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Therapy of multidrug resistant human prostate tumors in the prostate of nude mice by simultaneous targeting of the epidermal growth factor receptor and vascular endothelial growth factor receptor on tumor‐associated endothelial cells
Author(s) -
Busby J. Erik,
Kim SunJin,
Yazici Sertac,
Nakamura Toru,
Kim JangSeong,
He Junqin,
Maya Marva,
Wang Xuemei,
Do KimAnh,
Fan Dominic,
Fidler Isaiah J.
Publication year - 2006
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.20519
Subject(s) - prostate , medicine , epidermal growth factor receptor , vascular endothelial growth factor , kinase insert domain receptor , growth factor receptor inhibitor , epidermal growth factor , receptor , cancer research , prostate cancer , growth factor , vascular endothelial growth factor a , vegf receptors , cancer
BACKGROUND Inhibiting epidermal growth factor receptor (EGF‐R) and vascular endothelial growth factor receptor (VEGF‐R) activation with AEE788 can decrease prostate cancer (CaP) growth/progression. We determined whether tumor cells or tumor‐associated endothelial cells were the primary target by treating multidrug‐resistant (MDR) CaP growing in the prostate of nude mice. METHODS MDR human CaP cells with 30‐fold increased taxane‐resistance were implanted into nude mouse prostates. After 2 weeks, mice were randomized to control, paclitaxel, AEE788, and AEE788/paclitaxel for 10 weeks. Mice were necropsied and tumors stained. RESULTS AEE788 or AEE788 plus paclitaxel significantly reduced tumor incidence and tumor weight, and eradicated lymph node metastasis. Inhibiting VEGF‐R and EGF‐R phosphorylation induced apoptosis of tumor‐associated endothelial cells causing a second apoptotic wave of surrounding tumor cells. CONCLUSION Inhibiting VEGF‐R and EGF‐R activation on tumor‐associated endothelial cells with AEE788 combined with paclitaxel can bypass CaP cell resistance and prevent lymph node metastasis. Prostate © 2006 Wiley‐Liss, Inc.