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

Prostate. 2005 Nov 1;65(3):203-15. doi: 10.1002/pros.20283.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Apoptosis / drug effects
  • Capillary Permeability / drug effects
  • Cell Growth Processes / drug effects
  • Cell Line, Tumor
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism
  • Humans
  • In Situ Nick-End Labeling
  • Male
  • Mice
  • Mice, Nude
  • Microscopy, Fluorescence
  • Neovascularization, Pathologic / drug therapy
  • Paclitaxel / pharmacology
  • Phosphorylation
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Prostatic Neoplasms / blood supply*
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / enzymology
  • Prostatic Neoplasms / pathology
  • Protein Kinase Inhibitors / pharmacology*
  • Purines / pharmacology*
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*
  • Receptors, Vascular Endothelial Growth Factor / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Phytogenic
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Protein Kinase Inhibitors
  • Purines
  • ErbB Receptors
  • Receptors, Vascular Endothelial Growth Factor
  • AEE 788
  • Paclitaxel