Effect of VEGF receptor inhibitor PTK787/ZK222584 [correction of ZK222548] combined with ionizing radiation on endothelial cells and tumour growth

Br J Cancer. 2001 Dec 14;85(12):2010-6. doi: 10.1054/bjoc.2001.2166.

Abstract

The vascular endothelial growth factor (VEGF) receptor is a major target for anti-angiogenesis-based cancer treatment. Here we report the treatment effect of ionizing radiation in combination with the novel orally bioavailable VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 on endothelial cell proliferation in vitro and with tumour xenografts in vivo. Combined treatment of human umbilical vein endothelial cells with increasing doses of PTK787/ZK222584 and ionizing radiation abrogated VEGF-dependent proliferation in a dose-dependent way, but inhibition of endothelial cell proliferation was not due to apoptosis induction. In vivo, a combined treatment regimen of PTK787/ZK222584 (4 x 100 mg/kg) during 4 consecutive days in combination with ionizing radiation (4 x 3 Gy) exerted a substantial tumour growth delay for radiation-resistant p53-dysfunctional tumour xenografts derived from SW480 colon adenocarcinoma cells while each treatment modality alone had only a minimal effect on tumour size and neovascularization. SW480 tumours from animals that received a combined treatment regimen, displayed not only an extended tumour growth delay but also a significant decrease in the number of microvessels in the tumour xenograft. These results support the model of a cooperative anti-tumoral effect of angiogenesis inhibitor and irradiation and show that the orally bioavailable VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 is suitable for combination therapy with irradiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / blood supply
  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / pathology
  • Adenocarcinoma / radiotherapy
  • Administration, Oral
  • Angiogenesis Inhibitors / administration & dosage
  • Angiogenesis Inhibitors / pharmacology
  • Angiogenesis Inhibitors / therapeutic use*
  • Animals
  • Apoptosis / drug effects
  • Cell Division / drug effects
  • Colonic Neoplasms / blood supply
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / pathology
  • Colonic Neoplasms / radiotherapy
  • Combined Modality Therapy
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / radiation effects
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / radiotherapy
  • Phthalazines / administration & dosage
  • Phthalazines / pharmacology
  • Phthalazines / therapeutic use*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Pyridines*
  • Radiotherapy, Adjuvant
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptors, Growth Factor / antagonists & inhibitors*
  • Receptors, Vascular Endothelial Growth Factor
  • Xenograft Model Antitumor Assays

Substances

  • Angiogenesis Inhibitors
  • Enzyme Inhibitors
  • Neoplasm Proteins
  • Phthalazines
  • Pyridines
  • Receptors, Growth Factor
  • vatalanib
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor