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    The microtubule depolymerizing agent CYT997 causes extensive ablation of tumor vasculature in vivo

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    Publication date
    2011
    Author
    Burns, C.J.
    Fantino, E.
    Powell, A.K.
    Shnyder, Steven D.
    Cooper, Patricia A.
    Nelson, S.
    Christophi, C.
    Malcontenti-Wilson, C.
    Dubljevic, V.
    Harte, M.F.
    Joffe, M.
    Phillips, I.D.
    Segal, D.
    Wilks, A.F.
    Smith, G.D.
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    Keyword
    Angiogenesis inhibitors; Pharmacology;
    Animals;
    Antineoplastic agents;
    Cell line; Tumor;
    Cell proliferation; Drug effects;
    Colonic neoplasms; Blood supply; Drug therapy; Pathology;
    Dose-response relationship;
    Drug screening assays; Antitumor;
    Human umbilical vein endothelial cells;
    Humans;
    Liver neoplasms; Secondary;
    Male;
    Mice;
    Nude;
    Neovascularization;
    Pyridines;
    Pyrimidines;
    Time factors;
    Tubulin modulators;
    Vascular endothelial growth factor A/antagonists & inhibitors;
    Xenograft model antitumor assays;
    REF 2014
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    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.
    URI
    http://hdl.handle.net/10454/5902
    Citation
    Burns, C. J., Fantino, E., Powell, A. K., Shnyder, S. D., Cooper, P. A., Nelson, S., Christophi, C., Malcontenti-Wilson, C., Dubljevic, V., Harte, M. F., Joffe, M., Phillips, I. D., Segal, D., Wilks, A. F., Smith, G. D. (2011) The microtubule depolymerizing agent CYT997 causes extensive ablation of tumor vasculature in vivo. Journal of Pharmacology and Experimental Therapy, 339(3), 799-806.
    Link to publisher’s version
    http://dx.doi.org/10.1124/jpet.111.186965
    Type
    Article
    Collections
    Life Sciences Publications

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