Simultaneous blockade of platelet-derived growth factor-receptor and epidermal growth factor-receptor signaling and systemic administration of paclitaxel as therapy for human prostate cancer metastasis in bone of nude mice

Cancer Res. 2004 Jun 15;64(12):4201-8. doi: 10.1158/0008-5472.CAN-03-3763.

Abstract

Once prostate cancer metastasizes to bone, conventional chemotherapy is largely ineffective. We hypothesized that inhibition of phosphorylation of the epidermal growth factor receptor (EGF-R) and platelet-derived growth factor receptor (PDGF-R) expressed on tumor cells and tumor-associated endothelial cells, which is associated with tumor progression, in combination with paclitaxel would inhibit experimental prostate cancer bone metastasis and preserve bone structure. We tested this hypothesis in nude mice, using human PC-3MM2 prostate cancer cells. PC-3MM2 cells growing adjacent to bone tissue and endothelial cells within these lesions expressed phosphorylated EGF-R and PDGF-R alpha and -beta on their surfaces. The percentage of positive endothelial cells and the intensity of receptor expression directly correlated with proximity to bone tissue. Oral administration of PKI166 inhibited the phosphorylation of EGF-R but not PDGF-R, whereas oral administration of STI571 inhibited the phosphorylation of PDGF-R but not EGF-R. Combination therapy using oral PKI166 and STI571 with i.p. injections of paclitaxel induced a high level of apoptosis in tumor vascular endothelial cells and tumor cells in parallel with inhibition of tumor growth in the bone, preservation of bone structure, and reduction of lymph node metastasis. Collectively, these data demonstrate that blockade of phosphorylation of EGF-R and PDGF-R coupled with administration of paclitaxel significantly suppresses experimental human prostate cancer bone metastasis.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects
  • Benzamides
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / secondary*
  • Cell Division / drug effects
  • Enzyme Inhibitors / administration & dosage
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism
  • ErbB Receptors / physiology
  • Humans
  • Imatinib Mesylate
  • In Situ Nick-End Labeling
  • Male
  • Mice
  • Mice, Nude
  • Paclitaxel / administration & dosage*
  • Phosphorylation
  • Piperazines / administration & dosage
  • Platelet Endothelial Cell Adhesion Molecule-1 / analysis
  • Prostatic Neoplasms / blood supply
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • Pyrimidines / administration & dosage
  • Pyrroles / administration & dosage
  • Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors*
  • Receptors, Platelet-Derived Growth Factor / metabolism
  • Receptors, Platelet-Derived Growth Factor / physiology
  • Substrate Specificity
  • Xenograft Model Antitumor Assays

Substances

  • Benzamides
  • Enzyme Inhibitors
  • Piperazines
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Pyrimidines
  • Pyrroles
  • Imatinib Mesylate
  • PKI 166
  • ErbB Receptors
  • Receptors, Platelet-Derived Growth Factor
  • Paclitaxel