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Adenovirus-mediated delivery of antiangiogenic genes as an antitumor approach
E Régulier1, S Paul, M Marigliano
1TRANSGENE S.A., Strasbourg, France.
Abstract:
Based on the observation that the growth of solid tumors is dependent on the formation of new blood vessels, therapeutic strategies aimed at inhibiting angiogenesis have been proposed. A number of proteins with angiostatic activity have been described, but their development as therapeutic agents has been hampered by difficulties in their production and their poor pharmacokinetics. These limitations may be resolved using a gene therapy approach whereby the genes are delivered and expressed in vivo. Here we compared adenoviral delivery of endostatin, proliferin-related protein (PRP), and interferon-inducible protein 10 (IP10) genes. Recombinant adenoviruses carrying the three angiostatic genes express biologically active gene products as determined in vitro in endothelial cell proliferation and migration assays, and in vivo by inhibition of neoangiogenesis in rat chambers. Eradication of established tumors in vivo, in the murine B16F10 melanoma model in immunocompetent mice, was not achieved by intratumoral injection of the different vectors. However, the combination of intravenous plus intratumoral injections allowed rejection of tumors. Ad-PRP or Ad-IP10 were significantly more efficient than Ad-endostatin, leading to complete tumor rejection and prolonged survival in a high proportion of treated animals. These data support the use of in vivo gene delivery approaches to produce high-circulating and local levels of antiangiogenic agents for the therapy of local and metastatic human tumors.
Insights
Gene therapy using adenoviruses effectively delivers angiostatic genes like proliferin-related protein (PRP) and interferon-inducible protein 10 (IP10) to inhibit tumor growth. Combination therapy achieved complete tumor rejection and prolonged survival in mice.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Solid tumor growth relies on angiogenesis (new blood vessel formation).
- Angiostatic proteins inhibit angiogenesis but face production and pharmacokinetic challenges.
- Gene therapy offers a potential solution for delivering angiostatic agents in vivo.
Purpose of the Study:
- To compare adenoviral delivery of endostatin, proliferin-related protein (PRP), and interferon-inducible protein 10 (IP10) genes for cancer therapy.
- To evaluate the efficacy of these gene therapies in inhibiting angiogenesis and eradicating tumors.
Main Methods:
- Adenoviral vectors were engineered to deliver endostatin, PRP, and IP10 genes.
- In vitro assays assessed the biological activity of expressed proteins on endothelial cells.
- In vivo studies utilized rat chambers to evaluate neoangiogenesis inhibition and a murine melanoma model for tumor eradication.
Main Results:
- Adenoviral vectors successfully expressed biologically active angiostatic proteins in vitro and inhibited neoangiogenesis in vivo.
- Intratumoral injection alone did not eradicate established tumors.
- A combination of intravenous and intratumoral injections led to tumor rejection, with Ad-PRP and Ad-IP10 being more effective than Ad-endostatin.
Conclusions:
- Adenoviral gene delivery is a viable approach for producing antiangiogenic agents in vivo.
- Combination therapy with Ad-PRP or Ad-IP10 demonstrated significant efficacy in tumor rejection and improved survival.
- This strategy holds promise for treating local and metastatic human tumors.