title: CYT997: a novel orally active tubulin polymerization inhibitor with potent cytotoxic and vascular disrupting activity in vitro and in vivo.
abstract: CYT997 is a wholly synthetic compound that possesses highly potent cytotoxic activity in vitro through inhibition of microtubule polymerization. CYT997 blocks the cell cycle at the G(2)-M boundary, and Western blot analysis indicates an increase in phosphorylated Bcl-2, along with increased expression of cyclin B1. Caspase-3 activation is also observed in cells treated with CYT997 along with the generation of poly(ADP-ribose) polymerase. The compound possesses favorable pharmacokinetic properties, is orally bioavailable, and is efficacious per os in a range of in vivo cancer models, including some refractory to paclitaxel treatment. CYT997 exhibits vascular disrupting activity as measured in vitro by effects on the permeability of human umbilical vein endothelial cell monolayers, and in vivo by effects on tumor blood flow. CYT997 possesses a useful combination of pharmacologic and pharmacokinetic properties and has considerable potential as a novel anticancer agent.
authors.affiliation: Cytopia Research Pty Ltd, Richmond, Victoria, Australia. chris.burns@cytopia.com.au
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Burns
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Fantino
authors.forename: Ian D
authors.initials: ID
authors.lastname: Phillips
authors.forename: Stephen
authors.initials: S
authors.lastname: Su
authors.forename: Michael F
authors.initials: MF
authors.lastname: Harte
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Bukczynska
authors.forename: Mark
authors.initials: M
authors.lastname: Frazzetto
authors.forename: Max
authors.initials: M
authors.lastname: Joffe
authors.forename: Irma
authors.initials: I
authors.lastname: Kruszelnicki
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Neil
authors.initials: N
authors.lastname: Wilson
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Dilley
authors.forename: Soo S
authors.initials: SS
authors.lastname: Wan
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
authors.forename: Rosa
authors.initials: R
authors.lastname: Fida
authors.forename: Cathy
authors.initials: C
authors.lastname: Malcontenti-Wilson
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Wilks
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050257:Tubulin Modulators / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C543949:CYT997; D011725:Pyridines; D011743:Pyrimidines; D050257:Tubulin Modulators