A multi-kinase inhibitor
Vandetanib is a multi-kinase inhibitor that inhibits VEGFR2, VEGFR3, VEGFR1, EGFR, PDGFRβ, Tie-2, and FGFR1 in cell-free assays (IC50s = 40, 110, 1,600, 500, 1,100, 2,500, and 3,600 nM, respectively).1,2 It also binds to 142 additional kinases in a panel of 442 kinases (Kds = 4.6-7,900 nM). Vandetanib (1 and 2.5 ?M) induces apoptosis and cell cycle arrest at the G0/G1 phase in GEO colon and OVCAR-3 ovarian cancer cells.3 It inhibits proliferation of HAK1-B, KYN-2, and Huh7 hepatocarcinoma cells, as well as human umbilical vein endothelial cells (HUVECs), with IC50 values of 10, 8.1, 9.4, and 7.1 ?M, respectively.4 Vandetanib (200 mg/kg) increases survival and decreases tumor angiogenesis and VEGFR2 levels in a D54MG glioblastoma mouse xenograft model.5 It reduces tumor growth in a variety of mouse xenograft models, including lung, colon, and breast cancer models, when administered at doses of 25, 50, and 100 mg/kg per day.1 Formulations containing vandetanib have been used in the treatment of medullary thyroid cancer.
1.Wedge, S.R., Ogilvie, D.J., Dukes, M., et al.ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administrationCancer Res.62(16)4645-4655(2002) 2.Davis, M.I., Hunt, J.P., Herrgard, S., et al.Comprehensive analysis of kinase inhibitor selectivityNat. Biotechnol.29(11)1046-1051(2011) 3.Ciardiello, F., Caputo, R., Damiano, V., et al.Antitumor effects of ZD6474, a small molecule vascular endothelial growth factor receptor tyrosine kinase inhibitor, with additional activity against epidermal growth factor receptor tyrosine kinaseClin. Cancer Res.9(4)1546-1556(2003) 4.Inoue, K., Torimura, T., Nakamura, T., et al.Vandetanib, an inhibitor of VEGF receptor-2 and EGF receptor, suppresses tumor development and improves prognosis of liver cancer in miceClin. Cancer Res.18(14)3924-3933(2012) 5.Rich, J.N., Sathornsumetee, S., Keir, S.T., et al.ZD6474, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor, inhibits tumor growth of multiple nervous system tumorsClin. Cancer Res.11(22)8145-8157(2005)
Cell experiment: | Growth inhibition is measured by a modified MTT assay. Briefly, the cells are plated on 96-well plates at a density of 2000 cells per well and exposed to each gefitinib or vandetanib for 72?h. Each assay is performed in triplicate. The 50% inhibitory concentration (IC50) of each drug is determined as the mean±standard deviation (SD). |
Animal experiment: | One million H1650 cells or H1650/PTEN cells (H1650 cells with a transfected PTEN gene) are injected subcutaneously into the backs of each mouse. On 10th day after injection, mice are randomLy assigned to three groups, which receive either vehicle, vandetanib (15 mg/kg/day), or gefitinib (15 mg/kg/day). Vehicle, vandetanib, and gefitinib are administered once per day p.o., five times per week. Tumor volume (width×width×length/2) and body weight are determined periodically. Tumor volumes are expressed as mean±SD. Differences in tumor volume are evaluated using Student's t-test. |
参考文献: [1]. Wedge SR, et al. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res. 2002 Aug 15;62(16):4645-55. | |
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