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Cell-based protein delivery system for the inhibition of the growth of pancreatic cancer: NK4 gene-transduced oral mucosal epithelial cell sheet.
PURPOSE: Pancreatic resection for pancreatic cancer is the only curative modality, but the high incidence of local recurrence after surgery results in a very poor prognosis. This study aims to develop a new therapeutic tool that could inhibit the growth of remnant cancer cells, which is based on local delivery of NK4 (hepatocyte growth factor antagonist) secreted from an NK4 gene-transduced oral mucosal epithelial cell (OMEC) sheet (NK4-sheet), which is adhered to the resected surface.
EXPERIMENTAL DESIGN: OMECs, harvested and cultured according to 3T3 feeder layer technique, were seeded on a collagen mesh-overlayered, biodegradable VICRYL mesh to produce an OMEC sheet. NK4 gene transduction was mediated by recombinant adenovirus (Ad-NK4). Applicability of OMECs for cell-based NK4 delivery was examined. An experimental model using nude mice was established to determine the effect of an NK4-sheet on both tumor growth and angiogenesis.
RESULTS: NK4 secreted from Ad-NK4-transduced OMECs suppressed MRC-5-induced invasion of pancreatic cancer cell lines. Heterotopically implanted gene-transduced OMECs remained for >/==" BORDER="0">10 days while gradually decreasing. NK4-sheets inhibited both angiogenesis and tumor growth in vivo.
CONCLUSION: Autologous OMEC was found to be suited to this purpose because of no secretion of hepatocyte growth factor, ease in harvesting from a patient, reasonably high proliferation potential, and no immune reaction. Although NK4-sheets under development exhibited a low level and short period of NK4 secretion, it is expected that this system may have a great potentiality of protein delivery system to target tissue at clinical situations when it is loaded with multilayered OMECs.
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