Long-term expression of angiostatin suppresses metastatic liver cancer in mice
| Autor: | Ruian Xu, Xueying Sun, Sheung Tat Fan, Lai-yin Tse, Hua Li, Sue Xu, Hsiang-Fu Kung, Weidong Xiao, Geoffrey W. Krissansen, Pui-Chung Chan |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A Pathology medicine.medical_specialty Time Factors Lymphoma Angiogenesis Genetic enhancement Transgene Genetic Vectors Angiogenesis Inhibitors Apoptosis Endothelial Growth Factors Biology Drug Administration Schedule Metastasis Mice chemistry.chemical_compound medicine Animals Angiostatins Lymphokines Angiostatin Hepatology Vascular Endothelial Growth Factors Liver Neoplasms Gene Transfer Techniques Plasminogen Dependovirus medicine.disease Peptide Fragments Mice Inbred C57BL Vascular endothelial growth factor Vascular endothelial growth factor A Liver chemistry Hepatocytes Cancer research Intercellular Signaling Peptides and Proteins |
| Zdroj: | Hepatology. 37:1451-1460 |
| ISSN: | 0270-9139 |
| DOI: | 10.1053/jhep.2003.50244 |
| Popis: | Metastatic liver cancer has a very poor prognosis and lacks effective therapy. Anti-angiogenic therapies, which starve tumors of blood supply, have proven to be effective in preclinical models because tumor growth is angiogenesis dependent. However, long-term, high-level, and sustained expression of angiogenesis inhibitors, such as angiostatin, is necessary to prevent dormant tumors from becoming active again. To achieve this objective, we engineered a recombinant adeno-associated virus (AAV) vector encoding mouse angiostatin, an endogenous inhibitor of tumor vascularization. After intraportal delivery of this vector, high-level, stable transgene expression of angiostatin lasting for at least 6 months was observed locally in hepatocytes. Gene transfer of AAV-angiostatin via the portal vein led to significant suppression of the growth of both nodular and metastatic EL-4 lymphoma tumors established in the liver and prolonged the survival time of the mice. The growth of neovessels was inhibited significantly, and extensive apoptosis of tumor cells was observed. The anti-angiogenic activity of angiostatin was independent of vascular endothelial growth factor (VEGF). The AAV-angiostatin viruses did not appear to be toxic to mice, and there was no detectable apoptosis of hepatocytes. In conclusion, these encouraging results warrant future investigation of the use of AAV-mediated anti-angiogenic gene therapy for targeting unresectable liver metastases, especially after surgical removal of primary tumors. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text