Update on vascular disrupting agents for cancer therapy

Grzegorz Korpanty and Rolf A Brekken

Tumor vascular networks supply cancer cells with essential nutrients and oxygen. Since 1971, when Judah Folkman proposed the hypothesis of therapeutic targeting tumor angiogenesis, multiple compounds with anti-angiogenic activities have been discovered, some of which have demonstrated clear clinical benefits for patients with cancer. Tumor angiogenesis became a new target in combating the growth and metastasis of solid tumors. Apart from inhibitors of tumor angiogenesis, which affect the formation of new blood vessels, another class of drugs – vascular disrupting agents (VDAs) – that target endothelial cells of the already established tumor vessels are currently under clinical investigation. VDAs are divided into two types: small molecules and ligand-directed VDAs. Small molecules are further subdivided into two classes: the tubulin-binding agents and the synthetic flavonoids, which work to induce local production of cytokines. Ligand-directed VDAs consist of targeting and effector moieties that are combined together and designed to deliver toxic compounds selectively to the tumor vascular network. The review discusses the mechanisms of action of VDAs and their preclinical and clinical results.