Kruczynski Anna, Poli Maura, Dossi Romina, Chazottes Eric, Berrichon Géraldine, Ricome Christel, Giavazzi Raffaella, Hill Bridget T, Taraboletti Giulia
Research Center for Experimental Oncology, Pierre Fabre Research Institute, Parc Technologique du Canal, 3 rue des Satellites, BP 94244, 31432 Toulouse, Cedex 04, France.
Eur J Cancer. 2006 Nov;42(16):2821-32. doi: 10.1016/j.ejca.2006.06.019. Epub 2006 Sep 14.
The aim of this study was to investigate the anti-angiogenic, vascular-disrupting and anti-metastatic properties of vinflunine, the latest vinca alkaloid in phase III clinical development. The effects of vinflunine on in vitro endothelial cell functions relevant to the performance of an already formed vasculature and to the angiogenic process were evaluated. The in vivo anti-angiogenic properties of vinflunine were also investigated, as were its activity against a model of experimental metastasis. In vitro vinflunine induced a rapid change in the morphology of endothelial cells and disrupted the network of capillary-like structures, indicating potential vascular-disrupting activity. Furthermore, vinflunine showed anti-angiogenic properties, since it inhibited endothelial cell migration and the capacity of these cells to organise into a network of capillary-like structures. All these effects were observed under conditions that only marginally affect endothelial cell proliferation. In vivo, vinflunine inhibited bFGF-induced angiogenesis in Matrigel implants at doses 40-20-fold lower than its maximal therapeutic dose (MTD). Treatment of mice with vinflunine reduced the number of liver metastases induced by intrasplenic injection of LS174T cells, with significant effects also observed at low doses; i.e. 16-fold lower than the MTD. This study demonstrates that vinflunine expresses both vascular-disrupting and anti-angiogenic activities and induced marked effects against experimental metastases, all properties that support its ongoing clinical development.
本研究的目的是调查长春氟宁（处于III期临床开发阶段的最新长春花生物碱）的抗血管生成、血管破坏和抗转移特性。评估了长春氟宁对与已形成脉管系统功能及血管生成过程相关的体外内皮细胞功能的影响。还研究了长春氟宁的体内抗血管生成特性及其对实验性转移模型的活性。在体外，长春氟宁可使内皮细胞形态迅速改变，并破坏毛细血管样结构网络，表明其具有潜在的血管破坏活性。此外，长春氟宁显示出抗血管生成特性，因为它抑制内皮细胞迁移以及这些细胞组织形成毛细血管样结构网络的能力。所有这些效应都是在仅轻微影响内皮细胞增殖的条件下观察到的。在体内，长春氟宁可在比其最大治疗剂量（MTD）低40至20倍的剂量下抑制基质胶植入物中碱性成纤维细胞生长因子（bFGF）诱导的血管生成。用长春氟宁治疗小鼠可减少脾内注射LS174T细胞诱导的肝转移数量，在低剂量下也观察到显著效果，即比MTD低16倍。本研究表明，长春氟宁具有血管破坏和抗血管生成活性，并对实验性转移产生显著影响，所有这些特性都支持其正在进行的临床开发。
