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  • 1
    Keywords: CANCER CELLS ; CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; CELL ; CLINICAL-TRIAL ; COMBINATION ; evaluation ; Germany ; human ; IN-VIVO ; MODEL ; THERAPY ; NEW-YORK ; EFFICIENCY ; TRANSDUCTION ; primary ; prognosis ; DOMAIN ; culture ; GLYCOPROTEIN ; virus ; TRIAL ; TRIALS ; VECTORS ; VECTOR ; MEMBRANE ; CLINICAL-TRIALS ; chemotherapy ; EFFICIENT ; MELANOMA ; MALIGNANT-MELANOMA ; malignant melanoma ; CUTANEOUS MELANOMA ; ADENOVIRUS ; DACARBAZINE ; DOMAINS ; THERAPIES ; MELANOMA-CELLS ; VIROTHERAPY ; USA ; EFFICIENT TRANSDUCTION ; SHORT-TERM ; xenograft ; clinical trial ; ONCOLYTIC ADENOVIRUSES ; B ADENOVIRUSES ; CELLULAR RECEPTOR ; FUSOGENIC MEMBRANE-GLYCOPROTEINS ; REPLICATING ADENOVIRUS ; SUICIDE GENE-THERAPY ; ADENOVIRUS VECTORS ; IMMUNE-MEDIATED CONTROL ; oncolytic adenovirus
    Abstract: Advanced melanoma is associated with poor prognosis warranting the development of new therapeutics, such as oncolytic adenoviruses for immunovirotherapy. Since this approach critically depends on efficient transduction of targeted tumor cells, we screened a panel of 22 different adenovirus types for their internalization efficiency in melanoma cells. We demonstrated that the virions of Ad35, Ad38, and Ad3 have significantly higher internalization efficiency in melanoma cells than Ad5, so far the only adenovirus type used in clinical trials for melanoma. Therefore, we developed a conditionally replication-competent Ad5-based vector with the Ad35 fiber shaft and knob domains (Ad5/35) and compared its therapeutic efficacy with the homologous vector carrying the native Ad5 fiber. To further enhance virotherapy, we combined the oncolytic adenovirus vectors with intratumoral expression of measles virus fusogenic membrane glycoproteins H and F (MV-H/F) and dacarbazine chemotherapy. In a human melanoma xenograft model, established from a short-term culture of primary melanoma cells, we demonstrated that the Ad5/35-based therapy had a significantly greater anti-neoplastic effect than the homologous Ad5-based therapy. Furthermore, the combination of virotherapy, intratumoral expression of MV-H/F, and chemotherapy was clearly superior to single- or double-agent therapy. In conclusion, Ad35-based vectors are promising for the treatment of melanoma
    Type of Publication: Journal article published
    PubMed ID: 17960177
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  • 2
    Keywords: RECEPTOR ; CANCER CELLS ; CELLS ; EXPRESSION ; tumor ; CELL ; COMBINATION ; evaluation ; Germany ; human ; IN-VIVO ; MODEL ; THERAPY ; GENE ; EFFICIENCY ; COMPONENTS ; TISSUE ; TUMORS ; gene therapy ; DOMAIN ; animals ; treatment ; GLYCOPROTEIN ; virus ; VECTORS ; VECTOR ; MEMBRANE ; genetics ; COMPONENT ; EFFICIENT ; FIBER ; AD ; GENE-THERAPY ; heredity ; ifosfamide ; TUMOR-GROWTH ; VIRIONS ; development ; INTERNALIZATION ; USA ; animal ; microbiology ; LIMIT ; B ADENOVIRUSES ; CELLULAR RECEPTOR ; EPIDEMIC KERATOCONJUNCTIVITIS ; FUSOGENIC MEMBRANE-GLYCOPROTEINS ; REPLICATING ADENOVIRUS ; SUICIDE GENE-THERAPY
    Abstract: The clinical course of sarcoma warrants the development of new therapeutic options, such as gene therapy. However, the lack of coxsackievirus-adenovirus receptor (CAR) on sarcoma cells limits the efficacy of adenovirus type 5 (Ad5)-based gene therapy. In this study we evaluated 20 different adenoviral types and 1 Ads vector with RGD-containing fiber for their internalization efficiency in sarcoma cells. We demonstrated that adenovirus types 35, 3, 7, 11, 9, and 22 and Ad5LucRGD virions (ranked in descending order) have significantly higher internalization efficiency in the tested sarcoma cells when compared with Ads. On the basis of these results we developed a conditionally replication-competent adenoviral vector, Ad5 Delta 24.Ki center dot COX, and compared its oncolytic efficacy with that of Ads/35 Delta 24.Ki center dot COX, an Ads-based vector with the Ad35 fiber shaft and knob domains. Because both vectors differed only in the fiber, we were able to assess whether the adenoviral type with the most efficient internalization resulted also in enhanced treatment efficacy. We evaluated the antineoplastic activity of the oncolytic adenoviral vectors alone or in combination with the expression of measles virus fusogenic membrane glycoproteins and/or ifosfamide. The findings of our xenograft model were as follows: animals that received Ads/35-based therapy had significantly smaller tumors than animals treated with the homologous Ads-based vectors. In addition, we demonstrated that the combination of virotherapy, intratumoral expression of fusogenic membrane glycoproteins, and ifosfamide was clearly superior compared with treatment with individual components alone or as combinations of two components. In conclusion, Ad35-based vectors are promising for the treatment of sarcoma
    Type of Publication: Journal article published
    PubMed ID: 17184155
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