Himes R H
Department of Biochemistry, University of Kansas, Lawrence 66045-2106.
Pharmacol Ther. 1991;51(2):257-67. doi: 10.1016/0163-7258(91)90081-v.
The dimeric Vinca alkaloids represent a group of important anti-tumor compounds whose intracellular target is tubulin, the protein monomer of microtubules. In this review data on the binding of these drugs to tubulin and microtubules in vitro are examined. The binding to tubulin is linked to a protein self-association reaction described by Na and Timasheff (1986a) as a ligand-induced plus ligand-mediated isodesmic self-association reaction. The simplest model which fits the binding data is one in which there is one intrinsic site which is linked to the self-association process. Effects of solution variables on the binding and self-association explain the wide variation of reported apparent binding constants for Vinca alkaloids to tubulin. The Vinca drugs also bind to microtubules via a low number of sites at the ends of microtubules with apparent high affinity and which are involved in the inhibition of tubulin dimer addition to the microtubule ends, and to sites along the microtubule wall with apparent low affinity which are involved in the disruption of the microtubules into spiraled protofilaments. This review also compares available binding data for different natural and semi-synthetic Vinca alkaloids.
二聚体长春花生物碱是一类重要的抗肿瘤化合物，其细胞内靶点是微管蛋白，即微管的蛋白质单体。在这篇综述中，研究了这些药物在体外与微管蛋白和微管结合的数据。与微管蛋白的结合与一种蛋白质自缔合反应有关，Na和Timasheff（1986a）将其描述为配体诱导加配体介导的等键自缔合反应。符合结合数据的最简单模型是其中存在一个与自缔合过程相关的内在位点。溶液变量对结合和自缔合的影响解释了报道的长春花生物碱与微管蛋白表观结合常数的广泛差异。长春花药物还通过微管末端数量较少的位点与微管结合，这些位点具有明显的高亲和力，参与抑制微管蛋白二聚体添加到微管末端，并且还与微管壁上具有明显低亲和力的位点结合，这些位点参与将微管破坏成螺旋状原纤维。这篇综述还比较了不同天然和半合成长春花生物碱的现有结合数据。
