<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Genetic modification of oncolytic adenoviruses for anti-cancer-therapy"^^ . "Recombinant adenoviruses (Ad) have emerged as promising agents in therapeutic gene transfer, genetic vaccination and virotherapy. Virotherapy is defined as killing of cancer cells by specific virus infection, replication, cell lysis and virus spread by so called oncolytic viruses. “Armed” oncolytic Ad in which a therapeutic gene is genetically engineered into the virus and dependent on the tumour-selective replication of the virus for expression, represent a new and promising strategy for cancer treatment. This was achieved by using either an internal ribosomal entry site, a ‘self-cleaving’ 2A peptide or by an additional splice acceptor site to insert the reporter gene luciferase into the late transcription unit. In addition, I engineered novel melanoma-targeted, conditionally replicative Ad by replacing the promoter of the essential viral gene E1A with a cassette containing a human tyrosinase enhancer/promoter construct. While all oncolytic adenoviruses showed nearly similar cytotoxicity in melanoma cells, the melanoma specific Ads had a 10 – 1000 fold lower cytopathic effect in cell lines derived from various nonmelanocytic tissues. I showed that the mode of transgene expression and the locale of transgene insertion into the virus genome critically determine the efficacy of this approach. The most specific transgene expression (up to 1500 fold) was observed for an Ad which combines the tyrosinase promoter and the transgene expression by alternative splicing. In summary, I could show that transcriptional targeting combined with splice acceptor site mediated transgene expression is feasible and results in the highest levels of selectivity for replication and transgene expression. To combine the benefit of viral oncolysis with molecular chemotherapy, I inserted a suicide gene for gene directed enzyme prodrug therapy via optimized splice acceptor site into the virus genome. This approach resulted in indirect transcriptional targeting of genetic prodrug activation by the “armed”, melanoma specific Ad as well as in increased therapeutic effect of the oncolytic Ad. Therapeutic applications of Ad would benefit form a targeted virus cell entry into cancer cells. Such tropism-modification of Ad requires the ablation of their natural cell binding properties and the incorporation of cell-binding peptides. The short capsid fiber proteins of Ad subgroup F has recently been suggested as a tool for genetic Ad detargeting based on the reduced liver infectivity of corresponding fiber chimeric Ad-vectors in vitro and in vivo. Based on previous studies to determine functional insertion sites for peptide ligands into the Ad41 short fiber of Ad-vectors, I investigated the lytic potency of oncolytic Ad engineered with peptide ligands inserted in the Ad41 fiber. With the RGD model peptide I could demonstrate that the production of oncolytic Ad with ligands inserted into different loops of the fiber is feasible. Depending on the insertion site, viral replication, early and late viral gene expressions of the fiber-chimeric Ad differs in comparison to matching control viruses, carrying the same ligand in the HI loop of Ad5 fiber. The cytotoxicity of fiber-chimeric viruses is reduced irrespective of the insertion site. The results indicate that a decreased or delayed virus assembly could be a reason for my observation. Furthermore, I used fiber-chimeric virus as a novel platform for genetic targeting of Ad cell entry. I generated an ablated virus which targets EphA2 receptor expressing melanoma cells via inserted EphA2 peptide ligand. However, the lytic potency of the chimeric fiber Ad was significantly reduced compared to the matching control virus. Summarized, I developed an oncolytic Ad which combined effective oncolysis with targeted prodrug activation therapy of melanoma and I generated an oncolytic Ad showing peptide-dependent cell entry for targeted oncolysis of melanoma. "^^ . "2010" . . . . . . . . "Christina"^^ . "Quirin"^^ . "Christina Quirin"^^ . . . . . . "Genetic modification of oncolytic adenoviruses for anti-cancer-therapy (PDF)"^^ . . . "Quirin.phDVeroeffentlichung.pdf"^^ . . . "Genetic modification of oncolytic adenoviruses for anti-cancer-therapy (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Genetic modification of oncolytic adenoviruses for anti-cancer-therapy (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Genetic modification of oncolytic adenoviruses for anti-cancer-therapy (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Genetic modification of oncolytic adenoviruses for anti-cancer-therapy (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Genetic modification of oncolytic adenoviruses for anti-cancer-therapy (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #10851 \n\nGenetic modification of oncolytic adenoviruses for anti-cancer-therapy\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .