Efficient Human Interferon-α Gene Transfer to Neuroendocrine Tumor Cells with Long-Term and Stable Expression

Abstract

Interferon (IFN)-α has been used in the treatment of neuroendocrine (NE) tumors; however, the feasibility of IFN-α gene therapy has not been evaluated in NE tumor cells. In this study, human IFN-α2 (hIFN-α2) gene has been transferred into a NE tumor cell line BON. hIFN-α2-expressing BON cells were subcutaneously inoculated in nude mice. The results demonstrated that hIFN-α2 exerted significant antiproliferative effects on NE tumor cell lines (BON and LCC18) and other tumor cell lines (CA46 and SW480) as well as porcine aorta cell line. Furthermore, hIFN-α2 demonstrated its antineovascular activity in mice tumor and a direct antiangiogenic effect in chicken chorioallantoic membrane assay. hIFN-α2-expressing BON cells had a stable and long-term expression. Mice implanted with hIFN-α2-expressing BON cells showed a lower incidence, a delayed development and a significantly longer doubling time of the tumor compared to both wild-type (WT) and vector group. In addition, IFN-α significantly inhibited cell adhesion of WT BON cells. hIFN-α2-expressing BON tumors had a high level of hIFN-α2 protein. Finally, mice implanted with a mixture of WT and hIFN-α2-expressing BON cells (1:1) presented a delayed tumor development and had an even lower incidence of tumors than those implanted with hIFN-α2-expressing BON cells only. The doubling time of tumor was also longest in the mixture group. Our data suggest that hIFN-α2 gene therapy might be possible to be used as a new treatment for NE tumor patients. Further studies on the regulation of hIFN-α expression are needed, especially in combination with other cytokines, which could lead to a better understanding and improvements of hIFN-α gene therapy.