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首页> 外文期刊>Molecular pharmacology. >Mechanism of mitotic block and inhibition of cell proliferation by the semisynthetic Vinca alkaloids vinorelbine and its newer derivative vinflunine.
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Mechanism of mitotic block and inhibition of cell proliferation by the semisynthetic Vinca alkaloids vinorelbine and its newer derivative vinflunine.

机译：半合成长春花生物碱长春瑞滨及其更新的衍生物长春氟宁能抑制有丝分裂并抑制细胞增殖。

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The two second-generation Vinca alkaloids, vinorelbine and vinflunine, affect microtubule dynamics very differently from vinblastine, a first generation Vinca alkaloid. For example, vinblastine strongly suppresses the rate and extent of microtubule shortening in vitro, whereas vinorelbine and vinflunine suppress the rate and extent of microtubule growing events. We asked whether these differences result in differences in mitotic spindle organization that might be responsible for the superior antitumor activities of the two second-generation Vinca alkaloids. IC(50) values for inhibition of HeLa cell proliferation for vinflunine, vinorelbine, and vinblastine were 18, 1.25, and 0.45 nM, respectively, similar to the concentrations that induced mitotic block at the metaphase/anaphase transition (38, 3.8, and 1.1 nM, respectively), indicating that mitotic block is a major contributor to antiproliferative action for all three drugs. Mitotically blocked cells exhibited aberrant spindles, consistent with induction of block by suppression of microtubule dynamics. Despite differences in their actions on individual dynamic instability parameters, morphologically detectable differences in spindle effects among the three drugs were minimal, indicating that overall suppression of dynamics may be more important in blocking mitosis than specific effects on growth or shortening. We also found that the peak intracellular drug concentration at the mitotic IC(50) value was highest for vinflunine (4.2 +/- 0.2 microM), intermediate for vinorelbine (1.3 +/- 0.1 microM), and more than 10-fold lower for vinblastine (130 +/- 7 nM), suggesting that intracellular binding reservoir(s) may be partially responsible for vinflunine's high efficacy and minimal side effects.
机译：长春瑞滨和长春氟宁这两种第二代长春花生物碱对微管动力学的影响与第一代长春花生物碱长春花碱的影响非常不同。例如，长春碱强烈抑制体外微管缩短的速率和程度，而长春瑞滨和长春氟宁抑制微管生长事件的速率和程度。我们问这些差异是否会导致有丝分裂纺锤体组织的差异，这可能是两种第二代长春花生物碱的优异抗肿瘤活性所致。长春氟宁，长春瑞滨和长春碱抑制HeLa细胞增殖的IC（50）值分别为18、1.25和0.45 nM，类似于在中期/后期转变中诱导有丝分裂阻滞的浓度（38、3.8和1.1）分别为nM），表明有丝分裂阻滞是所有这三种药物的抗增殖作用的主要贡献者。线粒体阻断的细胞表现出异常的纺锤体，与通过抑制微管动力学诱导的阻断一致。尽管它们对单个动态不稳定性参数的作用有所不同，但三种药物在纺锤体作用上的形态学可检测差异极小，这表明在抑制有丝分裂方面，动力学的整体抑制可能比对生长或缩短的特定作用更重要。我们还发现长春氟宁（4.2 +/- 0.2 microM）在有丝分裂IC（50）值处的细胞内药物峰值最高，长春瑞滨（1.3 +/- 0.1 microM）的中间细胞内药物浓度最高，长春碱（130 +/- 7 nM），表明细胞内结合储库可能部分负责长春氟宁的高效治疗和最小的副作用。

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