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Dual inhibition of the epidermal growth factor and vascular endothelial growth factor phosphorylation for antivascular therapy of human prostate cancer in the prostate of nude mice
Author(s) -
Yazici S.,
Kim S.J.,
Busby J.E.,
He J.,
Thaker P.,
Yokoi K.,
Fan D.,
Fidler I.J.
Publication year - 2005
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20283
Subject(s) - medicine , prostate cancer , metastasis , epidermal growth factor , cancer research , vascular endothelial growth factor , prostate , endocrinology , cancer , receptor , vegf receptors
BACKGROUND Androgen‐independent prostate cancer (PCa) may be susceptible to modulation of the tumor microenvironment. We determined whether a dual tyrosine kinase inhibitor (AEE788) of the epidermal growth factor receptor (EGF‐R) and vascular endothelial growth factor receptor (VEGF‐R) combined with chemotherapy can produce therapy of human PCa in nude mice. METHODS PC‐3MM2 human PCa cells were injected into the prostate of nude mice. Three days later, the mice were randomized into four groups: saline control, paclitaxel, AEE788, and AEE788 and paclitaxel. The mice were treated for 5 weeks and necropsied. Tumor incidence, weight, and incidence of lymph node metastasis were recorded. Tumor tissue was analyzed immunohistochemically. RESULTS Treatment of mice with AEE788 or AEE788 plus paclitaxel significantly decreased tumor incidence, total tumor weight, and incidence of lymph node metastasis. AEE788 treatment alone or in combination with paclitaxel inhibited the phosphorylation of EGF‐R and VEGF‐R on tumor cells and tumor‐associated endothelial cells. Therapeutic efficacy correlated with an increase in apoptosis of tumor cells and tumor‐associated endothelial cells. CONCLUSION Blockade of EGF‐R and VEGF‐R signaling pathways coupled with chemotherapy suppressed the progressive growth and metastasis of human PCa cells growing orthotopically in nude mice. © 2005 Wiley‐Liss, Inc.