ; RECOMBINANT ADENOASSOCIATED VIRUS ; adeno-associated virus ; ADENOASSOCIATED VIRUS ; TUMOR CELLS ; RECOMBINANT ; adeno-associated virus 2 ; cervical carcinoma cells ; CANDIDATE GENES ; SUPEROXIDE-DISMUTASE ; HIGH-TITER ; INTRATRACHEAL INJECTION ; MNSOD-PL
    Abstract: Background and purpose: The success rate of any therapeutic approach depends on the therapeutic window, which can be increased by either raising the resistance of the normal tissue without protecting the tumor cells or by sensitizing the tumor cells but not the normal cells. Two promising candidate genes for normal tissue protection against radiation-induced damage may be the copper-zinc (CuZnSOD) and manganese superoxide-dismutase genes (MnSOD). The recombinant adeno-associated virus 2 (rAAV-2) offers attractive advantages over other vector systems: low immunogenicity, ability to infect dividing and non-dividing tissues and a low chance of insertional mutagenesis, due to extra-chromosomal localization. We report the production of novel rAAV-2-SOD vectors and the investigation of their modulating effects on HeLa-RC cells after irradiation. Material and methods: rAAV-2 vectors were cloned containing the human CuZnSOD or MnSOD as transgene and vector stocks were produced. In the initial experiments human cervix carcinoma (HeLa-RC) cells were chosen for their susceptibility to rAAV-2. On day 0, cells were seeded and transduced with the rAAV-2-SOD vectors. On day 3, cells were harvested, irradiated (0.5-8 Gy) and reseeded in different assays (FACS, SOD, MTT and colony assays). Results: Although 〉 70% of all cells expressed SOD and significant amounts Of functional SOD protein were detected, no radioprotective effect of SOD was observed after transduction of HeLa-RC cells. Conclusions: Novel rAAV-2-SOD vectors that could be produced at high titer, were able to efficiently infect cells and express the SOD genes. The absence of a radioprotective effect in HeLa-RC cancer cells indicates an additional safety feature and suggests that rAAV-mediated MnSOD overexpression might contribute to increasing the therapeutic index when applied for normal tissue protection. (C) 2004 Elsevier Ireland Ltd, All rights reserved
    Type of Publication: Journal article published
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  • 6
    Keywords: CANCER ; CELLS ; tumor ; BLOOD ; CELL ; Germany ; THERAPY ; TIME ; PATIENT ; TRANSPLANTATION ; treatment ; BONE-MARROW ; BREAST-CANCER ; TARGET ; chemotherapy ; EFFICIENT ; STEM-CELLS ; PROGENITOR CELLS ; CANCER-PATIENTS ; BODY ; CYCLOPHOSPHAMIDE ; CANCER PATIENTS ; PERIPHERAL-BLOOD ; MULTICENTER ; MULTIPLE-MYELOMA ; SINGLE ; HIGH-DOSE CHEMOTHERAPY ; multiple myeloma ; ONCOLOGY ; WEIGHT ; stem cells ; dexamethasone ; pegfilgrastim ; MOBILIZATION ; immunology ; STEM ; myeloma ; ADJUNCT ; ADMINISTRATION PEGFILGRASTIM ; apheresis ; DAILY FILGRASTIM ; peripheral blood stem cell ; PRETREATED LYMPHOMA PATIENTS ; REGIMEN ; STAGE-II
    Abstract: High-dose chemotherapy followed by autologous blood stem cell transplantation is the standard treatment for myeloma patients. In this study, CAD (cyclophosphamide, adriamycin, dexamethasone) chemotherapy and a single dose of peg. lgrastim (12 mg) was highly effective ve in mobilizing peripheral blood stem cells (PBSCs) for subsequent transplantation, with 88% of patients (n = 26) achieving the CD34(+) cell harvest target of 〉= 7.50 x 106 CD34(+) cells/ kg body weig ht, following a median of two apheresis procedures (range 1 -4) and with. rst apheresis performed at a median day 13 after CAD application (range 10 -20). Patients treated with peg. lgrastim showed a reduced time to. rst apheresis procedure from mobilization compared with. lgrastim-mobilized historical matched controls (n = 52, P = 0.015). The peg. lgrastim mobilization regimen allowed for transplantation of a median of 3.58 x 10 6 CD34(+) cells/ kg body weight while leaving suf. ficient stored cells for a second high-dose regimen and back-ups in most patients. Engraftment following transplantation was comparable to. lgrastim, with a median time of 14 days to leucocyte 〉= 1.0 x 109/l (range 10 -21) and 11 days to platelets 〉= 20 x 109/l (range 0 -15). The results of this study thus provide further support for the clinical utility of peg. lgrastim for the mobilization of PBSC following chemotherapy in cancer patients scheduled for transplantation
    Type of Publication: Journal article published
    PubMed ID: 17450182
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  • 7
    Keywords: CELLS ; IN-VITRO ; SURVIVAL ; tumor ; CELL ; Germany ; human ; IN-VIVO ; MODEL ; MODELS ; THERAPY ; VITRO ; SYSTEM ; SYSTEMS ; GENE ; TUMORS ; gene therapy ; TIME ; PATIENT ; SUSCEPTIBILITY ; virus ; MOUSE ; IN-SITU ; VECTORS ; DIFFERENCE ; VECTOR ; DELETIONS ; FISH ; MOUSE MODEL ; GENE-THERAPY ; adeno-associated virus ; mesothelioma ; PLEURAL MESOTHELIOMA ; ONCOLOGY ; RECOMBINANT ; malignant pleural mesothelioma ; suicide gene therapy ; THERAPIES ; TUMORIGENICITY ; methods ; BONE ; MPM ; VECTOR STOCKS
    Abstract: Background: The median survival time of patients with malignant pleural mesothelioma (MPM) remains poor. Therefore, novel therapeutic options are in high demand, and well characterized model systems for in vitro/vivo screening have to be established. Material and Methods: For this purpose, 3 MPM cell lines (H-Meso-1, MSTO-211H, and NCI-H28) were characterized and tested for susceptibility to recombinant adeno-associated virus 2 (rAAV2)-based vectors which have the potential for a loco-regional application. Results: Using multiplex fluorescence in situ hybridization, several recurrent chromosomal aberrations were observed for each of the MPM cell lines. Tumorigenicity of H-Meso-1 and MSTO-211H cells was shown in an intraperitoneal NOD/SCID mouse model, whereas NCI-H28 cells did not yield any tumors. Although all 3 cell lines were readily susceptible to rAAV2 vectors, differences in susceptibility were observed (H-Meso-1 〉 NCI-H28 〉 MSTO-211H). Furthermore, the efficacy of a potential suicide gene therapy using an rAAV2 suicide vector-transduced MPM cell line was determined in a proof-of-feasibility in vivo experiment. Conclusion: The characterized cell lines described here may serve as a model for in vitro and in vivo preclinical gene therapy for the treatment of MPM using rAAV2 suicide vectors
    Type of Publication: Journal article published
    PubMed ID: 18322411
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  • 8
    Keywords: EXPRESSION ; IN-VIVO ; THERAPY ; TYROSINE KINASE ; GENE ; TRANSDUCTION ; resistance ; CHRONIC MYELOID-LEUKEMIA ; AAV ; VIRUS VECTORS ; IMATINIB STI571
    Abstract: Gene transfer into chronic myelogenous leukemia (CML) cells may become of relevance for overcoming therapy resistance. Single-stranded pseudotyped adeno-associated viruses of serotypes 2/1 to 2/6 (ssAAV2/1--ssAAV2/6) were screened on human CML cell lines and primary cells to determine gene transfer efficiency. Additionally, double-stranded self-complementary vectors (dsAAVs) were used to determine possible second-strand synthesis limitations. On human CML cell lines, ssAAV2/2 and ssAAV2/6 were most efficient. On primary cells, ssAAV2/6 proved significantly more efficient (4.1 aEuroS +/-+/- aEuroS2.5%% GFP〈SU++〈/SU cells, p aEuroS== aEuroS0.011) than the other vectors (〈 1%%). The transduction efficiency could be significantly increased (45.5 aEuroS +/-+/- aEuroS13.4%%) by using dsAAV2/6 vectors (p aEuroS 〈 aEuroS0.001 vs. ssAAV2/6). In these settings, our data suggest conversion of single- to double-stranded DNA and cell binding/entry as rate-limiting steps. Furthermore, gene transfer was observed in both late and earlier CML (progenitor) populations. For the first time, efficient AAV gene transfer into human CML cells could be shown, with the potential for future clinical application.
    Type of Publication: Journal article published
    PubMed ID: 21323526
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  • 9
    Keywords: CELLS ; EXPRESSION ; INHIBITOR ; SURVIVAL ; tumor ; CELL ; Germany ; KINASE ; PHASE-I ; THERAPY ; TYROSINE KINASE ; VITRO ; SYSTEM ; GENE ; GENES ; PROTEIN ; cell line ; gene therapy ; LINES ; TIME ; PATIENT ; primary ; CELL-LINES ; treatment ; SUSCEPTIBILITY ; virus ; VECTORS ; VECTOR ; PROMOTER ; NUMBER ; PROMOTERS ; RATES ; CELL-LINE ; FUSION ; LINE ; STRATEGIES ; GENE-THERAPY ; RECOMBINANT ADENOASSOCIATED VIRUS ; GREEN FLUORESCENT PROTEIN ; adeno-associated virus ; ADENOASSOCIATED VIRUS ; mesothelioma ; MALIGNANT MESOTHELIOMA ; TUMOR-CELL-LINES ; THYMIDINE KINASE ; AGENT ; GFP ; RECOMBINANT ; REGRESSION ; adeno-associated virus 2 ; adeno-associated virus-2 ; elongation factor-1 alpha ; FUSION GENE ; GANCICLOVIR ; I CLINICAL-TRIAL ; malignant pleural mesothelioma ; suicide gene therapy ; TRANSGENE EXPRESSION ; VIRAL VECTOR
    Abstract: Although great efforts have been made to improve conventional therapy for diffuse malignant pleural mesothelioma, the median survival time of the patients after appearance of clinical symptoms remains poor. Due to confinement of the primary tumor to the pleural space, locoregional approaches are attractive strategies to improve the clinical outcome. In this context locoregional gene therapy using the recombinant adeno-associated virus 2 (rAAV-2) may be a new approach. Vectors were constructed containing a fusion gene, consisting of the Herpes simplexvirus thymidine kinase (HSV-TK) and the green fluorescent protein (GFP) genes; the former serving as suicide gene by converting the prodrug ganciclovir (GCV) into a toxic agent, thereby killing infected cells. Among a number of different tumor cell lines, rAAV-2 achieved high GFP expression levels in three mesothelioma cell lines (H-Meso-1, MSTO-211H, NCl-H28). A variety of rAAV-2-constructs containing different promoters were tested. The vector with the elongation factor-1alpha (EF-1alpha) promoter showed the highest expression rates. Expression could be further increased by addition of the tyrosine kinase inhibitor genistein. Using the rAAV-2-based suicide system, a nearly complete eradication of transduced and GCV-treated mesothelioma cells was observed. rAAV-2-based suicide gene therapy may be a new approach for locoregional treatment of mesothelioma. (C) 2004 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 15474666
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  • 10
    Keywords: CELLS ; SURVIVAL ; CELL ; CLINICAL-TRIAL ; Germany ; THERAPY ; SYSTEM ; SYSTEMS ; SITE ; SITES ; GENE ; GENES ; DRUG ; TISSUE ; gene therapy ; TRANSDUCTION ; gene transfer ; GENE-TRANSFER ; PATIENT ; SEQUENCE ; SEQUENCES ; treatment ; cytokines ; TARGET ; score ; TRIAL ; TRIALS ; VECTORS ; DESIGN ; resistance ; VECTOR ; CLINICAL-TRIALS ; chemotherapy ; genotoxicity ; REGION ; REGIONS ; SOFT ; PARAMETERS ; PROGENITOR CELLS ; SAFETY ; FREQUENT ; SELECTION ; INTEGRATION SITES ; adeno-associated virus-2 vector ; drug resistance ; DRUG-RESISTANCE ; EXPERIMENTAL BRAIN-TUMORS ; GENE-THERAPY ; HEMATOPOIETIC STEM-CELLS ; HERPES-SIMPLEX-VIRUS ; INTEGRATION SITE ; MARROW-REPOPULATING CELLS ; multidrug resistance-1 gene ; MULTIDRUG-RESISTANCE ; mutagenesis ; myeloprotective gene transfer ; PROJECT ; RECOMBINANT ADENOASSOCIATED VIRUS ; RESISTANCE MDR-1 GENE ; retroviral insertion ; retroviral vector ; RETROVIRAL VECTORS ; RETROVIRUS-MEDIATED TRANSFER ; SARCOMA ; SUICIDE GENE ; suicide gene transfm ; THYMIDINE KINASE GENE
    Abstract: Soft tissue sarcomas are a challenge for medical oncology and gene therapy. Protective and sensitising approaches that target normal and malignant tissue, respectively, both have their role for opening the therapeutic window. Recent data show that an intensive maintenance chemotherapy significantly reduces metastatic spread and improves disease-free survival in selected patient groups. However, delays of treatment due to cytopenia are frequent. Cytostatic drug resistance gene transfer to haematopoietic progenitor cells using retroviral vectors may allow further improvement of therapy results. In recent years, retroviral vector design, transduction techniques and engraftment capability of transduced cells have been optimised. Safety considerations of retroviral gene transfer have attracted public attention and can be addressed by analysis of genomic vector integration sites. A data bank project, 'retroviral insertion estimate of chromosomal integration' (RISC), containing 〉 200 integration sequences, has been set up by the authors' group to recognise critical genomic regions and genes involved with possible transforming capacity. Monitoring these parameters will allow the selection of the most suitable vectors for clinical application. Sarcoma cells seem to be highly susceptible to a variety of vectors, such as recombinant adeno-associated virus-2 (rAAV-2) vectors, adenoviral vectors or oncolytic herpes simplex viruses. Results from the first clinical trials with adenoviral vectors encoding for cytokines are promising. The other systems await further development towards clinical applications. Perspectives for further research are discussed in this review
    Type of Publication: Journal article published
    PubMed ID: 14640950
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