MECHANISMS OF TAXOL ACTION IN VIVO

这项研究的目的是通过以下方式了解其机制： 紫杉醇在体内表现出对细胞的作用。 我们希望测试 微管相关蛋白（MAP）是重要的假说 参与细胞对紫杉醇的反应，或者通过促进 MT稳定与紫杉醇一致，或通过与紫杉醇相互作用- 稳定的MT产生有害的后果，如有丝分裂停滞。 已知紫杉醇靶向微管（MT）系统， 抑制细胞生长，破坏细胞内 组织，阻止细胞有丝分裂，并最终导致细胞死亡。 因此，改变MT稳定性或其本身在其功能上改变的MAP， 与稳定的MT的相互作用可能会调节 紫杉醇诱导的MT稳定直接或间接参与 下游事件。 变异，变异在存在、丰富或调节方面的变异 这些人类细胞类型中的MAP有望改变紫杉醇的 细胞毒性潜力。 我们已经确定了一个候选MAP，enslavin，一个110 kDa的MAP， 存在于多种人类细胞中。 恩斯赫德表现出异常顽强的 在紫杉醇存在下与MT的体外和体内结合， 而在紫杉醇处理的细胞中，内皮细胞沿着MT和有丝分裂纺锤体聚集。 细胞 我们的初步数据提高了不同水平或 神经系统调节的改变实际上可能与不同的 紫杉醇在几种人类细胞系中的作用和效力。 我们提出 实验旨在了解1）enssynthesis的相互作用， MT在几种临床相关细胞类型中的作用，2）细胞的 调节神经元数量或功能，以及3） 伴随紫杉醇给药的增强，以及这些的后遗症 改变，如果有的话，对紫杉醇的细胞毒性作用。 获得的信息 这些研究将有助于我们理解 紫杉醇作用于MT系统。 此外，我们的研究结果可以让我们 预测紫杉醇治疗各种肿瘤细胞的疗效。 最终，我们对紫杉醇作用机制的研究可能是有益的 设计更好的紫杉醇使用策略， 改进的紫杉醇类药物。

The purpose of the proposed research is to understand the mechanism by which Taxol manifests its effects on cells in vivo. We wish to test the hypothesis that microtubule-associated proteins (MAPs) are important participants in the cellular response to Taxol, either by contributing to MT stabilization in concert with Taxol, or by interacting with Taxol- stabilized MTs to produce deleterious consequences such as mitotic arrest. Taxol is known to target the microtubule (MT) system, causing MT stabilization that inhibits cell growth, disrupts intracellular organization, blocks cells in mitosis, and eventually leads to cell death. Therefore, MAPs that alter MT stability or are themselves altered in their interaction with stabilized MTs might be expected to either modulate Taxol-induced MT stabilization directly or to participate indirectly in downstream events. Variation in the presence, abundance, or regulation of these MAPs among human cell types would be expected to alter Taxol's cytotoxic potential. We have identified a candidate MAP, ensconsin, a 110kDa MAP that is present in a variety of human cells. Ensconsin shows unusually tenacious association with MTs both in vitro and in vivo in the presence of Taxol, and ensconsin accumulates along MTs and mitotic spindles in Taxol-treated cells. Our preliminary data raise the possibility that diverse levels or altered regulation of ensconsin may actually be correlated with disparate effects and potency of Taxol in several lines of human cells. We propose experiments aimed at understanding 1) the interaction of ensconsin with MTs in several clinically relevant cell types, 2) the cell's mechanism of regulation of ensconsin amount or function, and 3) the alterations in ensconsin that accompany Taxol administration, and the sequelae of these alterations, if any on Taxol's cytotoxic effects. The information gained from these studies will aid in our understanding of the mechanism by which Taxol acts on the MT system. In addition, our results may allow us to predict the efficacy of Taxol treatment of various tumor cells. Eventually, our studies of Taxol's mechanism of action may be beneficial in designing better strategies for the use of Taxol, or in designing improved Taxol-like drugs.