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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.
AuthorsYanping Luo, Vincent P Hradil, David J Frost, Saul H Rosenberg, Gary B Gordon, Sherry J Morgan, Gerard D Gagne, Bryan F Cox, Stephen K Tahir, Gerard B Fox
JournalAnti-cancer drugs (Anticancer Drugs) Vol. 20 Issue 6 Pg. 483-92 (Jul 2009) ISSN: 1473-5741 [Electronic] England
PMID19398903 (Publication Type: Journal Article)
Chemical References
  • ABT751
  • Angiogenesis Inhibitors
  • Sulfonamides
  • Tubulin
Topics
  • Actin Cytoskeleton (drug effects, metabolism)
  • Angiogenesis Inhibitors (administration & dosage, pharmacology, therapeutic use)
  • Animals
  • Binding Sites
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Endothelial Cells (drug effects, pathology)
  • Endothelium, Vascular (drug effects, metabolism, pathology)
  • Female
  • Humans
  • Magnetic Resonance Imaging
  • Microtubules (drug effects, metabolism)
  • Neoplasm Transplantation
  • Neoplasms, Experimental (blood supply, drug therapy, metabolism, pathology)
  • Neovascularization, Pathologic (drug therapy, metabolism, pathology)
  • Protein Binding
  • Rats
  • Rats, Inbred F344
  • Sulfonamides (administration & dosage, pharmacology, therapeutic use)
  • Tubulin (metabolism)

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