A comparison of thermodynamic parameters for vinorelbine- and vinflunine-induced tubulin self-association by sedimentation velocity.
A comparison of thermodynamic parameters for vinorelbine- and vinflunine-induced tubulin self-association by sedimentation velocity.
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发表时间：
1998-05
影响因子：
3.6
通讯作者：
S. Lobert;J. W. Ingram;B. Hill;J. Correia
中科院分区：
文献类型：
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作者：
S. Lobert;J. W. Ingram;B. Hill;J. Correia
我们提出了一个比较的螺旋形成的两个长春花生物碱：一个新的二氟长春瑞滨衍生物20 '，20'-二氟-3 '，4'-二氢长春瑞滨（F12158，或长春氟宁）和母体化合物，长春瑞滨的能量。木麻黄生物碱是通过抑制微管组装和诱导微管蛋白自缔合成螺旋聚集体而在中期停止细胞分裂的抑制剂。长春新碱、长春碱和长春瑞滨对微管蛋白的总体亲和力似乎与其临床剂量相关，其中具有最高总体亲和力的长春新碱以最低剂量使用。然而，化疗剂的剂量也由毒性决定。在这里描述的物理化学研究中，我们使用沉降速度来比较长春瑞滨和长春氟宁诱导的猪脑微管蛋白在50 μ M GDP或50 μ M GTP存在下的自缔合。与长春瑞滨相比，长春氟宁对微管蛋白的总体亲和力低3-16倍，并诱导更小的聚合物。沉降速度提供了迄今为止唯一的直接证据表明长春氟宁是一种微管蛋白结合药物。停流光散射表明，最短的松弛时间的聚合物再分布长春氟宁与诱导的最短螺旋一致。在5度、15度、25度和37度收集的数据显示，随着温度的升高，20，w值增加，并且与熵驱动的过程一致。这些数据与我们的假设完全一致，即长春氟宁可能导致临床神经毒性相对于长春瑞滨、长春碱和长春新碱降低。
We present a comparison of the energetics of spiral formation for two vinca alkaloids: a novel difluorinated vinorelbine derivative 20',20'-difluoro-3',4'-dihydrovinorelbine (F12158, or vinflunine) and the parent compound, vinorelbine. Vinca alkaloids are antineoplastic agents that halt cell division at metaphase by inhibiting microtubule assembly and inducing tubulin self-association into spiral aggregates. The overall affinities for tubulin of vincristine, vinblastine, and vinorelbine seem to correlate with their clinical doses, where vincristine with the highest overall affinity is used at the lowest doses. Doses of chemotherapeutic agents, however, also are determined by toxicities. In the physicochemical study described here, we used sedimentation velocity to compare vinorelbine- and vinflunine-induced self-association of porcine brain tubulin in the presence of 50 micro M GDP or 50 micro M GTP. Vinflunine demonstrates 3-16-fold lower overall affinity for tubulin and induces smaller polymers compared with vinorelbine. Sedimentation velocity provides the only direct evidence to date that vinflunine is a tubulin-binding drug. Stopped-flow light scattering demonstrates the shortest relaxation times for polymer redistribution for vinflunine consistent with induction of the shortest spirals. Data collected at 5 degrees, 15 degrees, 25 degrees, and 37 degrees show increasing 20,w values with increasing temperature and are consistent with an entropically driven process. These data are entirely consistent with our hypothesis that vinflunine is likely to result in reduced clinical neurotoxicity relative to vinorelbine, vinblastine, and vincristine.