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Vascular Disrupting Agents: A Novel Mechanism of Action in the Battle Against Non-Small Cell Lung Cancer

^aDivision of Medical Oncology and ^bDirezione Sanitaria, "S.G. Moscati" Hospital, Avellino, Italy

Key Words. Vascular disrupting agents • Ligand-directed VDAs • ASA404 • CA4P • NPI-2358 • NSCLC

Correspondence: Correspondence: Cesare Gridelli, M.D., Division of Medical Oncology, "S.G. Moscati" Hospital, Contrada Amoretta, Città Ospedaliera, 83100 Avellino, Italy. Telephone: 39-0825-203573; Fax: 39-0825-203556; e-mail: cgridelli{at}libero.it

Received December 23, 2008; accepted for publication April 27, 2009.

Section editors: disclosures to come.

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias.

Targeting vasculature, essential in oxygen and nutrient supply, represents a new frontier in the treatment of cancer. Apart from angiogenesis inhibitors that compromise the formation of new blood vessels, a second class of vascular disrupting agents (VDAs) targets endothelial cells and pericytes of the already established tumor vasculature, resulting in tumor ischemia and necrosis. VDAs have been divided into two types: ligand-directed VDAs and small molecules. Ligand-directed VDAs consist of targeting and effector moieties that are linked together. Their clinical efficacy appears limited because of cost and a lack of specificity and toxicity. Small molecules include two classes: the synthetic flavonoids, which work through induction of local cytokine production, and the tubulin-binding agents.

The aim of this review is to discuss the hypothesized molecular mechanisms of action of VDAs and their early preclinical and clinical results, emphasizing ASA404, combretastatin A-4 disodium phosphate, ABT-751, and NPI-2358, reported in the treatment of non-small cell lung cancer, which is the leading cause of cancer death worldwide, and also to discuss future developments in this cancer population.