Preclinical Efficacy of Vascular Disrupting Agents in Non–Small-Cell Lung Cancer

Abstract

There is increasing interest in the use of vascular targeted therapy for the treatment of non–small-cell lung cancer (NSCLC). Current approaches include antiangiogenic drugs, which prevent growth of new vessels, and tumor vascular disrupting drugs, which further compromise the function of tumor vasculature and induce vascular failure. Preclinical studies have led to the development of the two main classes of tumor vascular disrupting agent—tubulin polymerization inhibitors such as combretastatin A4 phosphate (CA4P) and the flavonoid class that includes flavone acetic acid (FAA) and ASA404 (vadimezan). Each class of drug has shown antitumor activity in preclinical models of lung cancer, including both rodent tumors and human tumor xenografts. Tubulin polymerization inhibitors act primarily by disrupting the tubulin network of the endothelial cell cytoskeleton, leading to shape changes and increased vascular permeability, but these agents also affect the actin cytoskeleton and endothelial cell junctions. Flavonoid vascular disrupting agents appear to accentuate pathologic signaling by cytokines such as tumor necrosis factor and vascular endothelial growth factor, leading to changes in the actin cytoskeleton, increased vascular permeability, and endothelial apoptosis. Several approaches to the measurement of vascular disrupting effects in preclinical models have been developed. They include measurement of tumor blood flow, the induction of tumor hypoxia, and the release of serotonin from platelets, measured in plasma as the metabolite 5-hydroxyindoleacetic acid. Both classes of agent combine with standard cytotoxic drugs in the treatment of experimental tumors, but consideration of the timing of combination administration is important because tumor vascular disruption will affect delivery of a second agent.