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Transduction of Soluble Flt-1 Gene to Peritoneal Mesothelial Cells Can Effectively Suppress Peritoneal Metastasis of Gastric Cancer

¹ Department of Surgical Oncology, ² Department of Vascular Regeneration, and ³ Department of Surgery and Bioengineering, Institute of Medical Science, The University of Tokyo; ⁴ Department of Medical Science, University of Occupational and Environmental Health, Fukuoka, Japan; and ⁵ Department of Molecular Medicine, Sapporo Medical University, Sapporo, Japan

The prognosis of gastric cancer with peritoneal metastasis has not improved. Despite many promising studies, gene therapy has limited clinical application because of the lack of suitable vector systems to enable selective gene transduction to tumor cells. The aim of this study was to clarify whether gene therapy targeted to peritoneal mesothelial cells (PMCs) can inhibit peritoneal dissemination of gastric cancer. In vitro experiments showed that adenovirus expressing LacZ infected human omental tissue-derived PMCs more efficiently than human gastric cancer cell lines MKN1 and MKN45. When adenovirus expressing LacZ was injected into the peritoneal cavity of nude mice, the expression was detected in the peritoneum for at least 4 weeks. Furthermore, when adenovirus expressing soluble Flt-1 (Ad-sFLT-1) was i.p. administered in vivo, a high level of sFlt-1 protein could be detected in peritoneal lavage for 8 weeks. When MKN45 cells were i.p. inoculated 3 days after adenoviral vector injection, Ad-sFLT-1 markedly reduced the number of metastatic nodules larger than 1 mm in diameter on the peritoneal surface, and significantly prolonged the survival of nude mice without any significant side effects. Thus, peritoneal dissemination was significantly suppressed by a single i.p. injection of Ad-sFlt-1. Anti-angiogenic gene therapy targeted to PMCs could be a novel and practical strategy against peritoneal dissemination of gastric cancer, because it does not require tumor-specific gene transfer.

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