Blood vessels are the tubes through which the blood circulates in the body. They include an interconnected network of arteries, arterioles, capillaries, venules, and veins. Angiogenesis (an-gee-o-gen-eh-sis) is a multistep biological process that stimulates the development of new blood vessels and tumor metastases while maintaining existing blood vessels. Endogenous positive and negative regulating factors control the process. "Endogenous" refers to something produced inside an organism or cell; whereas as "exogenous" is the opposite, i.e., produced external to the organism or cell.
Tumor angiogenesis is the growth of blood vessels between a tumor and its surrounding tissue. New blood vessels help the tumor to grow by feeding the cancer cells with essential nutrients and oxygen. Anti-angiogenesis agents or "inhibitors" are substances which prevent or destabilize the angiogenic process in a number of different ways (e.g., inhibition of endothelial cell growth and migration, suppression of the synthesis and degradation of the vessel basement membrane and extracellular matrix and blockage of angiogenic factors). There are many anti-angiogenesis agents in development and a number of agents currently being evaluated in clinical trials. Many have unique ways in which they perform their anti-angiogenic function.
Angiostatin is a piece (a fragment) of a protein, plasminogen, which plays a role in blood clotting. Angiostatin is normally secreted by tumors (at least in laboratory mice) and appears to halt the process of developing new blood vessels which is necessary to tumor development. It is hoped that Angiostatin may be used to develop a new class of anti-angiogenesis agents.
Endostatin is a piece (a fragment) of a protein, collagen 18, which appears in all blood vessels. Endostatin is normally secreted by tumors (at least in laboratory mice) and appears to halt the process of developing new blood vessels which is necessary to tumor development. It is hoped that Endostatin may be used to develop a new class of anti-angiogenesis agents.
Vascular Endothelial Growth Factor (VEGF) is a protein involved in the process that stimulates angiogenesis by binding to specific receptors on nearby blood vessels to grow extensions to existing blood vessels. An increased amount of VEGF in the bloodstream has been correlated with a poor prognosis in some tumor types. To date there are no surrogate markers for evaluating angiogenesis inhibitor efficacy. A monoclonal antibody, called rhuMab VEGF, has been developed that is designed to bind to VEGF and thus preventing the VEGF from binding to the receptors on the nearby blood vessels. It is hoped that this will prevent tumor growth. Bevacizumab (a.k.a. Avastin) is also a VEGF-based inhibitor.
Thrombospondin is one of a family of glycoproteins that are made in cells, secreted by cells, and incorporated into cells including blood platelets. The thrombospondins are known to interact with blood coagulation and anticoagulant factors. They are involved in cell adhesion, platelet aggregation (clumping), cell proliferation (growth), angiogenesis (blood vessel formation), tumor metastasis, and tissue repair. Thrombospondin-1 and thrombospondin-2 have been shown to be potent inhibitors of angiogenesis and suppressors of tumor growth in laboratory mice.
Matrix metalloproteinase is a member of a group of enzymes that can break down proteins that are normally found in the spaces between cells in tissues. These enzymes need zinc or calcium to work properly. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis. Several matrix metalloproteinase inhibitors are being studied; among them is BMS-275291.