Dhawan V, Swaffar D S
Division of Basic Pharmaceutical Sciences, School of Pharmacy, Northeast Louisiana University, Monroe 71209, USA.
Anticancer Drugs. 1999 Apr;10(4):397-404. doi: 10.1097/00001813-199904000-00008.
Paclitaxel (Taxol) is known to act by polymerizing and stabilizing microtubules. In spite of a known target, the existence of additional targets is suggested by a poor understanding of the mechanism(s) underlying eventual cell death by paclitaxel and by the drug's high efficacy, as compared to other spindle poisons. Based on the enhanced sensitivity of a mutant DNA double-strand break repair-deficient Chinese hamster ovary cell line to paclitaxel as well as to various topoisomerase (Topo) II poisons, it was hypothesized that paclitaxel, in addition to having an effect on microtubules, may also alter the activity of Topo II. This study demonstrates the unique, in vitro effects of paclitaxel on Topo II activity as investigated by monitoring the decatenation of kinetoplast DNA and relaxation of supercoiled plasmid DNA by Topo II. Unlike classical anti-topoisomerase drugs, low concentrations of paclitaxel (0.02-500 nM) stimulated Topo II catalytic activity, while higher concentrations over 5 microM inhibited the activity of Topo II. Furthermore, these effects of paclitaxel appear to be mediated through a direct interaction of paclitaxel with Topo II rather than an interaction with DNA or DNA-Topo II complexes. Collectively, the evidence presented suggests the existence of an atypical interaction between Topo II and paclitaxel that may disrupt the normal functioning of the enzyme.
已知紫杉醇（泰素）通过使微管聚合和稳定来发挥作用。尽管有一个已知的靶点，但由于对紫杉醇最终导致细胞死亡的机制了解不足，以及与其他纺锤体毒物相比该药物具有高效性，因此提示存在其他靶点。基于一种突变的DNA双链断裂修复缺陷型中国仓鼠卵巢细胞系对紫杉醇以及各种拓扑异构酶（Topo）II毒物的敏感性增强，有人推测紫杉醇除了对微管有作用外，还可能改变Topo II的活性。本研究通过监测Topo II对动质体DNA的解连环作用和超螺旋质粒DNA的松弛作用，证明了紫杉醇对Topo II活性具有独特的体外效应。与经典的抗拓扑异构酶药物不同，低浓度的紫杉醇（0.02 - 500 nM）刺激Topo II催化活性，而高于5 microM的较高浓度则抑制Topo II的活性。此外，紫杉醇的这些效应似乎是通过紫杉醇与Topo II的直接相互作用介导的，而不是与DNA或DNA - Topo II复合物的相互作用。总体而言，所提供的证据表明Topo II与紫杉醇之间存在一种非典型相互作用，这种相互作用可能会扰乱该酶的正常功能。
