DIVERSE NATURAL PRODUCTS THAT STABILIZE MICROTUBULES

稳定微管的多种天然产品

• 批准号: 6377506
• 负责人: SUSAN BAND HORWITZ
• 金额: $ 32.1万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-06 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6377506
• 关键词: analog; antineoplastics; apoptosis; binding proteins; binding sites; biological signal transduction; caveolins; cell cycle; cell cycle proteins; chemical structure; cytoskeleton; cytotoxicity; drug screening /evaluation; flow cytometry; lactones; microtubule associated protein; microtubules; multidrug resistance; neoplasm /cancer pharmacology; paclitaxel; pharmacokinetics; phosphorylation; prodrugs; thiazoles; tissue /cell culture

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.

FDA对卵巢，乳腺癌和肺癌的批准在治疗人类恶性肿瘤方面具有重要进步。但是，紫杉醇存在严重的问题。它在许多肿瘤中缺乏治疗活性，其水性不溶性，外周神经病和中性粒细胞减少症等毒性以及诱导耐药性的倾向。四种新天然产品的出现，它们的化学结构高度多样，但其作用机理与紫杉醇相似，这是一个令人兴奋且充满挑战的前景。该赠款的三个特定目标将为选择临床试验的药物提供信息。 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。 识别腹膜内，dincoderlide和Eletearobin化合物可阻断或刺激信号通路。 2）检查一系列耐紫杉醇的细胞系中，雌内酮，二甲甲甲甲苯和雌激素的敏感性，其耐药机制各不相同。开发对这些药物具有抗药性的细胞系，并结合了定量表达分析的使用，该分析将允许在分析其耐药性表型的分析中同时评分数千个基因的表达水平。研究Caveolin-1的关系，我们已证明在某些耐药细胞中已上调与耐药性的发展。 3）使用类似物来定义雌酮，dosodermolide和eletearobin的结构活性关系（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通常的药效团，这将有助于设计新药物，而新药在结构上比紫杉醇更简单。