A perspective on vascular disrupting agents that interact with tubulin: Preclinical tumor imaging and biological assessment

Department of Radiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9058, USA.
Integrative Biology (Impact Factor: 3.76). 02/2011; 3(4):375-87. DOI: 10.1039/c0ib00135j
Source: PubMed


The tumor microenvironment provides a rich source of potential targets for selective therapeutic intervention with properly designed anticancer agents. Significant physiological differences exist between the microvessels that nourish tumors and those that supply healthy tissue. Selective drug-mediated damage of these tortuous and chaotic microvessels starves a tumor of necessary nutrients and oxygen and eventually leads to massive tumor necrosis. Vascular targeting strategies in oncology are divided into two separate groups: angiogenesis inhibiting agents (AIAs) and vascular disrupting agents (VDAs). The mechanisms of action between these two classes of compounds are profoundly distinct. The AIAs inhibit the actual formation of new vessels, while the VDAs damage and/or destroy existing tumor vasculature. One subset of small-molecule VDAs functions by inhibiting the assembly of tubulin into microtubules, thus causing morphology changes to the endothelial cells lining the tumor vasculature, triggered by a cascade of cell signaling events. Ultimately this results in catastrophic damage to the vessels feeding the tumor. The rapid emergence and subsequent development of the VDA field over the past decade has led to the establishment of a synergistic combination of preclinical state-of-the-art tumor imaging and biological evaluation strategies that are often indicative of future clinical efficacy for a given VDA. This review focuses on an integration of the appropriate biochemical and biological tools necessary to assess (preclinically) new small-molecule, tubulin active VDAs for their potential to be clinically effective anticancer agents.

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Available from: Li Liu, Jul 16, 2015
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    • "Vascular disruption has been proposed as a therapy for solid tumors based on the principle of starving cancer of a supply of nutrients [1], [2], [3]. Indeed, many pre-clinical studies have reported successful application of antivascular agents particularly in combination with other therapies [4], [5], [6], [7], [8], [9]. "
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    • "In the current study, BPR0L075 treatment caused collapse of pre-established vasculature in vitro and ex vivo, which may potentially contribute to the loss of tumor blood vessel integrity in vivo, leading to compromised delivery of substances to tumor, including the luciferin substrate. Tumor vessels are known to be susceptible to microtubule-binding agents [9], [10], [25], [26], [27]. Highly proliferative endothelial cells in the immature tumor vasculature are considered to increasingly rely on microtubule network to maintain their elongated, three-dimensional shape, thus rendering them intrinsically sensitive to disruption by agents that bind to tubulin and affect the endothelial cells' cytoskeleton [28], [29], [30], [31]. "
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