Difficult to treat cancer entities such as sarcomas and peritoneal carcinosis challenged by suicide gene-armed virotherapeutic vector systems MeV and VACV

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URI: http://hdl.handle.net/10900/56040
Dokumentart: PhDThesis
Date: 2014
Language: English
Faculty: 4 Medizinische Fakultät
Department: Medizin
Advisor: Lauer, U.M. (Prof. Dr.)
Day of Oral Examination: 2014-08-19
DDC Classifikation: 610 - Medicine and health
Keywords: Peritonealkarzinose , Onkologie
Other Keywords: Onkolyse
License: http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=de http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=en
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Virotherapy is one of the novel anti-cancer strategies currently being investigated in preclinical experiments and clinical trials to fight cancer. Virotherapy is based on attenuated, replication-competent oncolytic viruses which selectively infect, replicate in and kill tumor cells without significantly harming healthy tissue. To advance the inherited oncolytic effect of viruses, trans¬genes like anti-angiogenic, immuno-stimulatory or suicide genes were inserted into the viral genome. For our examinations we chose two genetically modified viral vector systems, MeV (MeV-SCD) and VACV (GLV-1h68/GLV-1h95), which hold an outstanding safety profile and recently have entered extensive clinical testing as state-of-the-art viro-therapeutics. Both vector systems encode for marker genes and were armed with the suicide gene SCD which converts the non-toxic prodrug 5-FC into the common chemotherapeutic 5-FU. MeV-SCD, GLV-1h68 and GLV-1h95 were investigated with regard to their ability of infection, replication behaviour and oncolysis in vitro as potential virotherapeutics in the fight against cancer. Summing up our findings we could demonstrate that MeV-SCD was able to kill primarily therapy-resistant sarcoma cell lines expressing high levels of CD46 but failed to kill the latter expressing low levels of CD46. GLV-1h68 however was able to kill primarily therapy-resistant sarcoma cell lines, the peritoneal carcinosis causing cell lines CC531s and SKOV3ip.1 and also all the cell lines called ‘in vivo non-responders’ by Worschech et al. (2009). The SCOS cells, which were highly resistant to MeV-SCD, also resisted GLV-1h68 treatment to a lower extent. The armed vector GLV-1h95 finally led to massive cell mass reduction of SCOS cells. The additional effect of the suicide gene therapy with GLV-1h95 and 5-FC especially became obvious in our experiments with low MOI 0.1. Healthy PHHs were infected by GLV-1h68 but stayed mostly unaffected at MOI 0.1. Therefore, our virotherapeutics should be short-listed to fight against peritoneal carcinosis and sarcomas in order to overcome current therapy resistances.

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