ABT-751, a novel tubulin-binding agent, decreases tumor perfusion and disrupts tumor vasculature.
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.
Luo
Yanping
Y
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. yanping.luo@abbott.com
Hradil
Vincent P
VP
Frost
David J
DJ
Rosenberg
Saul H
SH
Gordon
Gary B
GB
Morgan
Sherry J
SJ
Gagne
Gerard D
GD
Cox
Bryan F
BF
Tahir
Stephen K
SK
Fox
Gerard B
GB
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*
C490492:ABT751; D020533:Angiogenesis Inhibitors; D013449:Sulfonamides; D014404:Tubulin