Vascular-targeting activity of ZD6126, a novel tubulin-binding agent.
The tubulin-binding agent ZD6126 is a novel vascular-targeting agent in clinical development for the treatment of solid tumors. In vivo, ZD6126 is rapidly converted into N-acetylcolchinol (ZD6126 phenol). In this study, we have explored the antivascular property of N-acetylcolchinol in vitro and ZD6126 in vivo. In cell culture, N-acetylcolchinol induced rapid changes in the morphology of human umbilical vein and lung microvessel endothelial cells. Within 40 min, the compound induced endothelial cell contraction, destabilization of the tubulin cytoskeleton, induction of actin stress fibers, and membrane blebbing. These effects occurred at noncytotoxic concentrations and were rapidly reversed on removal of the drug. Nonconfluent endothelial cells were more sensitive than confluent, quiescent cells. Among different cell types, endothelial cells were the most sensitive to the induction of morphological changes, whereas smooth muscle cells were not affected. In vitro, N-acetylcolchinol rapidly disrupted a network of newly formed cords. In vivo, ZD6126 caused shut down of newly formed vessels in the Matrigel plug assay, shortly after injection. This study indicates that rapid alteration of endothelial cell morphology may be responsible for the loss of tumor blood vessel integrity, vessel shut down, and extensive tumor necrosis induced by ZD6126 in experimental tumor models.
Micheletti
Gianluca
G
Department of Oncology, Mario Negri Institute for Pharmacological Research, 24125 Bergamo, Italy.
Poli
Maura
M
Borsotti
Patrizia
P
Martinelli
Michele
M
Imberti
Barbara
B
Taraboletti
Giulia
G
Giavazzi
Raffaella
R
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D003078:Colchicine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000098:blood supply; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism
D020533:Angiogenesis Inhibitors; C455219:N-acetylcochinol-O-phosphate; D009943:Organophosphorus Compounds; D014404:Tubulin; C017815:N-acetylcolchinol; D003078:Colchicine