The tyrosine kinase inhibitor, AZD2171, inhibits vascular endothelial growth factor receptor signaling and growth of anaplastic thyroid cancer in an orthotopic nude mouse model.
OBJECTIVE
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.


METHODS
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.
Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Fernando
F
Gomez-Rivera
Alfredo A
AA
Santillan-Gomez
Maher N
MN
Younes
Seungwon
S
Kim
David
D
Fooshee
Mei
M
Zhao
Samar A
SA
Jasser
Jeffrey N
JN
Myers
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology* / Q000517:prevention & control; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011799:Quinazolines / Q000627:therapeutic use*; D015996:Survival Rate; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000517:prevention & control; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays; D007211:Indoles
D011799:Quinazolines; D040301:Vascular Endothelial Growth Factor Receptor-2; C500926:cediranib; D007211:Indoles