Tonn J C, Haugland H K, Saraste J, Roosen K, Laerum O D
Department of Neurosurgery, University of Würzburg, Germany.
J Neurosurg. 1995 Jun;82(6):1035-43. doi: 10.3171/jns.1995.82.6.1035.
The aim of this study was to investigate the antimigratory and antiinvasive potential of vincristine sulfate (VCR) on human glioma cells and to analyze whether phenytoin (5,5-diphenylhydantoin; DPH) might act synergistically with VCR. Vincristine affects the cytoplasmic microtubules; DPH has been reported to enhance VCR cytotoxicity in murine cells. In two human glioma cell lines, GaMG and D-37MG, we found VCR to reduce monolayer growth and colony formation in a dose-dependent fashion at concentrations of 10 ng/ml and above. Phenytoin increased the cytotoxic and cytostatic effects of VCR in monolayer cells but not in spheroids. Multicellular spheroids were used to investigate directional migration. A coculture system of GaMG and D-37MG spheroids with fetal rat brain aggregates was used to analyze and quantify tumor cell invasion. A dose-dependent inhibition of migration and invasion by VCR was observed in both cell lines without further enhancement by DPH. Immunofluorescence microscopy with antibodies against alpha-tubulin revealed dose-dependent morphological alterations in the microtubules when the cells were exposed to VCR but not after incubation with DPH. Based on the combination of standardized in vitro model systems currently in use and the present data, the authors strongly suggest that VCR inhibits migration and invasion of human glioma cells. This is not altered by DPH, which inhibits cell proliferation in combination with VCR.
本研究的目的是探讨硫酸长春新碱（VCR）对人胶质瘤细胞的抗迁移和抗侵袭潜能，并分析苯妥英（5,5-二苯基乙内酰脲；DPH）是否可能与VCR产生协同作用。长春新碱影响细胞质微管；据报道，DPH可增强VCR对鼠细胞的细胞毒性。在两种人胶质瘤细胞系GaMG和D-37MG中，我们发现VCR在浓度为10 ng/ml及以上时，以剂量依赖的方式降低单层生长和集落形成。苯妥英增强了VCR对单层细胞的细胞毒性和细胞生长抑制作用，但对球体细胞无此作用。使用多细胞球体研究定向迁移。采用GaMG和D-37MG球体与胎鼠脑聚集体的共培养系统分析和量化肿瘤细胞侵袭。在两种细胞系中均观察到VCR对迁移和侵袭的剂量依赖性抑制，且未被DPH进一步增强。用抗α-微管蛋白抗体进行免疫荧光显微镜检查发现，当细胞暴露于VCR时，微管出现剂量依赖性形态改变，但与DPH孵育后未出现这种改变。基于目前使用的标准化体外模型系统和现有数据，作者强烈建议VCR抑制人胶质瘤细胞的迁移和侵袭。DPH与VCR联合使用时可抑制细胞增殖，但不会改变这一作用。
