Angiostatin and endostatin gene therapy on murine lung metastases model utilizing cationic vector-mediated intravenous gene delivery

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Inhibition of angiogenesis by production of antiangiogenic factors should be a viable approach for cancer gene therapy. Recently, nonviral vectors have been suggested as an alternative to viruses. In this study, we investigated whether intravenous administration of endostatin gene complexed with GL67/DOPE or PEI22K could inhibit the development of lung metastatic lesions in murine models. The biological activity of the expressed endostatin was also determined by its ability to prevent the growth of lung metastases using stable transfectants from murine NFSa Y83 fibrosarcoma cells expressing endostatin. RT-PCR analysis in various organs of mice after intravenous injection of endostatin gene complexed with GL67/DOPE or PEI22K showed that the highest levels of mRNA expression were found in the lung, followed by heart, spleen, kidney and liver. In addition, immunohistochemistry of whole lungs after intravenous injection of the complexes showed that transfected cells were localized in a variety of cell types, including respiratory cells. Single intravenous injection of endostatin gene complexed either GL67/DOPE or PEI22K at the time of 3 days or 7 days from fibrosarcoma cells implantation resulted in striking inhibition of formation of lung metastases after 2 weeks (compared to empty plasmid complexed each vector, 87-98% reduction in the number of lung metastases and 53-59% reduction in lung weight). These results demonstrated the potential usefulness of intravenous delivery of an antiangiogenic gene, using cationic vector-mediated gene transfer, for treatment of disseminated cancers in lung.