TY - JOUR
T1 - The tyrosine kinase inhibitor, AZD2171, inhibits vascular endothelial growth factor receptor signaling and growth of anaplastic thyroid cancer in an orthotopic nude mouse model
AU - Gomez-Rivera, Fernando
AU - Santillan-Gomez, Alfredo A.
AU - Younes, Maher N.
AU - Kim, Seungwon
AU - Fooshee, David
AU - Zhao, Mei
AU - Jasser, Samar A.
AU - Myers, Jeffrey N.
PY - 2007/8/1
Y1 - 2007/8/1
N2 - 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 (IC50 for cell proliferation, 500 nmol/L). In the ATC cell lines DRO and ARO, IC50 was 7.5 Amol/L. AZD2171 induced apoptosis in 50% of endothelial and ATC cells at 3 and 10 Amol/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.
AB - 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 (IC50 for cell proliferation, 500 nmol/L). In the ATC cell lines DRO and ARO, IC50 was 7.5 Amol/L. AZD2171 induced apoptosis in 50% of endothelial and ATC cells at 3 and 10 Amol/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.
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U2 - 10.1158/1078-0432.CCR-06-2636
DO - 10.1158/1078-0432.CCR-06-2636
M3 - Article
C2 - 17671138
AN - SCOPUS:34547666982
SN - 1078-0432
VL - 13
SP - 4519
EP - 4527
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 15
ER -