Background
Receptors for VEGF have central roles in vasculogenesis and angiogenesis and thus serve as targets for cancer therapy.1,2 Cediranib is a potent inhibitor of VEGF receptor tyrosine kinases, including VEGFR1, 2, and 3 (IC50s = 5, 1, and 3 nM, respectively).3 It also potently inhibits a variety of other receptor and non-receptor tyrosine kinases, including several in the platelet-derived growth factor, fibroblast growth factor, and endothelial growth factor receptor families.3,4 Cediranib blocks tubule formation by human umbilical vein endothelial cells in vitro and prevents angiogenesis as well as xenograft tumor growth in vivo.3 Because of these effects, cediranib has potential use in a range of cancers.5,6,7
1.Rini, B.I.Vascular endothelial growth factor-targeted therapy in metastatic renal cell carcinomaCancer115(10 Suppl)2306-2312(2009)
2.Burger, R.A.Overview of anti-angiogenic agents in development for ovarian cancerGynecol. Oncol.121(1)230-238(2011)
3.Wedge, S.R., Kendrew, J., Hennequin, L.F., et al.AZD2171: A highly potent, orally bioavailable vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancerCancer Res.65(10)4389-4400(2005)
4.Davis, M.I., Hunt, J.P., Herrgard, S., et al.Comprehensive analysis of kinase inhibitor selectivityNat. Biotechnol.29(11)1046-1051(2011)
5.Bhargava, P., and Robinson, M.O.Development of second-generation VEGFR tyrosine kinase inhibitors: Current statusCurr. Oncol. Rep.13(2)103-111(2011)
6.Conti, A., Santoni, M., Amantini, C., et al.Progress of molecular targeted therapies for advanced renal cell carcinomaBiomed Res. Int.2013419176(2013)
7.Castelli, C., Tazzari, M., Negri, T., et al.Structured myeloid cells and anti-angiogenic therapy in alveolar soft part sarcomaJ. Transl. Med.11(1)237(2013)
Protocol
Kinase experiment: | The inhibitory activity of Cediranib is determined against a range of recombinant tyrosine kinases [KDR, Flt-1, Flt-4, c-Kit, PDGFR-α, PDGFR-β, CSF-1R, Flt-3, FGFR1, Src, Abl, epidermal growth factor receptor (EGFR), ErbB2, Aur-A, and Aur-B] using ELISA methodology[1]. |
Cell experiment: | Proliferation of MG63 osteosarcoma cells is induced by PDGF-AA, which selectively activates PDGFR-α homodimer signaling. Cells are cultured in DMEM without phenol red containing 1% charcoal stripped FCS, 2 mM glutamine, and 1% nonessential amino acids for 24 hours. Cediranib or vehicle is added with PDGF-AA ligand (50 ng/mL) and plates reincubated for 72 hours. Cellular proliferation is determined using a bromodeoxyuridine[1]. |
Animal experiment: | Rats: Young female Alderley Park rats (6 weeks of age, Wistar derived, n=5) are dosed orally, once daily for 28 days with Cediranib (1.25-5 mg per kg per day) or vehicle. Additional rats (five per group) are treated with Cediranib (5 mg per kg per day) or vehicle for 28 days and maintained for a further 28 days without treatment, to examine the effect of compound withdrawal. Histologic paraffin wax sections of the femorotibial joints and ovaries are stained with H&E. Morphometric image analysis of femorotibial sections is done, with growth plate areas from both the femur and tibia in each joint being combined for an analysis of the effect of compound treatment. The area of corpora lutea in H&E-stained ovary sections is similarly determined by morphometric analysis[1]. |
参考文献: [1]. Wedge SR, et al. AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res, 2005, 65(10), 4389-4400. |
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