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Cancer Research

Angiostatin & Endostatin

Endogenous Inhibitors of Angiogenesis

Sigma has recently introduced angiostatin and endostatin - the endogenous inhibitors of angiogenesis. The products are recombinantly expressed in Pichia pastoris. Inhibition activity is assessed by the ability to inhibit tumor metastases using an in vivo anti-tumor efficacy test using B16BL6 melanoma cells.


Proteins
Angiostatin K1-3, Human, recombinant A1477
Endostatin, Human, recombinant E8154
Endostatin, Mouse, recombinant E8279
Antibodies
Monoclonal Anti-Angiostatin, Human A0976
Anti-Angiostatin, Human A1101
Monoclonal Anti-Endostatin, Mouse E3904
Anti-Endostatin, Mouse E3779

Angiogenesis, the sprouting of new capillary growth from pre-existing blood vessels, is a multi-step process1 and is a rate-limiting step in tumor growth. Avascular tumors are limited in size by the diffusion distance of oxygen, nutrients, and cellular waste through the interstitium. Although tumors often initially co-opt the existing vasculature, an angiogenic switch, i.e., the production of factors that induce angiogenic sprouting of the vasculature, is a necessary part of the phenotype of a successful tumor. Under normal conditions, there is a balance between endogenous angiogenic inducers and endogenous angiogenic inhibitors that keeps the angiogenic process in check and prevents inappropriate vascularization of tissues.

Angiogenesis inhibitors are often derived from circulating extracellular matrix proteins, e.g. fibronectin, prolactin, collagen XVIII (endostatin), hepatocyte growth factor fragment NK1 and angiostatin. Virtually all endogenous angiogenesis inhibitors suppress tumor growth in animal models. Angiostatin was the first example of an endogenous inhibitor isolated from the serum and urine of tumor-bearing animals. Other inhibitors, including endostatin, TSP-1 and serpin antithrombin, have subsequently been purified from the body fluids of tumor-bearing animals.

Angiostatin is an amino-terminal fragment of plasminogen that contains the first three or four kringle (K) domains.2 Agents containing K1-3,3 K1-4,2 K1-5,4 and K1-4 plus a fragment of K55 show potent anti-angiogenic and/or anti-tumor growth activity. These fragments, as well as the individual kringle modules, are also inhibitory toward endothelial cell migration and/or proliferation in vitro. Studies with recombinant angiostatin show that the tumor inhibitory activity resides in a fragment of K1-3.5 X-ray crystallography indicates that K1-3 forms a central cavity that may contain a protein recognition site essential for angiostatic activity.7

Endostatin is a cleaved product of the carboxyl-terminal domain of collagen XVIII.8,9 It was originally found in conditioned media from a murine endothelial tumor cell line, hemangio-endothelioma.10,11 Endostatin inhibits endothelial cell migration in vivo and in vitro and induces endothelial cell apoptosis.11 It inhibits tumor growth and impairs blood vessel maturation in wound healing.7 Endostatin has an important role in endothelial cell adhesion and cytoskeletal organization.12 Endostatin can be found in vessel walls (elastic fibers) and basement membranes.10,13 Recombinant Endosatin expressed in yeast causes G1 arrest of endothelial cells, and endostatin treatment results in apoptosis of HUVE and HMVE cells.14

Subject to U.S. Patent No. 5409946 and sold under license from Abbott Laboratories.

References

  1. Folkman, J. and Shing, Y., J. Biol. Chem., 267, 10931-10934 (1992).
  2. Cao, Y.H., et al., J. Biol. Chem., 271, 29461-29467 (1996).
  3. Joe, Y.A., et al., Int. J. Cancer, 82, 694-699 (1999).
  4. Cao, R.H., et al., Proc. Natl. Acad. Sci. USA, 96, 5728-5733 (1999).
  5. Gately, S., et al., Proc. Natl. Acad. Sci. USA, 94, 10868-10872 (1997).
  6. MacDonald, N.J., et al., Biochem. Biophys. Res. Commun., 264, 469-477 (1999).
  7. Marta, C. et al., J. Mol. Biol., 318, 1009-1017 (2002).
  8. Bloch, W., et al., FASEB J., 14, 2373-2376 (2000).
  9. Sasaki, T., et al., J. Mol. Biol., 301, 1179-1190 (2000).
  10. Zatterstrom, U.K., et al., Cell Struct. Funct., 25, 97-101 (2000).
  11. O’Reilly, M.S., et al., Cell, 88, 277-285 (1997).
  12. Dixelius, J., et al., Cancer Res., 62, 1944-1947 (2002).
  13. Miosge, M., et al., FASEB J., 13, 1743-1750 (1999).
  14. Dhanabal M, et al., Biochem Biophys Res Commun., 258, 345-52 (1999).

U.S. Patent Nos. 6,024,688; 5,861,372; 5,639,725; 5,792,845; 5,885,795, 5,854,205. Sold under license from EntreMed.

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