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.
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Authors | Yanping 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 |
Journal | Anti-cancer drugs
(Anticancer Drugs)
Vol. 20
Issue 6
Pg. 483-92
(Jul 2009)
ISSN: 1473-5741 [Electronic] England |
PMID | 19398903
(Publication Type: Journal Article)
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Chemical References |
- ABT751
- Angiogenesis Inhibitors
- Sulfonamides
- Tubulin
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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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