Selective Killing of Prostate Tumor Cells by Cytocidal Viruses

摘要

The goal was to develop novel vectors for therapy of prostate tumors based on vesicular stomatitis virus (VSV). The novelty in our approach is our ability to enhance the selectivity of VSV-induced killing of tumor cells versus normal cells by manipulating the viral genes that control the antiviral interferon response. Aim 1 was to identify mutations in VSV genes that enhance the differential killing of prostate tumor cells versus normal cells. Aim 2 was to identify VSV mutants that enhance the antiviral interferon response in prostate cells. Aim 3 was to determine whether VSV mutants have greater efficacy and safety than wild-type VSV in reducing prostate tumors in nude mice. We identified VSV mutants with enhanced ability to kill prostate tumor cells versus normal prostatic epithelial cells in culture (Aim 1). We showed that the same mutant had enhanced ability to induce antiviral interferon responses (Aim 2), and was an effective killer of interferon-nonresponsive prostate tumors established in nude mice. However, we found that other prostate tumors are responsive to interferons, and are resistant to treatment with oncolytic VSV in vivo. These data suggest that screening of prostate tumors for susceptibility may be necessary prior to treatment with oncolytic VSV.