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Previously, we have shown that the genetically modified human neural stem cells (NSCs) show remarkable migratory and tumor-tropic capability to track down brain tumor cells and deliver therapeutic agents with significant therapeutic benefit. Human NSCs that were retrovirally transduced with cytosine deaminase (CD) gene showed remarkable ‘bystander killer effect’ on the glioma cells after application of the prodrug, 5-fluorocytosine (5-FC). Interferon-β (IFN-β) is known for its antiproliferative effects in a variety of cancers. In our pilot clinical trial in glioma, the IFN-β gene has shown potent antitumor activity in patients with malignant glioma. In the present study, we sought to examine whether human NSCs genetically modified to express both CD and IFN-β genes intensified antitumor effect on experimental glioma. In vitro studies showed that CD/IFN-β-expressing NSCs exerted a remarkable bystander effect on human glioma cells after the application of 5-FC, as compared with parental NSCs and CD-expressing NSCs. In animal models with human glioma orthotopic xenograft, intravenously infused CD/IFN-β-expressing NSCs produced striking antitumor effect after administration of the prodrug 5-FC. Furthermore, the same gene therapy regimen prolonged survival periods significantly in the experimental animals. The results of the present study indicate that the multimodal NSC-based treatment strategy might have therapeutic potential against gliomas. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is the most aggressive type of all primary brain tumors, with an overall median survival <1 year after diagnosis. Despite introduction of multimodal treatment approaches, the prognosis has not improved significantly over the past 50 years. In this study we investigated the effect of intracerebroventricular (ICV) injection of an adeno-associated virus (AAV) vector encoding human interferon-β (AAV-hIFN-β) on glioblastoma growth. Recently, we found that peritumoral parenchymal transduction with an AAV-hIFN-β was exceptionally efficient in eradicating GBM brain tumors. However, the extensive infiltration and migration displayed by glioblastoma cells in patients may leave a significant number of tumor cells outside a local therapeutic zone created by intraparenchymal delivery of AAV vectors. Here we show that pretreatment of mice by ICV infusion of an AAV-IFN-β completely prevents tumor growth in an orthotopic model of GBM. Furthermore, ICV infusion of AAV-IFN-β into mice bearing preestablished U87 intracranial tumors improved their survival compared to mice infused through the same route with a control AAV vector. These data suggest that ICV injection of AAV vectors encoding antitumor proteins is a promising approach deserving further consideration for the treatment of GBM.Cancer Gene Therapy (2009) 16, 664–671; doi:10.1038/cgt.2009.8; published online 6 February 2009 [ABSTRACT FROM AUTHOR]

We have previously reported that adenoviral vector-mediated interferon (IFN)-β gene therapy inhibits orthotopic growth of human prostate cancer cells in nude mice. The purpose of this study was to determine efficacy and mechanisms of this therapy in immune-competent mice. TRAMP-C2Re3 mouse prostate cancer cells infected with 100 multiplicity of infection (MOI) of adenoviral vector encoding for mouse IFN-β (AdmIFN-β), but not AdE/1 (a control adenoviral vector), produced approximately 60 ng/105 cells/24 h of IFN-β. The tumorigenicity of AdmIFN-β-transduced cells was dramatically reduced in the prostates of C57BL/6 mice. A single intratumoral injection of 2 × 109 PFU (plaque-forming unit) of AdmIFN-β inhibited tumor growth by 70% and prolonged survival of tumor-bearing mice. Intriguingly, this AdmIFN-β therapy did not alter the growth of tumors in inducible nitric oxide synthase (iNOS)-null C57BL/6 mice. Immunohistochemical analysis revealed that treatment of tumors with AdmIFN-β in wild-type C57BL/6 mice led to increased iNOS expression, decreased microvessel density, decreased cell proliferation, and increased apoptosis. Furthermore, quantitative reverse-transcriptional PCR analysis showed that AdmIFN-β therapy, in C57BL/6 but not the iNOS-null counterparts, reduced levels of the mRNAs for angiopoietin, basic fibroblast growth factor, matrix metalloproteinase-9, transforming growth factor-β1, vascular endothelial growth factor (VEGF)-A, and VEGF-B, as well as the antiapoptotic molecule endothelin-1. These data indicated that IFN-β gene therapy could be effective alternative for the treatment of locally advanced prostate cancer and suggest an obligatory role of NO in IFN-β antitumoral effects in vivo.Cancer Gene Therapy (2006) 13, 676–685. doi:10.1038/sj.cgt.7700941; published online 10 February 2006 [ABSTRACT FROM AUTHOR]