Geldof A A, Minneboo A, Heimans J J
Department of Endocrinology/Nucl. Medicine, Academisch Ziekenhuis Vrije Universiteit, Amsterdam, The Netherlands.
J Neurooncol. 1998 Apr;37(2):109-13. doi: 10.1023/a:1005848623771.
Neurotoxicity forms a major limitation in many clinical applications of vincristine and other powerful vinca alkaloid anticancer drugs. Using the nerve growth factor (NGF) dependent neurite outgrowth from the PC12 pheochromocytoma cell line as an in vitro assay for neurotoxicity, the effect of different concentrations of vincristine (0.55; 1.1 and 11 nM) was compared with that of vindesine and vinblastine. Vincristine in comparatively low concentration (0.55 nM) could significantly decrease the percentage of neurite forming cells from 74% to 32% within a three day incubation period. Especially the longer neurites (> 2 x cell body) proved to be extremely sensitive for vincristine effects. Vinblastine and vindesine were also able to decrease, dose dependently and significantly, the percentage of neurite forming cells. However, the effects observed were less severe than that of vincristine. The sequentially increasing level of neurotoxicity due to vinblastine, vindesine and vincristine, as observed in the neurite outgrowth inhibition correlates well with previous findings from animal models and with data from the clinical practice. Withdrawal of vincristine resulted in a rapid restoration of neurite formation, suggesting the potential reversibility of neurotoxic effects in these cells. These results provide a validation of the PC12 neurite outgrowth assay as a suitable and reliable model for predicting neurotoxicity.
神经毒性是长春新碱和其他强效长春花生物碱抗癌药物在许多临床应用中的主要限制因素。利用PC12嗜铬细胞瘤细胞系中依赖神经生长因子（NGF）的神经突生长作为神经毒性的体外检测方法，比较了不同浓度长春新碱（0.55、1.1和11 nM）与长春地辛和长春碱的作用效果。在三天的孵育期内，相对低浓度（0.55 nM）的长春新碱可使形成神经突的细胞百分比从74%显著降至32%。特别是较长的神经突（>2倍细胞体长度）对长春新碱的作用极为敏感。长春碱和长春地辛也能够剂量依赖性且显著地降低形成神经突的细胞百分比。然而，观察到的作用不如长春新碱严重。在神经突生长抑制中观察到的长春碱、长春地辛和长春新碱导致的神经毒性水平依次升高，这与先前动物模型的研究结果以及临床实践数据高度相关。撤去长春新碱后，神经突形成迅速恢复，表明这些细胞中的神经毒性作用具有潜在的可逆性。这些结果验证了PC12神经突生长检测方法作为预测神经毒性的合适且可靠模型的有效性。
