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.

Abstract

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. 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. 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. 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.