lnterferon‐β gene therapy for cancer: Basic research to clinical application

Yoshida, Jun; Mizuno, Masaaki; Wakabayashi, Toshihiko

doi:10.1111/j.1349-7006.2004.tb02194.x

Cited by 74 publications

(45 citation statements)

References 26 publications

(26 reference statements)

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“…Despite the clinical activity of IFN-β on malignant gliomas (Lin et al, 2004;Yoshida et al, 2004;Ito et al, 2010), its antitumor mechanism in vivo remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Induction of Apoptosis in Glioma Cells and Upregulation of Fas Expression Using the Human Interferon-β Gene

Guo¹,

Gan²,

Gao³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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We investigated whether IFN-β inhibits the growth of human malignant glioma and induces glioma cell apoptosis using the human IFN-β gene transfected into glioma cells. A eukaryonic expression vector (pSV2IFNβ) for IFN-β was transfected into the glioma cell line SHG44 using liposome transfection. Stable transfection and IFN-β expression were confirmed using an enzyme-linked immunosorbent assay (ELISA). Cell apoptosis was also assessed by Hoechst staining and electron microscopy.

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“…Despite the clinical activity of IFN-β on malignant gliomas (Lin et al, 2004;Yoshida et al, 2004;Ito et al, 2010), its antitumor mechanism in vivo remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Induction of Apoptosis in Glioma Cells and Upregulation of Fas Expression Using the Human Interferon-β Gene

Guo¹,

Gan²,

Gao³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…[28][29][30][31] However, this is the first study in which continuous, long-term delivery of hIFN-b was achieved through a liver-targeted, AAV-mediated gene therapy approach.…”

Section: Discussionmentioning

confidence: 99%

Antitumor efficacy of AAV-mediated systemic delivery of interferon-β

Streck

Dickson

et al. 2005

Cancer Gene Ther

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Type I interferons (a/b) have significant antitumor activity although their short half-life and systemic side effects have limited their clinical utility. An alternative dosing schedule of continuous, low-level delivery, as is achieved by gene therapy, rather than intermittent, high concentration pulsed-dosing, might avoid the toxicity of interferon while maintaining its antitumor efficacy. We have tested a gene therapy approach in murine tumor models to treat malignancies that have shown responsiveness to interferon in clinical trials. The tumor cell lines used were moderately sensitive to the direct effects of human interferon-b (hIFN-b) in vitro. For in vivo testing, systemic delivery of hIFN-b was generated following liver-targeted delivery of adeno-associated virus (AAV) vector carrying the hIFN-b transgene. This prevented engraftment of subcutaneous human gliomas, and orthotopic, localized (intrarenal) and disseminated (primarily pulmonary) human renal cell carcinomas; and caused regression of established tumors at these sites. In a syngeneic, immunocompetent model of melanoma, AAV IFN-b treatment limited subcutaneous tumor growth and prevented disseminated disease. A significant decrease in mean intratumoral vessel density was demonstrated in hIFN-b-treated tumors, suggesting that in addition to a direct tumoricidal effect, the antitumor efficacy of AAV IFN-b in this study was due to its ability to inhibit angiogenesis.

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“…High concentrations of IFN-β induce apoptosis of cancer cell lines in vitro [9]. Although the exact mechanism remains unclear, it may involve the Jak1 and signal transduction activation transcription factor 1 (Stat1) intracellular signaling pathways [10].…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal Stem Cells Overexpressing IFN-β Inhibit Breast Cancer Growth and Metastases through Stat3 Signaling in a Syngeneic Tumor Model

Ling

Marini

Konopleva

et al. 2010

Cancer Microenvironment

108

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We previously demonstrated that mesenchymal stem/stromal cells (MSC) are recruited to tumors and that IFN-β produced by MSC inhibited tumor growth in xenograft models. Because of a deficient immune system, murine xenograft models cannot fully recapitulate tumor and immune cell interactions during progression. Therefore we investigated the capacity of MSC to migrate to and engraft into primary breast tumor sites and subsequently explore mechanisms of tumor inhibition by MSC-delivered IFN-β in a syngeneic, immunocompetent murine model. Herein we report that 1) systemically administrated MSC migrate to established 4 T1 breast cancer sites and localize among the tumor-stroma border and throughout the tumor mass; 2) high levels of IFN-β secreted by MSC are detectable in the tumor microenvironment but not in circulation; 3) intratumorally produced IFN-β inactivates constitutive phosphorylation of signal transducer activator transcription factor 3 (Stat3), Src, and Akt and down-regulates cMyc and MMP2 expression in 4 T1 cells, and 4) in mice with established breast cancer IFN-β expressing MSC administered systemically resulted in inhibition of primary cancer growth and in dramatic reduction of pulmonary and hepatic metastases. 5) MSC-IFN-β treated, but not control mice, maintained normal levels of splenic mature dendritic (DC), CD8+ T cells and CD4+/Foxp3+ regulatory T-cells (Treg). Our findings suggest that MSC are capable of migrating to tumor sites in an immunocompetent environment, that IFN-β produced by MSC suppresses breast cancer growth through inhibition of Stat3 signaling, and dramatically reduces pulmonary and hepatic metastases.

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lnterferon‐β gene therapy for cancer: Basic research to clinical application

Cited by 74 publications

References 26 publications

Induction of Apoptosis in Glioma Cells and Upregulation of Fas Expression Using the Human Interferon-β Gene

Induction of Apoptosis in Glioma Cells and Upregulation of Fas Expression Using the Human Interferon-β Gene

Antitumor efficacy of AAV-mediated systemic delivery of interferon-β

Mesenchymal Stem Cells Overexpressing IFN-β Inhibit Breast Cancer Growth and Metastases through Stat3 Signaling in a Syngeneic Tumor Model

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