DIVERSE NATURAL PRODUCTS THAT STABILIZE MICROTUBULES

FDA批准紫杉醇用于卵巢癌、乳腺癌和肺癌，这在人类恶性肿瘤的治疗方面取得了重要进展。然而，紫杉醇存在严重的问题;其在许多肿瘤中缺乏治疗活性，其水不溶性，其毒性如周围神经病变和中性粒细胞减少症，以及其诱导耐药性的倾向。四种新的天然产物的出现是一个令人兴奋和具有挑战性的前景，它们的化学结构高度多样化，但其作用机制与紫杉醇相似。该补助金的三个具体目标将为临床试验药物的选择提供信息。1)确定紫杉醇和其他稳定微管的化合物对信号通路和细胞周期进程的影响。 研究紫杉醇对微管细胞骨架的影响与导致细胞死亡的信号通路之间的关系。 确定埃博霉素，discodermolide和eleutherobin化合物阻断或刺激信号通路。2)检查一系列耐药机制不同的紫杉醇耐药细胞系对埃博霉素、discodermolide和五加苷的敏感性。开发对这些药物具有耐药性的细胞系，并结合使用定量表达分析，这将允许在分析其耐药性表型时同时对数千个基因的表达水平进行评分。研究caveolin-1与耐药性发展的关系，我们已经证明caveolin-1在一些耐药细胞中上调。3)使用类似物定义埃博霉素、discodermolide和五加皮素的构效关系（SAR），以确定生物活性的结构要求。使用这些信息来定义这些药物和紫杉醇共同的药效团，这将有助于设计结构比紫杉醇更简单的新药。

The approval of Taxol by the FDA for ovarian, breast and lung carcinomas has an important advance in the treatment of human malignancies. However, there are serious problems with Taxol; its lack of therapeutic activity in many tumors, its aqueous insolubility, its toxicities such as peripheral neuropathies and neutropenia and its propensity to induce drug resistance. The advent of four new natural products whose chemical structures are highly diverse but whose mechanism of action is similar to that of Taxol, is an exciting and challenging prospect. The three specific objectives of this grant will provide information for the selection of drugs for clinical trials. 1) Determine the effects of Taxol and other compounds that stabilize microtubules, on signaling pathways and cell cycle progression. Investigate the relationship between the effects of Taxol on the microtubule cytoskeleton and on signaling pathways that lead to cell death. Identify among the epothilones, discodermolide and eleutherobin compounds that block or stimulate signaling pathways. 2) Examine the sensitivity of epothilone, discodermolide and eleutherobin in a series of Taxol-resistant cell lines whose mechanisms of resistance vary. Develop cell lines that are resistant to these drugs and incorporate the use of quantitative expression analysis that will allow scoring expression levels of several thousand genes simultaneously in the analysis of their drug resistant phenotypes. Study the relationship of caveolin-1, that we have shown to be upregulated in some drug-resistant cells, to the development of drug resistance. 3) Define the structure activity relationships (SAR) for the epothilones, discodermolide and eleutherobin using analogs to determine the structural requirements for biological activity. Use this information for defining a pharmacophore, that is common to these drugs and Taxol, that will help in the design of new drugs which will be structurally simpler than Taxol.