Hess C, Vuong V, Hegyi I, Riesterer O, Wood J, Fabbro D, Glanzmann C, Bodis S, Pruschy M
Department of Radiation Oncology, University Hospital Zurich, CH-8091 Zurich, Switzerland.
Br J Cancer. 2001 Dec 14;85(12):2010-6. doi: 10.1054/bjoc.2001.2166.
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.
血管内皮生长因子（VEGF）受体是基于抗血管生成的癌症治疗的主要靶点。在此，我们报告了电离辐射与新型口服生物可利用的VEGF受体酪氨酸激酶抑制剂PTK787/ZK222584联合使用对体外内皮细胞增殖以及体内肿瘤异种移植的治疗效果。用递增剂量的PTK787/ZK222584和电离辐射联合处理人脐静脉内皮细胞，以剂量依赖的方式消除了VEGF依赖性增殖，但内皮细胞增殖的抑制并非由于诱导凋亡。在体内，连续4天给予PTK787/ZK222584（4×100mg/kg）联合电离辐射（4×3Gy）的联合治疗方案，对源自SW480结肠腺癌细胞的耐辐射p53功能失调肿瘤异种移植产生了显著的肿瘤生长延迟，而单独的每种治疗方式对肿瘤大小和新血管形成仅有最小的影响。接受联合治疗方案的动物的SW480肿瘤不仅显示出延长的肿瘤生长延迟，而且肿瘤异种移植中的微血管数量也显著减少。这些结果支持血管生成抑制剂与辐射协同抗肿瘤作用的模型，并表明口服生物可利用的VEGF受体酪氨酸激酶抑制剂PTK787/ZK222584适用于与辐射联合治疗。
