Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
Br J Pharmacol. 2013 Apr;168(7):1558-69. doi: 10.1111/bph.12068.
In polychemotherapy protocols, that is for treatment of neuroblastoma and Ewing sarcoma, Vinca alkaloids and cell cycle-arresting drugs are usually administered on the same day. Here we studied whether this combination enables the optimal antitumour effects of Vinca alkaloids to be manifested.
Vinca alkaloids were tested in a preclinical mouse model in vivo and in vitro in combination with cell cycle-arresting drugs. Signalling pathways were characterized using RNA interference.
In vitro, knockdown of cyclins significantly inhibited vincristine-induced cell death indicating, in accordance with previous findings, Vinca alkaloids require active cell cycling and M-phase transition for induction of cell death. In contrast, anthracyclines, irradiation and dexamethasone arrested the cell cycle and acted like cytostatic drugs. The combination of Vinca alkaloids with cytostatic therapeutics resulted in diminished cell death in 31 of 36 (86%) tumour cell lines. In a preclinical tumour model, anthracyclines significantly inhibited the antitumour effect of Vinca alkaloids in vivo. Antitumour effects of Vinca alkaloids in the presence of cytostatic drugs were restored by caffeine, which maintained active cell cycling, or by knockdown of p53, which prevented drug-induced cell cycle arrest. Therapeutically most important, optimal antitumour effects were obtained in vivo upon separating the application of Vinca alkaloids from cytostatic therapeutics.
Clinical trials are required to prove whether Vinca alkaloids act more efficiently in cancer patients if they are applied uncoupled from cytostatic therapies. On a conceptual level, our data suggest the implementation of polychemotherapy protocols based on molecular mechanisms of drug-drug interactions.
This article is commented on by Solary, pp 1555-1557 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12101.
在多药化疗方案中，用于治疗神经母细胞瘤和尤文肉瘤时，长春花生物碱类药物和细胞周期阻滞药物通常在同一天给药。在此，我们研究了这种组合是否能使长春花生物碱类药物发挥最佳的抗肿瘤作用。
长春花生物碱类药物在临床前小鼠模型中进行了体内和体外检测，并与细胞周期阻滞药物联合使用。采用 RNA 干扰技术对信号通路进行了表征。
体外实验中，细胞周期蛋白的敲低显著抑制了长春新碱诱导的细胞死亡，这与之前的研究结果一致，表明长春花生物碱类药物需要有活性的细胞周期和 M 期转变才能诱导细胞死亡。相比之下，蒽环类药物、辐射和地塞米松阻滞细胞周期并发挥细胞毒性药物的作用。长春花生物碱类药物与细胞毒性药物联合应用，可使 36 种（86%）肿瘤细胞系的细胞死亡减少 31 种。在临床前肿瘤模型中，蒽环类药物显著抑制长春花生物碱类药物在体内的抗肿瘤作用。在细胞周期阻滞药物存在的情况下，咖啡因可维持细胞的有丝分裂，或通过敲低 p53 阻止药物诱导的细胞周期阻滞，从而恢复长春花生物碱类药物的抗肿瘤作用。从治疗角度来看，最重要的是，在将长春花生物碱类药物的应用与细胞毒性治疗分开后，在体内获得了最佳的抗肿瘤效果。
需要进行临床试验以证明如果将长春花生物碱类药物与细胞毒性治疗分离使用，是否能使癌症患者更有效地受益于这些药物。从理论上讲，我们的数据提示，基于药物相互作用的分子机制，制定多药化疗方案。
本文的评论文章见本期 Solary 等的 1555-1557 页。要查看该评论文章，请访问 http://dx.doi.org/10.1111/bph.12101。
