Restriction of neuroblastoma angiogenesis and growth by interferon-α/β

Streck, Christian J.; Zhang, Youbin; Miyamoto, Ryo; Zhou, Junfang; Ng, Catherine Y.; Nathwani, Amit C.; Davidoff, Andrew M.

doi:10.1016/j.surg.2004.04.014

Cited by 30 publications

(28 citation statements)

References 17 publications

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“…Although there may also have been some direct tumor cell cytotoxic activity of IFN-h in our tumor model, there were clearly profound effects on vessel morphology and physiology as a consequence of continuous delivery of IFN-h. The method of IFN-h dosing, using AAV vectors to attain continuous delivery of IFN-h, is likely responsible for the different antiangiogenic mechanism of action observed in our study, as we were unable to achieve the same antitumor efficacy or vascular remodeling with frequent administration of recombinant IFN-h protein (30).…”

Section: Discussionmentioning

confidence: 72%

“…Construction of the pAV2 hIFN-h, pAV2 FIX, and pAV2 Tie2 vector plasmids has previously been described (30). These vector plasmids each include the cytomegalovirus immediate-early enhancer, h-actin promoter, a chicken h-actin/rabbit h-globin composite intron, and a rabbit h-globin polyadenylation signal mediating the expression of the cDNA for hIFN-h, hFIX, or the truncated, soluble murine Tie2 receptor.…”

Section: Aav Vector Productionmentioning

confidence: 99%

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Continuous Delivery of IFN-β Promotes Sustained Maturation of Intratumoral Vasculature

Dickson¹,

Hamner²,

Streck³

et al. 2007

Molecular Cancer Research

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IFNs have pleiotropic antitumor mechanisms of action. The purpose of this study was to further investigate the effects of IFN-B on the vasculature of human xenografts in immunodeficient mice. We found that continuous, systemic IFN-B delivery, established with liver-targeted adeno-associated virus vectors, led to sustained morphologic and functional changes of the tumor vasculature that were consistent with vessel maturation. These changes included increased smooth muscle cell coverage of tumor vessels, improved intratumoral blood flow, and decreased vessel permeability, tumor interstitial pressure, and intratumoral hypoxia. Although these changes in the tumor vasculature resulted in more efficient tumor perfusion, further tumor growth was restricted, as the mature vasculature seemed to be unable to expand to support further tumor growth. In addition, maturation of the intratumoral vasculature resulted in increased intratumoral penetration of systemically administered chemotherapy. Finally, molecular analysis revealed increased expression by treated tumors of angiopoietin-1, a cytokine known to promote vessel stabilization. Induction of angiopoietin-1 expression in response to IFN-B was broadly observed in different tumor lines but not in those with defects in IFN signaling. In addition, IFN-B -mediated vascular changes were prevented when angiopoietin signaling was blocked with a decoy receptor. Thus, we have identified an alternative approach for achieving sustained vascular remodeling-continuous delivery of IFN-B. In addition to restricting tumor growth by inhibiting further angiogenesis, maturation of the tumor vasculature also improved the efficiency of delivery of adjuvant therapy. These results have significant implications for the planning of combination anticancer therapy.

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Section: Discussionmentioning

confidence: 72%

Section: Aav Vector Productionmentioning

confidence: 99%

Continuous Delivery of IFN-β Promotes Sustained Maturation of Intratumoral Vasculature

Dickson¹,

Hamner²,

Streck³

et al. 2007

Molecular Cancer Research

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“…18 The hIFN-b cDNA was purchased from InvivoGen (San Diego, CA). These plasmids include the CMV-IE enhancer, b-actin promoter, a chicken b-actin/rabbit b globin composite intron, and a rabbit b globin polyadenylation signal (CAG) mediating the expression of the cDNA for human IFN-b or human clotting factor IX.…”

Section: Effects Of Ifn-b In Vitromentioning

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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“…9 This hypothesis is supported by numerous studies using gene therapy approaches in both murine and human solid tumor models. [10][11][12][13][14][15][16][17] Moreover, we and others have shown that intralesional delivery of the IFN-b gene, which allows for the accumulation of higher intratumoral concentrations of IFN-b, is able to suppress primary tumors, prolong the survival of tumor-bearing mice, and protect against a second challenge in syngeneic mice. 12,18,19 Nitric oxide (NO) is a small molecule produced by mammalian cells.…”

Section: Introductionmentioning

confidence: 99%

Inducible nitric oxide synthase activity is essential for inhibition of prostatic tumor growth by interferon-β gene therapy

et al. 2006

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We have previously reported that adenoviral vector-mediated interferon (IFN)-b 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 immunecompetent mice. TRAMP-C2Re3 mouse prostate cancer cells infected with 100 multiplicity of infection (MOI) Furthermore, quantitative reverse-transcriptional PCR analysis showed that AdmIFN-b 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-b1, vascular endothelial growth factor (VEGF)-A, and VEGF-B, as well as the antiapoptotic molecule endothelin-1. These data indicated that IFN-b gene therapy could be effective alternative for the treatment of locally advanced prostate cancer and suggest an obligatory role of NO in IFN-b antitumoral effects in vivo.

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Restriction of neuroblastoma angiogenesis and growth by interferon-α/β

Cited by 30 publications

References 17 publications

Continuous Delivery of IFN-β Promotes Sustained Maturation of Intratumoral Vasculature

Continuous Delivery of IFN-β Promotes Sustained Maturation of Intratumoral Vasculature

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

Inducible nitric oxide synthase activity is essential for inhibition of prostatic tumor growth by interferon-β gene therapy

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