CYT997: a novel orally active tubulin polymerization inhibitor with potent cytotoxic and vascular disrupting activity in vitro and in vivo.
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.
Burns
Christopher J
CJ
Cytopia Research Pty Ltd, Richmond, Victoria, Australia. chris.burns@cytopia.com.au
Fantino
Emmanuelle
E
Phillips
Ian D
ID
Su
Stephen
S
Harte
Michael F
MF
Bukczynska
Patricia E
PE
Frazzetto
Mark
M
Joffe
Max
M
Kruszelnicki
Irma
I
Wang
Bing
B
Wang
Yue
Y
Wilson
Neil
N
Dilley
Rodney J
RJ
Wan
Soo S
SS
Charman
Susan A
SA
Shackleford
David M
DM
Fida
Rosa
R
Malcontenti-Wilson
Cathy
C
Wilks
Andrew F
AF
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
C543949:CYT997; D011725:Pyridines; D011743:Pyrimidines; D050257:Tubulin Modulators