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An angiogenesis inhibitor is a substance that inhibits angiogenesis (the growth of new blood vessels). It can be endogenous or come from outside as drug or a dietary component. Every solid tumor (in contrast to liquid tumors like leukemia) needs to generate blood vessels to keep it alive once it reaches a certain size. Usually, blood vessels are not built elsewhere in an adult body unless tissue repair is actively in process. The angiostatic agent endostatin and related chemicals can suppress the building of blood vessels, preventing the cancer from growing indefinitely. In tests with patients, the tumor became inactive and stayed that way even after the endostatin treatment was finished. The treatment has very few side effects but appears to have very limited selectivity. Other angiostatic agents like thalidomide and natural plant-based substances are being actively investigated.

Contents

Endogenous

Inhibitors Mechanism
soluble VEGFR-1 and NRP-1 decoy receptors[1] for VEGF-B and PIGF
Angiopoietin 2 antagonist of angiopoietin 1
TSP-1 and TSP-2 inhibit cell migration, cell proliferation, cell adhesion and survival of endothelial cells
angiostatin and related molecules inhibit cell proliferation and induce apoptosis of endothelial cells
endostatin inhibit cell migration, cell proliferation and survival of endothelial cells
vasostatin, calreticulin inhibit cell proliferation of endothelial cells
platelet factor-4 inhibits binding of bFGF and VEGF
TIMP and CDAI inhibit cell migration of endothelial cells
Meth-1 and Meth-2
IFN-α, and , CXCL10, IL-4, -12 and -18 inhibit cell migration of endothelial cells, downregulate bFGF
prothrombin (kringle domain-2), antithrombin III fragment inhibit cell proliferation of endothelial cells
prolactin inhibit bFGF and VEGF
VEGI affects cell proliferation of endothelial cells
SPARC inhibit binding and activity of VEGF
osteopontin inhibit integrin signalling
maspin inhibits proteases
canstatin
proliferin-related protein
restin

Exogenous

Exogenous angiogenesis inhibitors may be drugs or a dietary components. Some of them are endogenous as well.

Drugs

Known inhibitors include the drug bevacizumab which binds vascular endothelial growth factor (VEGF), inhibiting its binding to the receptors that promote angiogenesis.

Research and development in this field has been driven largely by the desire to find better cancer treatments. Tumors can grow only if they form new blood vessels. By stopping the growth of blood vessels, scientists hope to shut off the means by which tumors can extend themselves and spread inside the body. In animal studies, angiogenesis inhibitors have successfully stopped the formation of new blood vessels.

The pharmaceutical thalidomide is such an antiangiogenic agent. When pregnant women take an antiangiogenic agent, the developing fetus will not form blood vessels properly and thereby stop the proper development of fetal limbs and circulatory systems. The results of the late 1950s and early 1960s when pregnant women were given the drug were children with tiny flippers for arms and legs.

In addition to their use as anti-cancer drugs, angiogenesis inhibitors are being investigated for their use as anti-obesity agents, as blood vessels in adipose tissue never fully mature, and are thus destroyed by angiogenesis inhibitors.

Matrix metalloproteinase inhibitors that may be antiangiogenic are batimastat and marimastat.

According to a study published in the August 15, 2004 issue of the journal Cancer Research, cannabinoids, the active ingredients in marijuana, restrict the sprouting of blood vessels to brain tumors by inhibiting the expression of genes needed for the production of vascular endothelial growth factor (VEGF).[2]

Overview table
Inhibitors Antiangiogenic
use in
Mechanism
bevacizumab Cancer binds VEGF
carboxyamidotriazole inhibit cell proliferation and cell migration of endothelial cells
TNP-470
CM101 activate immune system
IFN-α downregulate angiogenesis stimulators and inhibit cell migration of endothelial cells
IL-12 stimulate angiogenesis inhibitor formation
platelet factor-4 inhibits binding of angiogenesis stimulators
suramin prostate cancer
SU5416
thrombospondin
VEGFR antagonists
angiostatic steroids + heparin inhibit basement membrane degradation
Cartilage-Derived Angiogenesis Inhibitory Factor
matrix metalloproteinase inhibitor‎s
angiostatin inhibit cell proliferation and induce apoptosis of endothelial cells
endostatin inhibit cell migration, cell proliferation and survival of endothelial cells
2-methoxyestradiol inhibit cell proliferation and cell migration and induce apoptosis of endothelial cells
tecogalan inhibit cell proliferation of endothelial cells
thrombospondin inhibit cell migration, cell proliferation, cell adhesion and survival of endothelial cells
prolactin inhibit bFGF and VEGF
αVβ3 inhibitors induce apoptosis of endothelial cells
linomide inhibit cell migration of endothelial cells

Diet

Some common components of the Oriental diet (and to a much lesser extent, the Western diet) also act as mild angiogenesis inhibitors. In particular, the following foodstuffs contain significant inhibitors and have been suggested as part of a healthy diet for this and other benefits:

References

  1. ^ Pleiotropic Action of VEGF in the CNS
  2. ^ http://www.aacr.org/home/public--media/aacr-press-releases/press-releases-2004.aspx?d=139
  3. ^ Farina HG, Pomies M, Alonso DF, Gomez DE (October 2006). "Antitumor and antiangiogenic activity of soy isoflavone genistein in mouse models of melanoma and breast cancer". Oncol. Rep. 16 (4): 885–91. PMID 16969510. http://www.spandidos-publications.com/or/article.jsp?article_id=or_16_4_885.  
  4. ^ Takaku T, Kimura Y, Okuda H (May 2001). "Isolation of an antitumor compound from Agaricus blazei Murill and its mechanism of action". J. Nutr. 131 (5): 1409–13. PMID 11340091.  
  5. ^ Kimura, Y (2004), "Isolation of an anti-angiogenic substance from Agaricus blazei Murill: its antitumor and antimetastatic actions", Cancer Sci 95 (9): 758–764, doi:10.1111/j.1349-7006.2004.tb03258.x  
  6. ^ Stanley G, Harvey K, Slivova V, Jiang J, Sliva D (April 2005). "Ganoderma lucidum suppresses angiogenesis through the inhibition of secretion of VEGF and TGF-beta1 from prostate cancer cells". Biochem. Biophys. Res. Commun. 330 (1): 46–52. doi:10.1016/j.bbrc.2005.02.116. PMID 15781230.  

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