Adenovirus-mediated Smad4 gene transfer inhibit.s tumor growth and metastasis of human pancreatic carcinoma

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Pancreatic cancer is one, of the most difficult neoplasms to treat curatively, because of its highly invasive and metastatic potential. We previously generated an antagonist. for HOF which played an important role in invasion and metastasis of human pancreatic cancer. This HGF-antagonist., NK4 has competitive inhibitory effects on interaction between HGF and C-MET receptor. Furthermore, NK4 inhibits proliferation and migration of distinct. type of endotbelial cells stimulated by angiogenic factor. In our privios study, adnovirus-mediated NK4 gene therapy suppressed the growth, invasiveness and metastasis of human pancreatic cancer cell lines with high expression of c-MET. However, there are a few pancreatic cancer cell lines with low level of c-MET expression, so we focused on Smad 4/DPC4. SMAD4 is a critical cofactor in signal transduction pathways activated in response to transforming growth factor-beta (TGF-beta)-related ligands, regulating cell growth and differentiation. Smad4 has been reported to express the inhibitory effects of on pancreatic tumour invasion and angiogenesis. Adenovirus mediated gene transfer in a panel of SMAD4 homozygouscleleted human pancreatic tumor cell lines should restore SMAD4 protein ex-pression and function. Thus adenovirus mediated Smad 4 gene therapy may be another attractive option for the treatment of pancreatic cancer. We are now preparing recombinat aclenovirus for cell growth and invasiveness of pancreatic cancer cell lines. The tumor growth of adenovirus-NK4 infected pancreatic cancer cells in nude mice will be analyzed.