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

• DOI: 10.1054/bjoc.2001.2166
• Publication Date: 2004-05-10T19:53:07Z
• Authors: C Hess; V Vuong; I Hegyi; O Riesterer; J Wood; D Fabbro; C Glanzmann; S Bodis; M Pruschy
• Keywords: 03 medical and health sciences; 0302 clinical medicine; Regular Article; 3. Good health

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 × 100 mg/kg) during 4 consecutive days in combination with ionizing radiation (4 × 3 Gy) exerted a substantial tumour growth delay for radiation-resistant p53-disfunctional 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 antitumoural 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. © 2001 Cancer Research Campaign http://www.bjcancer.com