Endostatin: An Endogenous Inhibitor of Angiogenesis and Tumor Growth

O’Reilly, Michael S.; Boehm, Thomas; Shing, Yuen; Fukai, Naomi; Vasios, George; Lane, William S.; Flynn, Evelyn; Birkhead, James R.; Olsen, Bjørn R.; Folkman, Judah

doi:10.1016/s0092-8674(00)81848-6

Cited by 4,075 publications

(2,918 citation statements)

References 33 publications

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“…54,55 All current treatments (surgical, laser and photodynamic therapy) merely delay severe vision loss, because they are directed at destroying new vessels but do not address the underlying angiogenic stimuli that frequently cause recurrences. 56 Currently, there are no antiangiogenic treatments available for patients with ocular neovascularization, but several new approaches such as intraocular injections of an aptamer that binds VEGF or an anti-VEGF antibody 57 or proteins with antiangiogenic activity [58][59][60] are being considered. Recombinant AAVmediated gene transfer offers an alternative for local sustained delivery of antiangiogenic proteins to intraocular tissues.…”

Section: Gene Transfer In Animal Models Of Retinal Degenerationmentioning

confidence: 99%

Recombinant AAV-mediated gene transfer to the retina: gene therapy perspectives

Rolling

2004

Gene Ther

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Section: Gene Transfer In Animal Models Of Retinal Degenerationmentioning

confidence: 99%

Recombinant AAV-mediated gene transfer to the retina: gene therapy perspectives

Rolling

2004

Gene Ther

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“…9,14 Endostatin inhibits tumor angiogenesis by interfering at multiple levels of the growth factor signaling for endothelial cell proliferation, migration, and vessel formation. 10,15,16 Previously, we have shown a significant treatment effect in orthotopic human RCC (Caki-2 ) xenografts in a nude mouse model 17 using intratumoral HSV-tk gene therapy. Neither HSV-tk adenovirus in the absence of GCV, nor GCV coupled with an adenovirus containing a LacZ marker gene had any antitumor effect.…”

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confidence: 99%

The combination of HSV-tk and endostatin gene therapy eradicates orthotopic human renal cell carcinomas in nude mice

et al. 2002

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Background and methods: Gene therapy may offer a new tool for the treatment of renal cell carcinoma ( RCC ). We have tested a combination of cytotoxic and antiangiogenic gene therapy for wild -type orthotopic human RCC xenografts in nude mice using intratumoral adenovirus -mediated herpes simplex virus thymidine kinase ( HSV -tk ) and endostatin ( ES ) gene therapy. In vivo magnetic resonance imaging, morphometry, immunocytochemistry, and survival were used to evaluate the treatment effect. Adenovirus -mediated marker gene transfers ( GFP ) were used as controls. Results: In vivo transduction efficiency, measured using GFP gene transfer, was 27 ± 7%. The combination gene therapy with HSV -tk and ES adenoviruses resulted in a significant antitumor effect ( P < .01 ) compared to single HSV -tk ( n.s. ) or ES ( n.s. ). In the survival study, all tumors with single gene therapy using HSV -tk, ES, and marker gene adenoviruses showed progression in magnetic resonance imaging. In contrast, the majority of the tumors in the combination treatment group remained dormant or were eradicated ( 57% ). Survival of these mice equaled healthy nude mice, and was significantly prolonged ( P < .0001 ) compared to HSV -tk ( P < .028 ) and ES ( n.s. ) groups. Conclusions: It is concluded that the inhibition of angiogenesis using ES gene transfer together with the cytotoxic HSV -tk gene therapy results in a significantly improved treatment effect in RCC compared to the single gene treatments.

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“…Endostatin is a dose-dependent, specific inhibitor of endothelial cell growth (O'Reilly et al, 1997). Recent in vitro studies using DNA and antibody array have identified its antiangiogenic effects on microvascular endothelial cells (Abdollahi et al, 2004).…”

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Endostatin expression in a pancreatic cell line is modulated by a TNFα-dependent elastase

2005

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Endostatin, an inhibitor of angiogenesis, is a 20 kDa fragment of the basement membrane protein, collagen XVIII. The formation of endostatin relies upon the action of proteases on collagen XVIII. TNFa, produced by activated macrophages, is a multifunctional proinflammatory cytokine with known effects on endothelial function. We postulated that TNFa may modulate the activities of proteases and thus regulate endostatin formation in pancreatic cells. Collagen XVIII/endostatin mRNA was expressed in one pancreatic cell line, SUIT-2, but not in BxPc-3. The 20 kDa endostatin was found in the cell-conditioned medium of SUIT-2 cells. Precursor forms only were found in the cells. Exogenous endostatin was degraded by cellular lysates of SUIT-2 cells. Elastase activity was found in cell extracts but not the cell-conditioned media of SUIT-2 cells. Incubation of SUIT-2 cells with TNFa increased intracellular elastase activity and also increased secretion of endostatin into the medium. We conclude that endostatin is released by SUIT-2 cells and that increases in intracellular elastase, induced by TNFa, are correlated with increased secretion. Endostatin is however susceptible to degradation by intracellular proteases and if tissue injury accompanies inflammation, endostatin may be degraded, allowing angiogenesis to occur.

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Endostatin: An Endogenous Inhibitor of Angiogenesis and Tumor Growth

Cited by 4,075 publications

References 33 publications

Recombinant AAV-mediated gene transfer to the retina: gene therapy perspectives

Recombinant AAV-mediated gene transfer to the retina: gene therapy perspectives

The combination of HSV-tk and endostatin gene therapy eradicates orthotopic human renal cell carcinomas in nude mice

Endostatin expression in a pancreatic cell line is modulated by a TNFα-dependent elastase

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