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Systemic gene delivery expands the repertoire of effective antiangiogenic agents
1Geraldine Brush Cancer Research Institute at the California Pacific Medical Center, San Francisco, California 94115, USA.
Abstract:
Cationic liposome-DNA complex (CLDC)-based intravenous gene delivery targets gene expression to vascular endothelial cells, macrophages and tumor cells. We used systemic gene delivery to identify anti-angiogenic gene products effective against metastatic spread in tumor-bearing mice. Specifically, CLDC-based intravenous delivery of the p53 and GM-CSF genes were each as effective as the potent antiangiogenic gene, angiostatin, in reducing both tumor metastasis and tumor angiogenesis. Combined delivery of these genes did not increase anti-tumor activity, further suggesting that each gene appeared to produce its antimetastatic activity through a common antiangiogenic pathway. CLDC-based intravenous delivery of the human wild type p53 gene transfected up to 80% of tumor cells metastatic to lung. Furthermore, it specifically induced the expression of the potent antiangiogenic gene, thrombospondin-1, indicating that p53 gene delivery in vivo may inhibit angiogenesis by inducing endogenous thrombospondin-1 expression. CLDC-based delivery also identified a novel anti-tumor activity for the metastasis suppressor gene CC3. Thus, CLDC-based intravenous gene delivery can produce systemic antiangiogenic gene therapy using a variety of different genes and may be used to assess potential synergy of combined anti-tumor gene delivery and to identify novel activities for existing anti-tumor genes.
Insights
Cationic liposome-DNA complex (CLDC) gene therapy effectively targets tumors and reduces metastasis. CLDC delivery of p53 and GM-CSF genes showed potent anti-angiogenic and anti-tumor effects, similar to angiostatin.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Cationic liposome-DNA complex (CLDC) facilitates targeted gene delivery.
- Intravenous gene delivery can target tumor cells, macrophages, and vascular endothelial cells.
- Anti-angiogenic therapies are crucial for combating metastatic cancer.
Purpose of the Study:
- To identify effective anti-angiogenic gene products for metastatic cancer using CLDC-based systemic gene delivery.
- To evaluate the anti-tumor and anti-metastatic efficacy of p53, GM-CSF, and CC3 genes.
- To investigate the mechanism of p53-mediated anti-angiogenesis.
Main Methods:
- Systemic gene delivery using CLDC in tumor-bearing mice.
- Evaluation of tumor metastasis and angiogenesis.
- Assessment of gene transfection efficiency and expression of specific genes (e.g., thrombospondin-1).
Main Results:
- CLDC delivery of p53 and GM-CSF genes significantly reduced tumor metastasis and angiogenesis, comparable to angiostatin.
- Combined delivery of p53 and GM-CSF did not enhance anti-tumor activity, suggesting a common anti-angiogenic pathway.
- p53 gene delivery effectively transfected metastatic lung tumor cells and induced thrombospondin-1 expression.
- The metastasis suppressor gene CC3 demonstrated novel anti-tumor activity.
Conclusions:
- CLDC-based intravenous gene delivery is a viable strategy for systemic anti-angiogenic gene therapy.
- This approach can be used to assess gene synergy and discover new activities of anti-cancer genes.
- p53 gene therapy may inhibit angiogenesis by upregulating endogenous thrombospondin-1.