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.
Liu
Minghui
M
Endocrine Oncology Unit, Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
Kilarski
Witold W
WW
Gerwins
Par
P
Oberg
Kjell
K
Zhou
Yinghua
Y
D000199:Actins / Q000032:analysis; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D003599:Cytoskeleton / Q000737:chemistry / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics* / Q000502:physiology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000032:analysis / Q000235:genetics* / Q000502:physiology / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D011994:Recombinant Proteins / Q000032:analysis / Q000235:genetics; D013552:Swine; D013997:Time Factors; D019892:eIF-2 Kinase / Q000032:analysis / Q000235:genetics / Q000502:physiology
D000199:Actins; D016898:Interferon-alpha; D011994:Recombinant Proteins; D019892:eIF-2 Kinase