Retroviral IFN-α Gene Transfer Combined with Gemcitabine Acts Synergistically via Cell Cycle Alteration in Human Pancreatic Carcinoma Cells Implanted Orthotopically in Nude Mice

Abstract

Standard chemotherapy for pancreatic carcinoma is based on the use of gemcitabine. The clinical benefit of interferon-α (IFN-α) in advanced pancreatic cancer has been shown. However, it has been demonstrated that to be effective, there is a need for a constant amount of IFN-α at the site of the tumor. Therefore, we examined transfection of the human pancreatic cancer cell line DAN-G with a retrovirus encoding for IFN-α and the effect of IFN-α gene expression alone or in combination with gemcitabine on growth inhibition of DAN-G pancreatic cancer cells in vitro and in vivo in orthotopically implanted DAN-G cells in nude mice. DAN-G cells could be efficiently transfected retrovirally by the human IFN-α gene and significantly enhanced the levels of IFN-α mRNA. In vitro gemcitabine led to an alteration of G₁/S phase progression in transduced as well as untransduced cells, whereas IFN-α led to a significant decrease in cell viability in the transduced cells via delay in the progression of the S phase but no alteration of G₁/S phase progression. In vivo, tumor volume in mice was reduced significantly with gemcitabine combined with IFN-α (76% ± 8.3%) compared with gemcitabine alone (62.9% ± 7.3%) or IFN-α alone (24.4% ± 5.2%) compared with untreated animals. We conclude that gemcitabine and IFN-α concomitantly inhibited tumor cell proliferation significantly.