ABT-751, a novel tubulin-binding agent, decreases tumor perfusion and disrupts tumor vasculature.

Abstract

ABT-751 is an orally bioavailable tubulin-binding agent that is currently under clinical development for cancer treatment. In preclinical studies, ABT-751 showed antitumor activity against a broad spectrum of tumor lines including those resistant to conventional chemotherapies. In this study, we investigated the antivascular properties of ABT-751 in a rat subcutaneous tumor model using dynamic contrast-enhanced magnetic resonance imaging. A single dose of ABT-751 (30 mg/kg, intravenously) induced a rapid, transient reduction in tumor perfusion. After 1 h, tumor perfusion decreased by 57% before recovering to near pretreatment levels within 6 h. In contrast, ABT-751 produced little change in muscle perfusion at either time point. To further elucidate mechanisms of drug action at the cellular level, we examined the effects of ABT-751 on endothelial cells using an in-vitro assay. ABT-751, at concentrations corresponding to plasma levels achieved in vivo, caused endothelial cell retraction and significant loss of microtubules within 1 h. The severity of these morphological changes was dose-dependent but reversible within 6 h after the discontinuation of the drug. Taken together, these results show that ABT-751 is a tubulin-binding agent with antivascular properties. Microtubule disruption and morphological changes in vascular endothelial cells may be responsible, at least in part, for the dysfunction of tumor blood vessels after ABT-751 treatment.

DOI: 10.1097/CAD.0b013e32832c0acf

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@article{Luo2009ABT751AN, title={ABT-751, a novel tubulin-binding agent, decreases tumor perfusion and disrupts tumor vasculature.}, author={Yanping Luo and Vincent P. Hradil and David J. Frost and Saul Rosenberg and Gary Gordon and Sherry J. Morgan and Gerard D. Gagn{\'e} and Bryan F. Cox and Stephen K. Tahir and Gerard B. Fox}, journal={Anti-cancer drugs}, year={2009}, volume={20 6}, pages={483-92} }