Department I of Internal Medicine, University at Cologne, Cologne, Germany.
Clin Cancer Res. 2010 Jul 1;16(13):3390-8. doi: 10.1158/1078-0432.CCR-10-0232. Epub 2010 Jun 22.
There is evidence that vascular endothelial growth factor (VEGF) is a critical microenvironmental factor that exerts angiogenesis-independent effects on the survival of chronic lymphocytic leukemia (CLL) cells. Vatalanib and pazopanib are potent orally available VEGF receptor tyrosine kinase inhibitors. We investigated the efficacy and selectivity of both compounds in CLL cells, simulated potential combination with conventional cytostatics, and tested the effect of both substances on CLL-like tumor xenografts.
Primary CLL and normal peripheral blood cells were tested for viability after incubation with varying concentrations of both inhibitors. Further, phosphorylation status of VEGF receptor on treatment, caspase activation, and poly(ADP-ribose) polymerase cleavage were assessed. Combinations of each inhibitor with fludarabine, vincristine, and doxorubicin were analyzed for possible synergistic effects in vitro. For in vivo testing, mice grafted with the CLL-like cell line JVM-3 were treated orally with each inhibitor.
Vatalanib and pazopanib decreased phosphorylation of the VEGF receptor, along with induction of apoptosis in CLL cells in clinically achievable concentrations. Healthy B cells were only mildly affected. Immunoblots showed downregulation of the antiapoptotic proteins XIAP and MCL1, whereas poly(ADP-ribose) polymerase cleavage was increased. Combinations with conventional cytostatic agents resulted in synergistic effects. Treatment of xenografted mice with 100 mg/kg of body weight for 21 days resulted in tumor inhibition rates of 76% (vatalanib) and 77% (pazopanib). In two mice, a total tumor eradication could be observed. No gross systemic toxicity occurred.
We conclude that VEGF inhibition is a promising new therapeutic approach in CLL. Vatalanib and pazopanib seem to be effective and safe candidates to be further evaluated for this purpose.
有证据表明，血管内皮生长因子（VEGF）是一种关键的微环境因子，对慢性淋巴细胞白血病（CLL）细胞的存活具有血管生成独立的作用。瓦他拉尼布和帕唑帕尼是两种有效的口服 VEGF 受体酪氨酸激酶抑制剂。我们研究了这两种化合物在 CLL 细胞中的疗效和选择性，模拟了与常规细胞毒药物的潜在联合，并测试了这两种物质对 CLL 样肿瘤异种移植物的影响。
用不同浓度的两种抑制剂孵育后，检测原代 CLL 和正常外周血细胞的活力。此外，还评估了 VEGF 受体在治疗时的磷酸化状态、半胱天冬酶激活和聚（ADP-核糖）聚合酶裂解。分析了每种抑制剂与氟达拉滨、长春新碱和阿霉素的联合应用，以评估体外协同作用的可能性。为了进行体内试验，用 CLL 样细胞系 JVM-3 移植的小鼠进行了口服治疗。
瓦他拉尼布和帕唑帕尼降低了 VEGF 受体的磷酸化水平，并在临床可达到的浓度下诱导 CLL 细胞凋亡。健康 B 细胞仅受到轻微影响。免疫印迹显示抗凋亡蛋白 XIAP 和 MCL1 下调，而聚（ADP-核糖）聚合酶裂解增加。与常规细胞毒药物联合使用可产生协同作用。用 100mg/kg 体重的剂量治疗移植的异种移植物小鼠 21 天，可使肿瘤抑制率达到 76%（瓦他拉尼布）和 77%（帕唑帕尼）。在两只小鼠中，观察到完全消除肿瘤。没有发生明显的全身毒性。
我们的结论是，VEGF 抑制是 CLL 的一种有前途的新治疗方法。瓦他拉尼布和帕唑帕尼似乎是有效的、安全的候选药物，可进一步对此进行评估。
