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

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.

• Authors: J Erik Busby, Sun-Jin Kim, Sertac Yazici, Toru Nakamura, Jang-Seong Kim, Junqin He, Marva Maya, Xuemei Wang, Kim-Anh Do, Dominic Fan, Isaiah J Fidler
• Journal: The Prostate (Prostate) Vol. 66 Issue 16 Pg. 1788-98 (Dec 01 2006) ISSN: 0270-4137 [Print] United States
• PMID: 17013882 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Purines
• ErbB Receptors
• Receptors, Vascular Endothelial Growth Factor
• AEE 788
• Paclitaxel

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Endothelial Cells
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Humans
• In Situ Nick-End Labeling
• Lymphatic Metastasis
• Male
• Mice
• Mice, Nude
• Paclitaxel (administration & dosage)
• Phosphorylation (drug effects)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Purines (administration & dosage, pharmacology)
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors, metabolism)
• Xenograft Model Antitumor Assays