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A gene therapy for cancer based on the angiogenesis inhibitor, vasostatin
1Key Laboratory of Biotherapy of Human Diseases, Ministry of Education, PR China and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan, The People's Republic of China.
Abstract:
The growth and persistence of solid tumors and their metastasis are angiogenesis-dependent. Vasostatin, the N-terminal domain of calreticulin inclusive of amino acids 1-180, is a potent angiogenesis inhibitor. To investigate whether intramuscular administration of vasostatin gene has the antitumor activity in mouse tumor models, we constructed a plasmid DNA encoding vasostatin and a control vector. Production and secretion of vasostatin protein by COS cells transfected with the plasmid DNA encoding vasostatin (pSecTag2B-vaso) were confirmed by Western blot analysis and ELISA. Conditioned medium from vasostatin-transfected COS cells apparently inhibited human umbilical vein endothelial cell (HUVEC) and mouse endothelial cell (SVEC4-10) proliferation, compared with conditioned medium from the COS cells transfected with control vector or non-transfected cells. Treatment with pSecTag2B-vaso twice weekly for 4 weeks resulted in the inhibition of tumor growth and the prolongation of the survival of tumor-bearing mice. The sustained high level of vasostatin protein in serum could be identified in ELISA. Angiogenesis was apparently inhibited in tumor by immunohistochemical analysis. Angiogenesis was also inhibited in the chicken embryo CAM assay and mouse corneal micropocket assay. The increased apoptotic cells were found within the tumor tissues from the mice treated with plasmid DNA encoding vasostatin. Taken together, the data in the present study indicate that the cancer gene therapy by the intramuscular delivery of plasmid DNA encoding vasostatin, is effective in the inhibition of the systemic angiogenesis and tumor growth in murine models. The present findings also provide further evidence of the anti-tumor effects of the vasostatin, and may be of importance for the further exploration of the application of this molecule in the treatment of cancer.
Insights
Intramuscular gene therapy using vasostatin effectively inhibits tumor growth and angiogenesis in mice. This cancer gene therapy approach shows promise for treating solid tumors by targeting systemic angiogenesis.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Solid tumor growth and metastasis depend on angiogenesis.
- Vasostatin, derived from calreticulin, is a known inhibitor of angiogenesis.
Purpose of the Study:
- To evaluate the antitumor activity of intramuscular vasostatin gene delivery in mouse models.
- To assess the impact of vasostatin on systemic angiogenesis and tumor progression.
Main Methods:
- Construction of a plasmid DNA encoding vasostatin (pSecTag2B-vaso) and a control vector.
- In vitro assessment of vasostatin's effect on endothelial cell proliferation.
- In vivo studies involving intramuscular administration of pSecTag2B-vaso in tumor-bearing mice.
- Analysis of vasostatin levels, tumor growth, survival, angiogenesis, and apoptosis.
Main Results:
- Vasostatin protein production and secretion confirmed.
- Vasostatin inhibited endothelial cell proliferation in vitro.
- Intramuscular vasostatin gene therapy reduced tumor growth and prolonged survival in mice.
- Inhibition of tumor angiogenesis and increased apoptosis observed.
- Vasostatin demonstrated anti-angiogenic effects in chicken embryo and mouse corneal assays.
Conclusions:
- Intramuscular delivery of vasostatin gene via plasmid DNA is an effective strategy for cancer gene therapy.
- This approach inhibits systemic angiogenesis and tumor growth in murine models.
- Vasostatin's anti-tumor effects warrant further investigation for clinical applications in cancer treatment.