出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/10/03 16:54:17」(JST)
An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels (angiogenesis). Some angiogenesis inhibitors are a normal part of the body's control, some are administered as drugs, and some come from diet.
Angiogenesis inhibitors were once thought to have potential as a "silver bullet" treatment applicable to many types of cancer, but this has not been the case in practice.[1] Nonetheless, inhibitors are used to treat cancer, macular degeneration in the eye, and other diseases that involve a proliferation of blood vessels.
When solid cancers are small, they are supplied with nutrients by diffusion from nearby blood vessels. In order to grow larger, they need their own blood vessels, which they create by angiogenesis promoters such as VEGF. Drugs that interrupt that process show promise in treating cancer. However, when one angiogenesis promoter is blocked, cancers eventually grow blood vessels using another angiogenesis promoter.
Angiogenesis inhibitors are also used to treat age-related macular degeneration, in which the blood vessels of the retina of the eye become overgrown and damage vision.
| Inhibitors | Mechanism |
|---|---|
| soluble VEGFR-1 and NRP-1 | decoy receptors[2] 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, -β and -γ, 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 angiogenesis inhibitors may be drugs or a dietary components. Some of them are endogenous as well.
| This section does not cite any references or sources. Please help improve this section by adding citations to reliable sources. Unsourced material may be challenged and removed. (June 2011) |
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.
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 metastasizing. After a series of clinical trials in 2004, Avastin got approval from the FDA, becoming the first commercially available anti-angiogenesis drug. FDA approval for breast cancer was later revoked on November 18, 2011.
Despite the therapeutic potential of anti-angiogenesis drugs, they also bring disasters when used inappropriately. The pharmaceutical thalidomide is such an antiangiogenic agent. 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, more than 10,000 children in 46 countries were born with deformities, most notably phocomelia, as a consequence of thalidomide use.
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).[3]
| 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.[4][5][6] |
| 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 | |
| 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[7] |
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:
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| リンク元 | 「antiangiogenesis」「血管新生抑制」「血管新生阻害」「antiangiogenic」「angiostatic」 |
| 拡張検索 | 「anti-angiogenic agent」「anti-angiogenic therapy」 |
| 関連記事 | 「angiogenic」「ant」「anti」 |