Angiogenesis inhibitor

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An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels (angiogenesis). Some angiogenesis inhibitors are endogenous and a normal part of the body's control and others are obtained exogenously through drugs or diet.

Angiogenesis inhibitors were once thought to have potential as a "silver bullet" treatment applicable to many types of cancer, but the limitations of anti-angiogenic therapy have been shown in practice.[1] Nonetheless, inhibitors are used to effectively treat cancer, macular degeneration in the eye, and other diseases that involve a proliferation of blood vessels.[2][3]

Mechanism of Action[edit]

When solid cancers are small, they are supplied with oxygen and nutrients by diffusion from nearby blood vessels. In order for a tumor to grow and metastasize, it must become vascularized through the action of angiogenesis promoters such as VEGF. Drugs that interrupt that process show promise in treating cancer.[4]

Endogenous Regulation[edit]

see main article: endogenous

Angiogenesis is regulated by the activity of endogenous stimulators and inhibitors. Unlike exogenous inhibitors, endogenous inhibitors are found in the body naturally and involved in the day-to-day process of regulating blood vessel formation. Endogenous inhibitors are often derived from the extracellular matrix or basement membrane proteins and function by interfering with endothelial cell formation and migration, endothelial tube morphogenesis, and down-regulation of genes expressed in endothelial cells.[5] During tumor growth, the action of angiogenesis stimulators surpasses the control of angiogenesis inhibitors, allowing for unregulated or less regulated blood vessel growth and formation.[6] Endogenous inhibitors are attractive targets for cancer therapy because they are less toxic and less likely to lead to drug resistance than some exogenous inhibitors.[7]

However, the use of endogenous inhibitors has its disadvantages as well. In animal studies, high doses of inhibitors were required to prevent tumor growth and the use of endogenous inhibitors would likely be long-term.[8]

Inhibitors Mechanism
soluble VEGFR-1 and NRP-1 decoy receptors[9] 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 (a fragment of COL4A2) inhibits endothelial cell migration, induces apoptosis[10]
proliferin-related protein mannose 6-phosphate binding lysosomal protein[11]

Exogenous Regulation[edit]

see main article: exogenous

Drugs[edit]

Known inhibitors include the drug bevacizumab (brand name Avastin), a kind of humanized mouse monoclonal antibody against vascular endothelial growth factor (VEGF).

Through binding to VEGFR and other VEGF receptors in endothelial cells, VEGF can trigger multiple cellular responses like promoting cell survival, preventing apoptosis, and remodeling cytoskeleton, all of which promote angiogenesis.

Because it traps VEGF in the blood, bevacizumab is an anti-angiogenesis factor. Lowering the concentration of VEGF results in reduced activation of the angiogenesis pathway, thus inhibiting new blood vessel formation in tumors.[citation needed]

Research and development in this field has been driven largely by the desire to find better cancer treatments. Tumors cannot grow larger than 2mm without angiogenesis. By stopping the growth of blood vessels, scientists hope to cut the means by which tumors can nourish themselves and thus metastasize. After a series of clinical trials in 2004, Avastin was approved by the FDA, becoming the first commercially available anti-angiogenesis drug. FDA approval of Avastin for breast cancer treatment was later revoked on November 18, 2011.[12]

Despite the therapeutic potential of anti-angiogenesis drugs, they can also be harmful when used inappropriately. Pharmaceutical thalidomide is one such antiangiogenic agent. Thalidomide was given to pregnant women to treat nausea. However, when pregnant women take an antiangiogenic agent, the developing fetus will not form blood vessels properly, thereby preventing the proper development of fetal limbs and circulatory systems. In the late 1950s and early 1960s, thousands of children were born with deformities, most notably phocomelia, as a consequence of thalidomide use.[13]

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.[14]

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).[15]

Inhibitors Antiangiogenic
use in
Mechanism
bevacizumab Cancer binds VEGF
itraconazole Cancer inhibits VEGFR phosphorylation, glycosylation, mTOR signaling, endothelial cell proliferation, cell migration, lumen formation, and tumor associated angiogenesis.[16][17][18]
carboxyamidotriazole inhibit cell proliferation and cell migration of endothelial cells
TNP-470 (an analog of fumagillin)
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
tetrathiomolybdate Cancer copper chelation which inhibits blood vessel growth
thalidomide 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
tasquinimod prostate cancer Unknown[19]

Diet[edit]

Some common components of human diets also act as mild angiogenesis inhibitors and have therefore been proposed for angioprevention, the prevention of metastasis through the inhibition of angiogenesis. In particular, the following foodstuffs contain significant inhibitors and have been suggested as part of a healthy diet for this and other benefits:

References[edit]

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  3. ^ Eugene W. M. Ng & Anthony P. Adamis (June 2005). "Targeting angiogenesis, the underlying disorder in neovascular age-related macular degeneration". Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 40 (3): 352–368. doi:10.1016/S0008-4182(05)80078-X. PMID 15947805. 
  4. ^ , PMID 12516034 http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm280536.htm, retrieved 2014-04-15  Missing or empty |title= (help)
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