Wiegering Armin, Korb Doreen, Thalheimer Andreas, Kämmerer Ulrike, Allmanritter Jan, Matthes Niels, Linnebacher Michael, Schlegel Nicolas, Klein Ingo, Ergün Süleyman, Germer Christoph-Thomas, Otto Christoph
Department of General, Visceral, Vascular and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacher Str. 6, D-97080, Würzburg, Germany ; Department of Biochemistry and Molecular Biology, Theodor-Boveri-Institute, Biocenter, University of Würzburg, D-97070, Würzburg, Germany.
Experimental Surgery, Department of General, Visceral, Vascular, and Pediatric Surgery, University Hospital of Würzburg, Oberdürrbacher Str. 6, D-97080, Würzburg, Germany.
Neoplasia. 2014 Nov 20;16(11):972-81. doi: 10.1016/j.neo.2014.09.008. eCollection 2014 Nov.
Clinical prognosis of metastasized colorectal carcinoma (CRC) is still not at desired levels and novel drugs are needed. Here, we focused on the multi-tyrosine kinase inhibitor E7080 (Lenvatinib) and assessed its therapeutic efficacy against human CRC cell lines in vitro and human CRC xenografts in vivo. The effect of E7080 on cell viability was examined on 10 human CRC cell lines and human endothelial cells (HUVEC). The inhibitory effect of E7080 on VEGF-induced angiogenesis was studied in an ex vivo mouse aortic ring angiogenesis assay. In addition, the efficacy of E7080 against xenografts derived from CRC cell lines and CRC patient resection specimens with mutated KRAS was investigated in vivo. A relatively low cytotoxic effect of E7080 on CRC cell viability was observed in vitro. Endothelial cells (HUVEC) were more susceptible to the incubation with E7080. This is in line with the observation that E7080 demonstrated an anti-angiogenic effect in a three-dimensional ex vivo mouse aortic ring angiogenesis assay. E7080 effectively disrupted CRC cell-mediated VEGF-stimulated growth of HUVEC in vitro. Daily in vivo treatment with E7080 (5 mg/kg) significantly delayed the growth of KRAS mutated CRC xenografts with decreased density of tumor-associated vessel formations and without tumor regression. This observation is in line with results that E7080 did not significantly reduce the number of Ki67-positive cells in CRC xenografts. The results suggest antiangiogenic activity of E7080 at a dosage that was well tolerated by nude mice. E7080 may provide therapeutic benefits in the treatment of CRC with mutated KRAS.
转移性结直肠癌（CRC）的临床预后仍未达到理想水平，因此需要新型药物。在此，我们聚焦于多酪氨酸激酶抑制剂E7080（乐伐替尼），并评估了其在体外对人CRC细胞系以及在体内对人CRC异种移植瘤的治疗效果。在10种人CRC细胞系和人内皮细胞（HUVEC）上检测了E7080对细胞活力的影响。在体外小鼠主动脉环血管生成试验中研究了E7080对VEGF诱导的血管生成的抑制作用。此外，在体内研究了E7080对源自CRC细胞系和具有KRAS突变的CRC患者切除标本的异种移植瘤的疗效。在体外观察到E7080对CRC细胞活力的细胞毒性作用相对较低。内皮细胞（HUVEC）对与E7080共孵育更敏感。这与E7080在三维体外小鼠主动脉环血管生成试验中表现出抗血管生成作用的观察结果一致。E7080在体外有效破坏了CRC细胞介导的VEGF刺激的HUVEC生长。每天用E7080（5mg/kg）进行体内治疗可显著延迟KRAS突变的CRC异种移植瘤的生长，肿瘤相关血管形成密度降低且无肿瘤消退。这一观察结果与E7080未显著减少CRC异种移植瘤中Ki67阳性细胞数量的结果一致。结果表明E7080在裸鼠耐受良好的剂量下具有抗血管生成活性。E7080可能在治疗具有KRAS突变的CRC中提供治疗益处。
