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Suicide gene-armed measles vaccine virus for the treatment of pancreatic cancer
Virotherapy comprises a novel therapeutic mode by selectively destroying cancer cells through employment of oncolytic viruses. Currently, virotherapeutic approaches are investigated especially in hard to treat tumor entities such as pancreatic carcinoma which exhibit very “aggressive” tumor biologies.
In our study, we used a Measles Virus (MeV) vector being “armed” with the SCD suicide gene (MeV-SCD; Berchtold et al., 2013) which exerts a strong tumoricidal bystander effect by conversion of the prodrug 5-FC into the chemotherapeutic compound 5-FU. We employed a panel of 8 well characterised human pancreatic cancer cell lines and investigated whether MeV-SCD is able to specifically target and lyse these tumor cells with and without the addition of the prodrug 5-FC. In detail, we (i) measured the density of MeV entry-receptor CD46, (ii) determined primary infection rates of targeted tumor cells, (iii) performed western blotting for expression monitoring of viral proteins and (iv) generated viral growth curves to quantify production of progeny virus particles. Additionally, all tumor cell lines were (v) tested regarding their sensitivity towards the chemotherapeutics 5-FU and gemcitabine.
As a result, we were able to show that all 8 pancreatic carcinoma cell lines express the MeV entry receptor CD46 in sufficient amounts and therefore are susceptible to infection with MeV-SCD. Further, primary infection rates differed between the different tumor cell lines and were found to correlate with CD46 expression rates. All 8 tumor cell lines were found to respond to the cytotoxic effects of 5-FU, but 4/8 exhibited a significantly reduced sensitivity. Interestingly, 3 out of these 4 “5-FU resistant” tumor cell lines were found to respond efficiently to the combination of MeV-SCD with the prodrug 5-FC.
In summary, 7 out of 8 pancreatic cancer cell lines were proven to be highly sensitive to MeV-SCD treatment alone. Only one cell line showed a primary resistance, which successfully could be overcome by addition of 5-FC, which significantly amplified the MeV-SCD-based oncolytic activity.