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Abstract
Peritoneal carcinomatosis is common in advanced pancreatic cancer. Despite current standard treatment, patients with this disease until recently were considered incurable. Cancer gene therapy using oncolytic viruses have generated much interest over the past few years. Here, we investigated a new gene directed enzyme prodrug therapy (GDEPT) approach for an oncosuppressive virotherapy strategy using parvovirus H1 (PV-H1) which preferentially replicates and kills malignant cells. Although, PV-H1 is not potent enough to destroy tumors, it represents an attractive vector for cancer gene therapy. We therefore sought to determine whether the suicide gene/prodrug system, yCD/5-FC could be rationally combined to PV-H1 augmenting its intrinsic oncolytic activity for pancreatic cancer prevention and treatment. We showed that the engineered recombinant parvovirus rPVH1-yCD with 5-FC treatment increased significantly the intrinsic cytotoxic effect and resulted in potent induction of apoptosis and tumor growth inhibition in chemosensitive and chemoresistant cells. Additionally, the suicide gene-expressing PV-H1 infection reduced significantly the constitutive activities of NFκB and Akt/PI3K. Combination of their pharmacological inhibitors (MG132 and LY294002) with rPVH1-yCD/5-FC resulted in substantial increase of antitumor activity. In vivo, high and sustained expression of NS1 and yCD was observed in the disseminated tumor nodules and absent in normal tissues. Treatment of mice bearing intraperitoneal pancreatic carcinomatosis with rPVH1-yCD/5-FC resulted in a drastic inhibition of tumor cell spreading and subsequent increase in long-term survival. Together, the presented data show the improved oncolytic activity of wPV-H1 by yCD/5-FC and thus provides valuable effective and promising virotherapy strategy for prevention of tumor recurrence and treatment. In the light of this study, the suicide gene parvovirotherapy approach represents a new weapon in the war against pancreatic cancer. Moreover, these preliminary accomplishments are opening new field for future development of new combined targeted therapies to have a meaningful impact on advanced cancer.
Highlights
Pancreatic cancer is one of the leading causes of cancer-related deaths worldwide [1]
Because pancreatic adenocarcinomas are diverse in their genetic alterations and histology, we first evaluated the sensitivity of different pancreatic tumor cell lines to the parental wild type PVH1
Thereafter we verified the capacity of the engineered recombinant rPV-H1 expressing GFP or yeast cytosine deaminase (yCD) to infect these tumor cell lines
Summary
Pancreatic cancer is one of the leading causes of cancer-related deaths worldwide [1]. Prognosis of this disease remains disappointing due to its late diagnosis, low surgical resectability rates, and notorious resistance to standard chemotherapy and radiation [2,3]. Peritoneal carcinomatosis is a frequent cause of death in patients with advanced pancreatic carcinoma. Cytoreductive surgery and conventional treatment strategy has been generally believed to have only a small impact on patients with peritoneal dissemination. Further therapeutic approaches are needed in addition to conventional chemotherapy for this devastating disease. Key challenges facing cancer therapy are the development of tumor-specific drugs and the implementation of potent multimodal treatment regimens
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