Preclinical studies of a new generation retroviral vector for ovarian cancer BRCA1 gene therapy
| Autor: | Patrice S. Obermiller, Jeffrey T. Holt, David L. Tait |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
DNA
Complementary endocrine system diseases Tumor suppressor gene Genetic enhancement Genetic Vectors Genes BRCA1 Ovary Polymerase Chain Reaction Viral vector Mice Transduction Genetic medicine Animals Humans Tissue Distribution Vector (molecular biology) skin and connective tissue diseases Ovarian Neoplasms Mice Inbred BALB C business.industry Obstetrics and Gynecology Genetic Therapy medicine.disease Xenograft Model Antitumor Assays medicine.anatomical_structure Retroviridae Oncology Cell culture Toxicity Immunology Cancer research Female Ovarian cancer business |
| Zdroj: | Gynecologic oncology. 79(3) |
| ISSN: | 0090-8258 |
| Popis: | Objective. The aim of this study was to determine the preclinical stability, toxicity, and efficacy of a second-generation complement-resistant retroviral BRCA1 vector, MFG-BRCA1, for ovarian cancer gene therapy. Methods. MFG-BRCA1 was packaged in human 293 renal cells and manufactured and tested under cGMP conditions and is allowed for use in humans by the Food and Drug Administration. Vector stability studies were performed in mice and human serum by PCR analysis. Toxicity in the animals was assessed at necropsy, evaluating for histological signs of inflammation and organ damage. Tissue culture efficacy studies were performed on ovarian and breast cancer cells. Animal efficacy studies were conducted in female nu/nu mice. Mice were injected intraperitoneally with SKOV-3 ovarian cancer cells and tumors were allowed to grow for 4 weeks. Mice were treated intraperitoneally with MFG-BRCA1 or control vectors. Survival of animals was compared in the MFG-BRCA1 versus the control groups. Results. MFG-BRCA1 was more stable in human serum than LXSN-BRCA1sv. Toxicity as demonstrated by an inflammatory peritonitis was minimal. Significantly fewer clones were obtained using the MFG-BRCA1 versus the MFG vector alone in both cell lines. Efficacy studies in animals of MFG-BRCA1 demonstrated a near threefold increase in survival over control vector and twofold increase compared to the first generation LXSN-BRCA1sv vector. Conclusion. The reengineered complement-resistant MFG-BRCA1 retroviral vector is more effective and more stable than the previous generation LXSN-BRCA1sv vector. |
| Databáze: | OpenAIRE |
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