Efficient human interferon-alpha gene transfer to neuroendocrine tumor cells with long-term and stable expression

• Interferon (IFN)-alpha has been used in the treatment of neuroendocrine (NE) tumors; however, the feasibility of IFN-alpha gene therapy has not been evaluated in NE tumor cells. In this study, human IFN-alpha2 (hIFN-alpha2) gene has been transferred into a NE tumor cell line BON. hIFN-alpha2-expressing BON cells were subcutaneously inoculated in nude mice. The results demonstrated that hIFN-alpha2 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-alpha2 demonstrated its antineovascular activity in mice tumor and a direct antiangiogenic effect in chicken chorioallantoic membrane assay. hIFN-alpha2-expressing BON cells had a stable and long-term expression. Mice implanted with hIFN-alpha2-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-alpha significantly inhibited cell adhesion of WT BON cells. hIFN-alpha2-expressing BON tumors had a high level of hIFN-alpha2 protein. Finally, mice implanted with a mixture of WT and hIFN-alpha2-expressing BON cells (1:1) presented a delayed tumor development and had an even lower incidence of tumors than those implanted with hIFN-alpha2-expressing BON cells only. The doubling time of tumor was also longest in the mixture group. Our data suggest that hIFN-alpha2 gene therapy might be possible to be used as a new treatment for NE tumor patients. Further studies on the regulation of hIFN-alpha expression are needed, especially in combination with other cytokines, which could lead to a better understanding and improvements of hIFN-alpha gene therapy.

Nyckelord

Actins/analysis

Animals

Cell Adhesion/drug effects/physiology

Cell Differentiation

Cell Line; Tumor

Cell Movement/drug effects/physiology

Cytoskeleton/chemistry/pathology

Gene Expression Regulation; Neoplastic/*genetics/physiology

Gene Therapy

Gene Transfer Techniques

Humans

Immunohistochemistry

Interferon-alpha/analysis/*genetics/physiology/therapeutic use

Mice

Mice; Nude

Neoplasm Invasiveness/physiopathology

Neovascularization; Pathologic/drug therapy

Neuroendocrine Tumors/*genetics/pathology/therapy

Recombinant Proteins/analysis/genetics

Swine

Time Factors

eIF-2 Kinase/analysis/genetics/physiology

MEDICINE

MEDICIN

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