Effect of VEGF receptor inhibitor PTK787/ZK222584 [correction of ZK222548] combined with ionizing radiation on endothelial cells and tumour growth.
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.
Hess
C
C
Department of Radiation Oncology, University Hospital Zurich, CH-8091 Zurich, Switzerland.
Vuong
V
V
Hegyi
I
I
Riesterer
O
O
Wood
J
J
Fabbro
D
D
Glanzmann
C
C
Bodis
S
S
Pruschy
M
M
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D003131:Combined Modality Therapy; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000532:radiotherapy; D010793:Phthalazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines; D018714:Radiotherapy, Adjuvant; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D010793:Phthalazines; D011725:Pyridines; D017978:Receptors, Growth Factor; C404768:vatalanib; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor