MECHANISMS OF TAXOL ACTION IN VIVO

紫杉醇体内作用机制

基本信息

批准号：
2712791
负责人：
JEANNETTE CHLOE BULINSKI
金额：
$ 23.84万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-06-01 至 1999-05-31
项目状态：
已结题

项目摘要

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.

拟议研究的目的是了解紫杉醇表现出其对体内细胞的影响。我们希望测试假设微管相关蛋白（地图）很重要通过贡献 MT稳定与紫杉醇一致，或与紫杉醇互动稳定的MTS产生有害后果，例如有丝分裂停滞。已知紫杉醇针对微管（MT）系统，导致MT 抑制细胞生长的稳定化，破坏细胞内组织，阻断细胞有丝分裂，最终导致细胞死亡。因此，改变MT稳定性或自己正在改变的地图与稳定的MT相互作用可能会调节紫杉醇引起的MT稳定或直接参与下游事件。存在的变化，丰度或调节预计人类细胞类型之间的这些地图将改变紫杉醇的细胞毒性潜力。我们已经确定了一张候选地图，Ensconsin，一张110kda地图存在于多种人类细胞中。 Ensconsin表现出异常顽强在紫杉醇存在的情况下，体外和体内MTS的关联，并沿MTS积聚，并在紫杉醇治疗中积累有丝分裂的纺锤体细胞。我们的初步数据增加了不同水平或 Ensconsin的调节实际上可能与不同的相关紫杉醇在几条人类细胞中的影响和效力。我们建议旨在理解的实验1）Ensconsin与 MTS中的几种临床相关细胞类型，2）细胞的机制调节ensconsin金额或功能，3）伴随紫杉醇管理的Ensconsin和这些后遗症改变紫杉醇的细胞毒性作用。获得的信息从这些研究中将有助于我们理解紫杉醇在MT系统上行动。此外，我们的结果可能使我们能够预测紫杉醇治疗各种肿瘤细胞的功效。最终，我们对紫杉醇行动机制的研究可能是有益的在设计使用紫杉醇或设计的更好的策略改善了类紫杉醇的药物。