title: 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.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. yanping.luo@abbott.com
authors.forename: Yanping
authors.initials: Y
authors.lastname: Luo
authors.forename: Vincent P
authors.initials: VP
authors.lastname: Hradil
authors.forename: David J
authors.initials: DJ
authors.lastname: Frost
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Gary B
authors.initials: GB
authors.lastname: Gordon
authors.forename: Sherry J
authors.initials: SJ
authors.lastname: Morgan
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Gagne
authors.forename: Bryan F
authors.initials: BF
authors.lastname: Cox
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Tahir
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Fox
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D014404:Tubulin / Q000378:metabolism*
chemical_list: C490492:ABT751; D020533:Angiogenesis Inhibitors; D013449:Sulfonamides; D014404:Tubulin