Screening of pancreatic cancer cell lines with oncolytic adenovirus Ad5ΔE1ACR2ΔE1B19k (Ad5ΔΔ) in combination with chemotherapeutics

Sammanfattning: Pancreatic cancer is one of the most aggressive and lethal forms of cancer, with high mortality and short survival. Chemotherapy using Gemcitabine is the most common treatment used but tumours frequently show resistance to the drug, necessitating the development of new and more potent therapy options. The use of replication-selective oncolytic adenoviruses constitutes a novel and promising way of combating cancer with proven efficacy and safety, as well as potentially synergistic effects when combined with chemotherapy. Previous work by Leitner et al (2009) has shown that combining Gemcitabine with an adenoviral mutant deleted in the anti-apoptotic E1B19K gene (Ad5Δ19K) increases the cytotoxic effect of the treatment in vitro and in vivo. Based on that work, an adenoviral mutant, Ad5ΔΔ, was created as a potential new candidate for treatment of pancreatic cancer. It has a deletion of the pRb-binding E1ACR2 region in addition to the E1B19K deletion, abolishing its ability to induce S-phase and to prevent apoptosis. It is hypothesised that, due to the double deletions, the mutant will show increased selectivity to cancer cells, making it safer than its single deleted counterpart (Ad5Δ19K) but still retaining efficacy. Ad5ΔΔ has already showed promising results in pancreatic cancer cell line PT45 and normal immortalised cells. In this project, the cytotoxic and replicative ability of Ad5ΔΔ is tested on a wider range of pancreatic cancer cells as well as its capacity to sensitise pancreatic cancer cells to Gemcitabine and Irinotecan, drugs used in treatment of pancreatic cancer. The results show efficient replication of the viral mutant in all cell lines and moderate cytotoxicity of viral single treatment. An antagonistic effect was observed between viral and Gemcitabine treatment in cell lines insensitive to chemotherapy. However, cells that showed sensitivity to single treatment with drugs could be significantly sensitised by combining Ad5ΔΔ infection with chemotherapy.