PURPOSE: Anaplastic thyroid cancer (ATC) is a locally aggressive type of thyroid tumor with high rate of distant metastases. With conventional treatment, the median survival ranges from 4 to 12 months; therefore, new treatment options are needed. AZD2171 is a tyrosine kinase inhibitor of the vascular endothelial growth factor receptors (VEGFR) VEGFR-1, VEGFR-2, and VEGFR-3. The objective of the study is to determine whether AZD2171 can inhibit VEGFR-2 signaling and decrease tumor growth and prolong survival of ATC in an orthotopic nude mouse model. EXPERIMENTAL DESIGN: We examined the effects of AZD2171 on phosphorylation of VEGFR-2, mitogen-activated protein kinase, and AKT in human umbilical vascular endothelial cells. To determine the antiproliferative and antiapoptotic effects of AZD2171, we did 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and flow cytometry assays, respectively. We assessed the antitumor effects of AZD2171 in a xenograft model of ATC using control, AZD2171, paclitaxel, and combination groups by measuring tumor size and survival. RESULTS: Treatment with AZD2171 led to dose-dependent inhibition of VEGFR-2 phosphorylation and its downstream signaling in human umbilical vascular endothelial cells (IC(50) for cell proliferation, 500 nmol/L). In the ATC cell lines DRO and ARO, IC(50) was 7.5 micromol/L. AZD2171 induced apoptosis in 50% of endothelial and ATC cells at 3 and 10 micromol/L concentrations, respectively. In vivo, AZD2171 led to a significant reduction in tumor size between control and AZD2171 (P = 0.002) or AZD2171 + paclitaxel group (P = 0.002) but not the paclitaxel alone group (P = 0.11). Survival was significantly higher among AZD2171 (P < 0.001) and combination groups (P < 0.001) compared with control. CONCLUSIONS: AZD2171 effectively inhibits tumor growth and prolongs survival of ATC-bearing mice. The main effect of AZD2171 is mediated through angiogenesis inhibition.
PURPOSE:Anaplastic thyroid cancer (ATC) is a locally aggressive type of thyroid tumor with high rate of distant metastases. With conventional treatment, the median survival ranges from 4 to 12 months; therefore, new treatment options are needed. AZD2171 is a tyrosine kinase inhibitor of the vascular endothelial growth factor receptors (VEGFR) VEGFR-1, VEGFR-2, and VEGFR-3. The objective of the study is to determine whether AZD2171 can inhibit VEGFR-2 signaling and decrease tumor growth and prolong survival of ATC in an orthotopic nude mouse model. EXPERIMENTAL DESIGN: We examined the effects of AZD2171 on phosphorylation of VEGFR-2, mitogen-activated protein kinase, and AKT in human umbilical vascular endothelial cells. To determine the antiproliferative and antiapoptotic effects of AZD2171, we did 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and flow cytometry assays, respectively. We assessed the antitumor effects of AZD2171 in a xenograft model of ATC using control, AZD2171, paclitaxel, and combination groups by measuring tumor size and survival. RESULTS: Treatment with AZD2171 led to dose-dependent inhibition of VEGFR-2 phosphorylation and its downstream signaling in human umbilical vascular endothelial cells (IC(50) for cell proliferation, 500 nmol/L). In the ATC cell lines DRO and ARO, IC(50) was 7.5 micromol/L. AZD2171 induced apoptosis in 50% of endothelial and ATC cells at 3 and 10 micromol/L concentrations, respectively. In vivo, AZD2171 led to a significant reduction in tumor size between control and AZD2171 (P = 0.002) or AZD2171 + paclitaxel group (P = 0.002) but not the paclitaxel alone group (P = 0.11). Survival was significantly higher among AZD2171 (P < 0.001) and combination groups (P < 0.001) compared with control. CONCLUSIONS:AZD2171 effectively inhibits tumor growth and prolongs survival of ATC-bearing mice. The main effect of AZD2171 is mediated through angiogenesis inhibition.
Authors: Ilary Ruscito; Maria Luisa Gasparri; Claudia Marchetti; Caterina De Medici; Carlotta Bracchi; Innocenza Palaia; Sara Imboden; Michael D Mueller; Andrea Papadia; Ludovico Muzii; Pierluigi Benedetti Panici Journal: Tumour Biol Date: 2016-01-11
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Authors: Patricia J McLaughlin; Ian S Zagon; Sunny S Park; Andrea Conway; Renee N Donahue; David Goldenberg Journal: BMC Cancer Date: 2009-10-18 Impact factor: 4.430