RT Journal Article
SR Electronic
T1 The Microtubule Depolymerizing Agent CYT997 Causes Extensive Ablation of Tumor Vasculature In Vivo
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 799
OP 806
DO 10.1124/jpet.111.186965
VO 339
IS 3
A1 Christopher J. Burns
A1 Emmanuelle Fantino
A1 Andrew K. Powell
A1 Steven D. Shnyder
A1 Patricia A. Cooper
A1 Stuart Nelson
A1 Christopher Christophi
A1 Cathy Malcontenti-Wilson
A1 Valentina Dubljevic
A1 Michael F. Harte
A1 Max Joffe
A1 Ian D. Phillips
A1 David Segal
A1 Andrew F. Wilks
A1 Gregg D. Smith
YR 2011
UL http://jpet.aspetjournals.org/content/339/3/799.abstract
AB The orally active microtubule-disrupting agent (S)-1-ethyl-3-(2-methoxy-4-(5-methyl-4-((1-(pyridin-3-yl)butyl)amino)pyrimidin-2-yl)phenyl)urea (CYT997), reported previously by us (Bioorg Med Chem Lett 19:4639–4642, 2009; Mol Cancer Ther 8:3036–3045, 2009), is potently cytotoxic to a variety of cancer cell lines in vitro and shows antitumor activity in vivo. In addition to its cytotoxic activity, CYT997 possesses antivascular effects on tumor vasculature. To further characterize the vascular disrupting activity of CYT997 in terms of dose and temporal effects, we studied the activity of the compound on endothelial cells in vitro and on tumor blood flow in vivo by using a variety of techniques. In vitro, CYT997 is shown to potently inhibit the proliferation of vascular endothelial growth factor-stimulated human umbilical vein endothelial cells (IC50 3.7 ± 1.8 nM) and cause significant morphological changes at 100 nM, including membrane blebbing. Using the method of corrosion casting visualized with scanning electron microscopy, a single dose of CYT997 (7.5 mg/kg i.p.) in a metastatic cancer model was shown to cause destruction of tumor microvasculature in metastatic lesions. Furthermore, repeat dosing of CYT997 at 10 mg/kg and above (intraperitoneally, b.i.d.) was shown to effectively inhibit development of liver metastases. The time and dose dependence of the antivascular effects were studied in a DLD-1 colon adenocarcinoma xenograft model using the fluorescent dye Hoechst 33342. CYT997 demonstrated rapid and dose-dependent vascular shutdown, which persists for more than 24 h after a single oral dose. Together, the data demonstrate that CYT997 possesses potent antivascular activity and support continuing development of this promising compound.