Antiangiogenesis-Based Cancer Drugs

Every part of the human body must have a constant supply of blood to survive. Blood carries vital substances to different part of body. Blood vessels are the "pipelines" that carry blood throughout the body. Normal cells are supplied with blood by vessels that develop as your body develops. A tumor develops from a single normal cell that has turned cancerous and then continues to divide, creating more cancer cells. At first these cells can use the nearby blood vessels, but as the tumor grows, some of these cells get further away from a blood supply. For the tumor to continue growing, it must have new blood vessel formation or angiogenesis. Antiangiogenesis treatment is the use of drugs or other substances to stop tumors from developing new blood vessels. Without a blood supply, tumors can't grow freely.

Table 10. Antiangiogenesis-Based Cancer Drugs

The growth of the endothelial cells that form the inner lining of the blood vessels is one of the most important step in establishing new blood vessels. Various angiogenesis inhibitors have been developed to target vascular endothelial cells and block tumor angiogenesis. Vascular endothelial growth factor (VEGF) Trap is a blocker of VEGF. It traps the VEGF being made by the tumor, stopping it from stimulating the VEGF receptor, and thus preventing the tumor from promoting blood vessel growth. A number of antibodies and small molecules target VEGF.

Vascular targeting agent (VTA) attacks the blood vessels of solid tumors and may have applications in diseases characterized by neo-vasculature. It attacks the vasculature within the tumor itself, reducing blood flow to deprive the tumor of oxygen and nutrients, causing tumor cell death. Unlike anti-angiogenesis drugs, which attempt to prevent the formation of new tumor blood vessels from developing, the VTA starves existing solid tumors by depriving them of the blood flow that feeds the tumor, causing tumor cell death. Combretastatin A4 Prodrug is a synthetic compound and acts as a VTA. AVE8062 (AC-7700) is a water-soluble derivative of combretastatin A4, which has strong suppressive effects on tumor blood flow. ZD6126 is a small molecule VTA.

Endothelin (ET), a protein normally produced in the body that can stimulate the growth and spread of cancer cells. Both endothelin and its receptor are found in various cancers including prostate, non-small cell lung, colorectal, breast and kidney cancers. There are two endothelin receptors, ET-A and ET-B. Atrasentan and ZD4054 selectively target this ET-A receptor.

Type XVIII collagen is a component of the matrix in endothelial and epithelial basement membranes. It possesses a unique carboxyl-terminal domain, a 182 amino acid polypeptide termed endostatin, which acts as an endogenous angiogenesis inhibitor when proteolytically cleaved from the native protein.

Panzem, 2-methoxyestradiol or 2ME2, has multiple mechanisms of action, including inhibiting angiogenesis, disrupting microtubule (cell structure) formation, down regulating hypoxia inducible factor-one alpha (HIF-1α, a survival protein), and inducing apoptosis (cell death). The mechanisms of Panzem are particularly relevant to the treatment of cancer involve inhibiting endothelial cell growth (anti-angiogenic activity) and killing tumor cells directly (pro-apoptotic activity). Panzem has activity in cell lines that are resistant to various chemotherapy agents including taxanes (microtubule stabilizing agents), etoposide, adriamycin and methotrexate (DNA synthesis interfering agents), and tamoxifen (anti-estrogen agent).

BMS 275291 is a second-generation selective matrix metalloproteinase (MMP) inhibitor as an anti-angiogenic drug for cancer.

Volocixmab (Anti-α5β1 Integrin) is a chimeric antibody that inhibits angiogenesis, including vessel formation induced by VEGF, basic fibroblast growth factor (bFGF), as well as other pro-angiogenic growth factors. The antibody binds to α5β1 integrin receptors that are present on activated endothelial cells and inhibits the formation of new blood vessels to the tumor, a process that is required for tumors to grow and metastasize.

ABT-510 is a synthetic peptide that mimics the antiangiogenic activity of the naturally occurring protein, thrombospondin-1 (TSP-1). ABT-510 blocks the actions of multiple pro-angiogenic growth factors known play a role in cancer related blood vessel growth, such as VEGF, bFGF, hepatocyte growth factor (HGF), and IL-8.

Neovastat is a naturally occuring antiangiogenic compound, extracted from cartilage, with multiple antiangiogenic mechanisms of action that provide broad therapeutic potential for a number of diseases. While most antiangiogenic agents target only one mechanism of the complicated angiogenic process, Neovastat acts on multiple fronts: blocking VEGF binding, inhibiting MMP (strong inhibition of gelatinolytic and elastinolytic activities for MMP-2, MMP-9, and MMP-12), induction of endothelial cell specific apoptosis, and increase in the level of angiostatin.

Zactima (ZD6474) is a novel, orally active, anti-cancer agent that selectively inhibits two key cancer pathways: tumor blood vessel development through VEGF receptor inhibition and tumor cell growth and survival through epidermal growth factor receptor inhibition.