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.
Gomez-Rivera
Fernando
F
Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Santillan-Gomez
Alfredo A
AA
Younes
Maher N
MN
Kim
Seungwon
S
Fooshee
David
D
Zhao
Mei
M
Jasser
Samar A
SA
Myers
Jeffrey N
JN
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