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Vascular Targeting Agents

© David Olle

Vascular targeting agents (VSAs) disrupt the functioning of the tumor blood vessel system while not affecting the normal vascular system of the body. In this manner, transport of nutrients and oxygen to the tumor cells is blocked, leading to death of the tumor. VSAs take advantage of abnormal physical characteristics and increased activity of the endothelial lining of the tumor blood vessels. VSAs are different than angiogenesis inhibitors which aim to prevent the formation of new blood vessels within the tumor. Angiogenesis inhibitors are only effective against blood vessels in active process of development, but are ineffective against already established blood vessels.

Nature of tumor blood vessels

The abnormal processes of tumor growth are reflected in characteristics of tumor blood vessels. 9They are incompletely developed with a thin, often discontinuous, inner (endothelial) lining. As a result, there is an increased movement of fluids and proteins across the endothelial lining leading to increased pressure in the tissues surrounding the blood vessels. This increased pressure can cause constrictions in the blood vessels. Tumor blood vessel diameters are irregular leading to slower and intermittent blood flow. Capillary blood is poorly oxygenated, leading to insufficient oxygen supply to the tumors. Low flow rates can lead to the phenomenon of red blood cell stacking (rouleaux formation). All these factors make the tumor vasculature very susceptible to collapse.

The endothelial lining of normal well-established blood vessels is metabolically inactive. In contrast, the active tumor epithelium produces many proteins that are present in only very small quantities in normal epithelium. 5 1These proteins can serve as antigens or markers for the vascular targeting agents.

Nature of vascular targeting agents

Vascular targeting agent molecules consist of two main components: a targeting moiety and an effector moiety. 7The targeting moiety is attracted to the antigen, receptor site, or other binding protein on the endothelial lining. The targeting moiety can be an antibody, peptide, or small molecule as described below. After the targeting moiety binds to the endothelium, the effector moiety acts on the blood vessel to stop blood flow through the vessel. The effector moiety can deliver a toxin, a vascular destabilizing substance, or initiate a clotting process.

Vascular targeting agents under development

1. Combretastatins 9

The most active compound of this group is known as Combretastatin A4 Prodrug and is currently in clinical trials. 6The drug attacks the immature endothelial cells to change their characteristics from flat to round shape. This change effectively blocks the interior of the blood vessels preventing blood flow.