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.