Construction of a Vesicular Stomatitis Virus Expressing Both a Fusogenic Glycoprotein and IL-12: A Novel Vector for Prostate Cancer Therapy
Abstract
Introduction: Vesicular Stomatitis Virus (VSV) infection of malignant cells results in oncolysis, sparing normal cells due to inherent differences in the interferon response pathway. In this study we explored enhancing VSV-G by engineering it to express the fusogenic glycoprotein from the Newcastle Disease Virus (VSV-F) to induce inter-cellular membrane fusion producing syncytia, which are incompatible with cell survival. Materials and Methods: Studies initially compared effects of VSV and VSV-F in vitro in prostate cancer cells lines, noting differential effects at different cell densities and the induction of apoptosis. Studies then compared effects of VSV vs VSV-F in a orthoptic mouse model of prostate cancer, focusing on tumor size at set time points and survival. Results: As the confluence of cells in the wells became greater, VSV-F showed more rapid cell kill than VSV-G (p<0.001). VSV-G mediated growth suppression by inducing apoptosis; this effect was slightly attenuated in VSV-F. In both single and serial viral injections VSV-F resulted in significant survival enhancement over control and VSV-G. Interestingly. Repetitive injections of VSV-G was no better than a single injection. Mechanistic studies suggested that some prostate cancer cell lines do not have as attenuated IFN response pathways, which can be over come by the high levels of IFN found within injected tumors. Discussion: Through the induction of the fusogenic protein, VSV-F maintain ns superior growth control of only moderately IFN responsive cell lines, most likely through an induced immune response.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2006
- Accession Number
- ADA462909
Entities
People
- Simmon J. Hall
Organizations
- Icahn School of Medicine at Mount Sinai