MECHANISMS OF TAXOL ACTION IN VIVO

拟议研究的目的是通过以下方式了解这一机制 紫杉醇在体内对细胞的作用。我们希望测试一下 关于微管相关蛋白(MAP)重要的假说 参与细胞对紫杉醇的反应，要么通过贡献 MT与紫杉醇协同稳定，或与紫杉醇相互作用- 稳定MTS以产生有害后果，如有丝分裂停止。 已知紫杉醇针对微管(MT)系统，导致微管 抑制细胞生长，扰乱细胞内的稳定 组织，阻止细胞有丝分裂，最终导致细胞死亡。 因此，改变MT稳定性或自身在其 与稳定的MTS的相互作用可能会调制 紫杉醇直接或间接参与MT的稳定作用 下游赛事。变化多端的存在、丰富或调节的变化 这些人类细胞类型的图谱有望改变紫杉醇的 潜在的细胞毒性。 我们已经确定了候选地图，恩斯康星，这是一个110 kDa的地图 存在于各种人类细胞中。恩斯康星州表现出不同寻常的顽强 在紫杉醇存在下与MTS在体外和体内的结合， 紫杉醇处理后，在MTS和有丝分裂纺锤体上有丝分裂蛋白聚集 细胞。我们的初步数据增加了不同水平或 对ENSCONIN的调节改变实际上可能与不同的 紫杉醇在几种人细胞系中的作用和效力。我们建议 旨在了解1)恩斯康星与 MTS在几种临床相关细胞类型中的表达，2)细胞机制 调节粘附素的数量或功能，以及3)在 伴随紫杉醇给药的恩斯康星以及这些药物的后遗症 紫杉醇的细胞毒作用的改变。所获得的信息 这些研究将有助于我们理解 紫杉醇作用于MT系统。此外，我们的结果可能使我们能够 预测紫杉醇对多种肿瘤细胞的治疗效果。 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，或设计 改良的紫杉醇类药物。

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.