AAV-mediated persistent bevacizumab therapy suppresses tumor growth of ovarian cancer.
| Publication Type | Academic Article |
| Authors | Xie Y, Hicks M, Kaminsky S, Moore M, Crystal R, Rafii A |
| Journal | Gynecol Oncol |
| Volume | 135 |
| Issue | 2 |
| Pagination | 325-32 |
| Date Published | 08/06/2014 |
| ISSN | 1095-6859 |
| Keywords | Angiogenesis Inhibitors, Antibodies, Monoclonal, Humanized, Carcinoma, Cell Proliferation, Dependovirus, Genetic Therapy, Ovarian Neoplasms, Tumor Burden |
| Abstract | RATIONALE: Anti-angiogenesis therapies such as bevacizumab, the monoclonal antibody to vascular endothelial growth factor (VEGF), have been used against ovarian cancer, but transient and low peritoneal drug levels are likely a factor in treatment failure. We hypothesized that a single administration of adeno-associated virus (AAV)-mediated intraperitoneal expression of bevacizumab would direct persistent expression and suppress growth and metastasis of ovarian cancer. METHODS: AAVrh.10BevMab, a rhesus serotype 10 adeno-associated viral vector coding for bevacizumab, was evaluated for the capacity of a single intraperitoneal administration to persistently suppress peritoneal tumor growth in an intraperitoneal model of ovarian carcinomatosis with human ovarian cancer cells in nude immunodeficient mice. RESULTS: The data demonstrates that AAVrh10.BevMab mediates persistent and high levels of bevacizumab in the peritoneal cavity following a single intraperitoneal administration in mice. In AAVrh10.BevMab treated A2780 human ovarian cancer-bearing mice, tumor growth was significantly suppressed (p<0.05) and the area of blood vessels in the tumor was decreased (p<0.04). Survival of mice with A2780 xenografts or SK-OV3 xenografts was greatly prolonged in the presence of AAVrh10.BevMab (p<0.001). Administration of AAVrh10.BevMab 4days after A2780-luciferase cell implantation reduced tumor growth (p<0.01) and increased mouse survival (p<0.0001). Combination of AAVrh10.BevMab with cytotoxic reagents paclitaxel or topotecan proved to be more effective in increasing survival than treatment with cytotoxic reagent alone. CONCLUSION: A single administration of AAVrh10.BevMab provides sustained and high local expression of bevacizumab in the peritoneal cavity, and significantly suppresses peritoneal carcinomatosis and increases survival in an ovarian cancer murine model. |
| DOI | 10.1016/j.ygyno.2014.07.105 |
| PubMed ID | 25108232 |
| PubMed Central ID | PMC5084530 |