Effects of PTK787/ZK 222584, a specific inhibitor of vascular endothelial growth factor receptor tyrosine kinases, on primary tumor, metastasis, vessel density, and blood flow in a murine renal cell carcinoma model.
Effects of PTK787/ZK 222584, a specific inhibitor of vascular endothelial growth factor receptor tyrosine kinases, on primary tumor, metastasis, vessel density, and blood flow in a murine renal cell carcinoma model.
复制标题
DOI：
--
复制
发表时间：
2000-09
期刊：
影响因子：
11.2
通讯作者：
J. Drevs;I. Hofmann;H. Hugenschmidt;C. Wittig;H. Madjar;M. Müller;J. Wood;G. Martiny-Baron;C. Unger;D. Marmé
中科院分区：
文献类型：
--
作者：
J. Drevs;I. Hofmann;H. Hugenschmidt;C. Wittig;H. Madjar;M. Müller;J. Wood;G. Martiny-Baron;C. Unger;D. Marmé
抗血管生成疗法是一种抑制肿瘤生长和转移形成的有前景的新策略。血管内皮生长因子（VEGF）及其受体，VEGF受体1（VEGF - R1；FLT - 1）和VEGF受体2（KDR），已被证明在肿瘤血管生成中起主要作用。PTK787/ZK 222584是一种对两种VEGF受体酪氨酸激酶的特异性抑制剂，在小鼠肾细胞癌模型中对其抗肿瘤和抗血管生成活性进行了研究。在肾癌细胞肾内接种后，小鼠会形成原发性肿瘤，并向肺和腹部淋巴结转移。以50mg/kg的剂量每日口服PTK787/ZK 222584进行治疗，在14天和21天后，原发性肿瘤分别显著减少61%和67%。在这两个时间点，肺转移的发生都受到显著抑制（分别减少98%和78%）。14天后，PTK787/ZK 222584治疗组没有出现淋巴结转移，而在治疗21天后，淋巴结转移减少了87%。通过抗CD31抗体免疫组化检测，PTK787/ZK 222584使肿瘤组织中的血管密度显著降低。使用彩色多普勒超声成像，发现PTK787/ZK 222584治疗下肿瘤供血肾动脉的血流有显著变化。血流变化与血管密度变化相关，但与肿瘤体积无关。该化合物在所有体内实验中耐受性良好，对动物体重或整体健康状况没有显著影响。这与用抗血管生成剂TNP - 470治疗的动物形成对比。每隔一天皮下注射30mg/kg TNP - 470的治疗在13天后由于动物体重减轻（>20%）和共济失调而不得不停止。这些结果表明，PTK787/ZK 222584是小鼠肾细胞癌中肿瘤生长、转移形成和肿瘤血管形成的有效抑制剂。此外，我们已经能够证明彩色多普勒超声成像可用于测量肿瘤的血流，并且血流与血管密度相关。因此，这可能是一种监测抗血管生成药物（如PTK787/ZK 222584）对肿瘤血管系统影响的有价值的非侵入性方法。
Antiangiogenic therapy is a promising new strategy to inhibit tumor growth and formation of metastases. Vascular endothelial growth factor (VEGF) and its receptors, VEGF-receptor 1 (VEGF-R1; FLT-1) and VEGF-R2 (KDR), have been shown to play a major role in tumor angiogenesis. PTK787/ZK 222584, a specific inhibitor of both VEGF-receptor tyrosine kinases, was investigated for its antitumoral and antiangiogenic activity in a murine renal cell carcinoma model. After intrarenal application of the renal carcinoma cells, mice develop a primary tumor and metastases to the lung and to the abdominal lymph nodes. Daily oral therapy with PTK787/ZK 222584 at a dose of 50 mg/kg resulted in a significant decrease of 61 and 67% in primary tumors after 14 and 21 days, respectively. The occurrence of lung metastases was significantly inhibited at both time points (98% reduction and 78% reduction, respectively). After 14 days, no lymph node metastases developed in the PTK787/ZK 222584-treated group, whereas after 21 days of treatment, the lymph node metastases were reduced by 87%. Vessel density in tumor tissues, detected by immunohistochemistry with an anti-CD31 antibody, was significantly decreased by PTK787/ZK 222584. Using color Doppler imaging ultrasound, significant changes in blood flow in the tumor feeding renal artery were found under treatment with PTK787/ZK 222584. Blood flow changes correlated with changes in vessel density but not with tumor volume. The compound was well tolerated in all in vivo experiments and had no significant effects on body weight or general well-being of the animals. This was in contrast to the animals treated with the antiangiogenic agent TNP-470. s.c. therapy with 30 mg/kg TNP-470 every other day had to be discontinued after 13 days because of animal weight loss (>20%) and ataxia. These results demonstrate that PTK787/ZK 222584 is a potent inhibitor of tumor growth, metastases formation, and tumor vascularization in murine renal cell carcinoma. Furthermore, we have been able to demonstrate that color Doppler imaging ultrasound can be used to measure blood flow to a tumor and that flow correlates with vessel density. Thus, this may be a valuable noninvasive method for monitoring the effects of antiangiogenic agents such as PTK787/ZK 222584 on tumor vasculature.