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Soluble Flt-1 gene therapy for peritoneal metastases using HVJ-cationic liposomes
1Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Japan.
Abstract:
Many studies have reported a close association between VEGF and tumor angiogenesis. The aim of the present study was to evaluate the effectiveness of gene therapy against cancer, including peritoneal metastasis, using a cDNA encoding a soluble type of Flt-1, one of the VEGF receptors. In a peritoneal metastasis model of MKN45 human gastric cancer cells, mice repetitively treated with intraperitoneal injections of HVJ-Fex, a type of HVJ-cationic liposome encapsulating a plasmid expressing soluble mFlt-1, exhibited smaller disseminated foci with fewer microvessels, thus resulting in a significantly longer survival period than the control mice. In another peritoneal metastasis model using HT1080S cells, a clone of HT1080 human fibrosarcoma cells stably transfected with hVEGF, treatments with HVJ-Fex also reduced the growth of disseminated foci without ascites formation. In conclusion, this study demonstrated that the peritoneal metastases of some cancers were largely dependent on VEGF, and that the repeated intraperitoneal transduction of a soluble flt-1 gene using HVJ-cationic liposomes suppressed peritoneal metastases, thereby contributing to a longer survival period.
Insights
Gene therapy using soluble Flt-1 delivered via HVJ-liposomes effectively suppressed peritoneal cancer metastasis in mice. This approach reduced tumor spread and microvessel formation, significantly improving survival rates in preclinical models.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Vascular Endothelial Growth Factor (VEGF) is crucial for tumor angiogenesis.
- Targeting VEGF signaling is a key strategy in cancer therapy.
- Peritoneal metastasis presents a significant clinical challenge.
Purpose of the Study:
- To evaluate the efficacy of gene therapy using soluble Flt-1 against cancer peritoneal metastasis.
- To assess the potential of HVJ-Fex, a liposomal delivery system for soluble Flt-1, in preclinical cancer models.
Main Methods:
- Utilized peritoneal metastasis models with MKN45 gastric cancer and HT1080S fibrosarcoma cells in mice.
- Administered repetitive intraperitoneal injections of HVJ-Fex, encapsulating a plasmid expressing soluble Flt-1.
- Evaluated tumor burden, microvessel density, ascites formation, and survival rates.
Main Results:
- HVJ-Fex treatment significantly reduced disseminated foci and microvessel formation in MKN45 models.
- Mice treated with HVJ-Fex showed significantly longer survival periods.
- In HT1080S models, HVJ-Fex treatment inhibited disseminated foci growth and prevented ascites formation.
Conclusions:
- Peritoneal metastases of certain cancers are highly dependent on VEGF.
- Intraperitoneal gene transfer of soluble Flt-1 using HVJ-cationic liposomes effectively suppresses peritoneal metastasis.
- This gene therapy approach offers a promising strategy for improving survival in peritoneal carcinomatosis.