Growth inhibition by tyrosine kinase inhibitors in mesothelioma cell lines

Eur J Cancer. 2009 Jun;45(9):1684-91. doi: 10.1016/j.ejca.2009.02.022. Epub 2009 Mar 25.

Abstract

Clinical outcome following chemotherapy for malignant pleural mesothelioma is poor and improvements are needed. This preclinical study investigates the effect of five tyrosine kinase inhibitors (PTK787, ZD6474, ZD1839, SU6668 and SU11248) on the growth of three mesothelioma cell lines (NCI H226, NCI H28 and MSTO 211H), the presence of growth factor receptors and inhibition of their downstream signalling pathways. GI50 values were determined: ZD6474 and SU11248, mainly VEGFR2 inhibitors, gave the lowest GI50 across all cell lines (3.5-6.9 microM) whereas ZD1839 gave a GI50 in this range only in H28 cells. All cell lines were positive for EGFR, but only H226 cells were positive for VEGFR2 by Western blotting. ZD6474 and ZD1839 inhibited EGF-induced phosphorylation of EGFR, AKT and ERK, whereas VEGF-induced phosphorylation of VEGFR2 was completely inhibited with 0.1 microM SU11248. VEGFR2 was detected in tumour samples by immunohistochemistry. VEGFR2 tyrosine kinase inhibitors warrant further investigation in mesothelioma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Blotting, Western / methods
  • Cell Division / drug effects
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical / methods
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism
  • Humans
  • Mesothelioma / metabolism
  • Mesothelioma / pathology*
  • Neoplasm Proteins / metabolism
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Antineoplastic Agents
  • Neoplasm Proteins
  • Protein Kinase Inhibitors
  • EGFR protein, human
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • Vascular Endothelial Growth Factor Receptor-2