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Combretastatin

Combretastatin represents a new class of therapeutic compounds known as vascular targeting agents. These agents may be useful in disease conditions or pathologies such as cancer, where an abnormal growth of blood vessels is an essential component to the disease and its progression. Combretastatin has shown the ability in both preclinical animal model and clinical trials to drastically reduce blood flow in tumors. This ability differentiates it from other drugs called angiogenesis inhibitors that are designed to work by preventing the growth of sprouting new blood vessels. Combretastatin is a family of several compounds that was licensed from Arizona State University in 1997. CA4 Prodrug, OXiGENE's lead compound, works by affecting the microtubules that form the cytoskeleton of the endothelial cells lining the tumor vasculature. When this tubulin structure is disrupted, the endothelial cells change shape from flat to round, stopping blood flow through the capillary, starving the tumor of nutrients, causing tumor cell death.

Combretastatin acts primarily on tumors because in tumors the blood vessels are newly formed and it is only in newly formed endothelial cells that tubulin alone is responsible for maintaining the structure. Actin, another protein present in endothelial cells, protect tubulin responsible for maintaining cell shape as the cell matures, however it is not present until days after the "birth" of the new endothelial cells.

Combretastatin is a synthetic compound developed by OXiGENE as a vascular targeting agent. It has been shown to attack the blood vessels of solid tumors and may have applications in other diseases characterized by neo-vasculature. It was originally derived from the root bark of the Combretum caffrum tree, also known as the Cape Bushwillow. Zulu warriors utilized a substance made from this tree to poison the tips of their arrows and spears and as a charm to ward off their enemies.

How It Works:

• Combretastatin A4 Prodrug is introduced into a patient's bloodstream using a conventional intravenous infusion.
• After infusion, the soluble prodrug rapidly distributes throughout the patient's bloodstream. Enzymes in the patient's blood convert the water-soluble prodrug into an active form of the prodrug.
• The active form of Combretastatin A4 prodrug quickly enters the cells that line the blood vessels; these cells are known as endothelial cells. Endothelial cells that line tumor-associated blood vessels are particularly sensitive to Combretastatin's effects because they are immature endothelial cells as compared to the more mature endothelial cells that line blood vessels in normal tissues. It is the immaturity of these cells that Combretastatin A4 Prodrug exploits.
• Once inside the immature endothelial cell, Combretastatin A4 Prodrug is able to disrupt the internal skeleton that gives the endothelial cell its characteristic flat shape (Combretastatin does not do this to mature endothelial cells because they are protected by Actin, which is not fully present in immature endothelial cells).
• Without an internal skeleton to maintain their elongated shape, the endothelial cells change from a flattened streamlined profile to a rounded, bloated profile.
• The bloated endothelial cells effectively plug the capillaries and prevent the blood flow necessary to feed the patient's tumor.