title: The microtubule depolymerizing agent CYT997 causes extensive ablation of tumor vasculature in vivo.
abstract: 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 (IC(50) 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.
authors.affiliation: YM BioSciences Australia, PO Box 11194, Frankston, VIC 3199, Australia. cburns@ymbiosciences.com.au
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Burns
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Fantino
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Powell
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shnyder
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Cooper
authors.forename: Stuart
authors.initials: S
authors.lastname: Nelson
authors.forename: Christopher
authors.initials: C
authors.lastname: Christophi
authors.forename: Cathy
authors.initials: C
authors.lastname: Malcontenti-Wilson
authors.forename: Valentina
authors.initials: V
authors.lastname: Dubljevic
authors.forename: Michael F
authors.initials: MF
authors.lastname: Harte
authors.forename: Max
authors.initials: M
authors.lastname: Joffe
authors.forename: Ian D
authors.initials: ID
authors.lastname: Phillips
authors.forename: David
authors.initials: D
authors.lastname: Segal
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Wilks
authors.forename: Gregg D
authors.initials: GD
authors.lastname: Smith
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013997:Time Factors; D050257:Tubulin Modulators / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C543949:CYT997; D011725:Pyridines; D011743:Pyrimidines; D050257:Tubulin Modulators; D042461:Vascular Endothelial Growth Factor A