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Synergistic antitumor effect of antiangiogenic factor genes on colon 26 produced by low-voltage electroporation
Masaya Uesato1, Yoshio Gunji, Takeshi Tomonaga
1Department of Academic Surgery (M9), Graduate School of Medicine, Chiba University 1-8-1, Inohana, Chuou-ku, Chiba-city, Chiba 260-8670, Japan.
Abstract:
Antiangiogenic factors are potent endothelial cell growth inhibitors that have been shown to inhibit angiogenesis in vitro and tumor growth in mice. We have demonstrated the synergistic antitumor effect of antiangiogenic genes (mouse angiostatin: pBLAST-mAngio; and mouse endostatin: p-BLAST42-mEndo XV) delivered to tumors by low-voltage electroporation in mouse colon 26 models. A synergistic antitumor effect was strongly suggested by in vivo tumor growth kinetics, as well as in survival studies with the mice. RT-PCR confirmed that the fragments of each gene were transferred by low-voltage electroporation in the tumor. Decreased microvessel density measurements in tumors also confirmed the efficacy of the synergistic antitumor effect of both genes. Significant growth inhibition was observed in mice treated with a 1:1 proportion of angiostatin and endostatin genes, and the order of the both genes transferred (first the endostatin gene, followed 1 week later by the angiostatin gene) had a profound inhibitory effect on tumor growth. These data suggest that in vivo delivery of antiangiogenic genes with low-voltage electroporation could be a possible therapeutic strategy for established solid tumors when both genes were applied in combination.
Insights
Combining antiangiogenic genes, mouse angiostatin and mouse endostatin, via low-voltage electroporation showed a synergistic antitumor effect in mouse models. This gene therapy approach significantly inhibited tumor growth and improved survival rates.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Antiangiogenic factors inhibit endothelial cell growth and angiogenesis.
- Tumor growth can be suppressed by inhibiting angiogenesis.
- Gene delivery methods are crucial for therapeutic efficacy.
Purpose of the Study:
- To investigate the synergistic antitumor effect of combining mouse angiostatin and mouse endostatin genes.
- To evaluate the efficacy of low-voltage electroporation for delivering these antiangiogenic genes.
- To determine the optimal delivery strategy for combined gene therapy.
Main Methods:
- Utilized mouse colon 26 models for in vivo studies.
- Employed low-voltage electroporation for gene delivery of pBLAST-mAngio and p-BLAST42-mEndo XV.
- Assessed tumor growth kinetics, survival rates, gene transfer via RT-PCR, and microvessel density.
Main Results:
- Demonstrated a synergistic antitumor effect from combined angiostatin and endostatin gene delivery.
- Confirmed successful gene transfer into tumors using low-voltage electroporation.
- Observed significant tumor growth inhibition and reduced microvessel density with a 1:1 gene proportion.
- Found that sequential delivery (endostatin then angiostatin) yielded a profound inhibitory effect on tumor growth.
Conclusions:
- Low-voltage electroporation is an effective method for in vivo delivery of antiangiogenic genes.
- Combined delivery of angiostatin and endostatin genes shows significant synergistic antitumor activity.
- Sequential gene delivery order impacts therapeutic efficacy, suggesting a potential optimized strategy for solid tumor treatment.
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