Two-domain vascular disruptive agents in cancer therapy.

Abstract

The two-domain vascular drug constructs are selective anti-cancer agents capable of specific targeting and subsequent elimination of endothelial cells lining tumor blood vessels. The destruction of existing vasculature within tumor tissue causes insufficient oxygenation of adjacent neoplastic cells and their necrotic death. The recognition (cognitive) domain of the vascular disruptive agents is responsible for recognizing markers specific for endothelial cells. This domain can be formed by variable regions of antibodies or by suitable ligands (such as those binding various integrin or growth factor receptors). The effector domain, in turn, can be constructed from proteins participating in blood clotting process, as well as from toxins, cytokines, radioactive isotopes or pro-apoptotic factors. This article outlines issues important for constructing such two-domain vascular disruptive agents and emphasizes the modularity of their assembly. Several pharmacokinetic and pharmacodynamic properties of these novel agents are discussed. Compared to known cytostatic substances exerting anti-angiogenic effects, such vascular disruptive agents can be much more effective as cytotoxic agents, especially in combination with proven anti-cancer drugs.