Zinc-dependent dimers observed in crystals of human endostatin

Ding, Yuanhua; Javaherian, Kashi; Lo, Kin-Ming; Chopra, Rajiv; Boehm, Thomas; Lanciotti, Julia; Harris, Bruce A.; Li, Yue; Shapiro, Robert; Hohenester, Erhard; Timpl, Rupert; Folkman, Judah; Wiley, Don C.

doi:10.1073/pnas.95.18.10443

Cited by 128 publications

(142 citation statements)

References 36 publications

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“…31 shown to inhibit the proliferation of endothelial cells and have a negative impact on the growth of metastases as well as primary tumors in a variety of preclinical cancer models when administered systemically. 10,12,31,32 An important aspect of tumor growth inhibition by interference with the angiogenic process is the need for long -term suppression. Given the general difficulty of maintaining chronic serum levels of biologically active proteins, strategies to deliver endostatin via a gene therapy approach have been initiated.…”

Section: Discussionmentioning

confidence: 99%

Adeno-associated virus–mediated gene transfer of endostatin inhibits angiogenesis and tumor growth in vivo

et al. 2002

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A variety of approaches has demonstrated that interfering with tumor -induced angiogenesis may be an effective strategy in cancer therapy. However, it is likely that to be most effective such strategies will require extended suppression of the angiogenic process. Gene therapy offers a possible approach to achieve sustained release of a therapeutically potent transferred gene product. In the present study the angiogenesis inhibitor endostatin was expressed through a recombinant adeno -associated viral ( rAAV ) vector and shown to be biologically active in vitro and in vivo. Intramuscular injection of rAAV -HuEndo ( 1Â10 9 i.u. ) led to a sustained serum endostatin level of $35 -40 ng / mL. This endostatin level was sufficient to inhibit tumor cell -induced angiogenesis and to suppress both the initiation and subsequent growth of a human colorectal cancer model.

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Section: Discussionmentioning

confidence: 99%

Adeno-associated virus–mediated gene transfer of endostatin inhibits angiogenesis and tumor growth in vivo

et al. 2002

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“…Furthermore, all three histidines (at positions 1, 3 and 11) and aspartic acid (at position 76) residues important for Zn binding are conserved. 41 Dose-dependent expression of endostatin We and others have determined that, among the new serotypes of AAV, AAV-1 has better transduction efficiency in muscle. 42,43 Therefore, AAV-1/cFcES vectors were produced in which cFcES is under the control of the human CMV enhancer and promoter (Figure 2a).…”

Section: Cloning Of Canine Endostatinmentioning

confidence: 99%

Endostatin therapy reveals a U-shaped curve for antitumor activity

et al. 2006

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Developing continuous systemic delivery of endostatin has been a goal of many laboratories. We have employed a method of gene therapy utilizing different viral constructs. Here, we report that a new serotype of adeno-associated viruses, which incorporates canine endostatin, provides dose-dependent transgene expression in the circulation after intramuscular injection in mice. Elevated levels of endostatin remained stable in the circulation for at least 4 months. In vitro assays determined that the protein expressed was biologically active. Antitumor activities of the above construct demonstrated a U-shape curve, where the maximum activity was observed within a certain critical concentration range. These data suggest that an optimum dose range may be required to achieve therapeutic efficacy in large animal models.

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“…The crystal structure of endostatin has been resolved (13,14). The fold of endostatin is intricate: the most prominent property is a highly twisted mixed b-sheet with 14 residues containing a-helix packing against one face of the sheet, with two pairs of disulfide bonds in a nested pattern, Cys33-Cys173 and Cys135-Cys165.…”

Section: Contribution Of Disulfide Bonds To the Structure Stabilitymentioning

confidence: 99%

Unraveling the mysteries of endostatin

Tang

Huang

et al. 2009

IUBMB Life

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SummaryEndostatin, a 20-kDa C-terminal proteolytic fragment of collagen XVIII, is a specific endogenous angiogenesis inhibitor discovered more than a decade. The structure, stability, and mechanism of actions of endostatin have been extensively investigated during the past 12 years, among which controversial reports remain unclarified. The mysteries include the following: 1) Why controversial efficacies were observed with endostatin regarding tumor inhibition? Particularly, why does an N-terminal modified endostatin show good clinical responses in China, whereas the clinical trials of the wild type endostatin were terminated at the early stage of phase II in the USA? 2) What is the contribution of zinc-binding to the stability and biological functions of endostatin? 3) Why does insoluble endostatin shrink tumors? 4) How to ensure that endostatin is correctly refolded? 5) How does endostatin exert its biological functions? Recent progress regarding the biophysical properties, biological functions, signaling pathways, and clinical trials of endostatin are reviewed here. Surprising findings show that the integrity of the N-terminal sequence, the capability of zinc-binding, and the correct folding are three essential elements for assurance of structural stability and biological functions of endostatin. This review provides clues to understand the mysteries of endostatin and its derivatives.

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Zinc-dependent dimers observed in crystals of human endostatin

Cited by 128 publications

References 36 publications

Adeno-associated virus–mediated gene transfer of endostatin inhibits angiogenesis and tumor growth in vivo

Adeno-associated virus–mediated gene transfer of endostatin inhibits angiogenesis and tumor growth in vivo

Endostatin therapy reveals a U-shaped curve for antitumor activity

Unraveling the mysteries of endostatin

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