Antitubulin drugs: Mechanisms of action and resistance

抗微管蛋白药物：作用机制和耐药性

• 批准号: 7158489
• 负责人: PARASKEVI GIANNAKAKOU
• 金额: $ 29.2万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-15 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7158489
• 关键词: P glycoprotein; antineoplastics; binding sites; cell line; chemical binding; chemical models; computer simulation; cytotoxicity; drug interactions; drug metabolism; drug resistance; human tissue; microtubules; molecular dynamics; neoplastic cell; paclitaxel; pharmacokinetics; physical model; point mutation; polymerase chain reaction; polymerization; tubulin

DESCRIPTION (provided by applicant): Our overall research initiative is focused on understanding the molecular mechanism of action and resistance to antitumor drugs that target the microtubule (MT) cytoskeleton. MT- targeting drugs are among the most effective agents introduced in cancer chemotherapy. Taxol is the prototype of MT-stabilizing drugs, and its activity in a broad range of human tumors has ignited intense interest in tubulin as a chemotherapy target. The emergence of drug resistant tumor cells, however, limits Taxol's ability to cure disease. Resistance to Taxol is primarily mediated through overexpression of P-glycoprotein (Pgp) and the presence of beta-tubulin mutations. Thus, while tubulin appears to be a very important chemotherapy target, there is an increasing need for novel MT-targeting agents with activity in resistant cells. One such agent is discodermolide, a marine-sponge natural product, with a similarity to Taxol's mechanism of action but with several unique features. Discodermolide has a nontaxane chemical structure and is active against Taxol-resistance cell lines, both those that overexpress Pgp or harbor beta-tubulin mutations. In addition, discodermolide is the only MT-stabilizing drug reported to date to be synergistic with Taxol in various human cancer cell lines. The molecular mechanism of this synergistic interaction, however, is currently unknown. In an effort to better understand how discodermolide and Taxol interact with their intracellular target, tubulin, we have established human cancer cell lines resistant to discodermolide and to the synergistic combination of discodermolide and Taxol. The specific aims of our proposal are :(a) Elucidate the molecular mechanism of resistance to discodermolide or to the discodermolide/-taxol combinations in the drug selected clones. (b) Perform structure-activity relationship (SAR) studies on discodermolide analogs to determine the structural requirements for biological activity. We will also perform molecular modeling and structural studies of discodermolide-tubulin binding (c) Introduce specific tubulin mutations into human cancer cells to investigate their effect on drug-binding.

描述（由申请人提供）：我们的整体研究计划的重点是了解针对微管（MT）细胞骨架的抗肿瘤药物的作用和抗性药物的分子机制。 MT靶向药物是癌症化学疗法中最有效的药物之一。紫杉醇是MT稳定药物的原型，其在广泛的人类肿瘤中的活性引起了对微管蛋白的强烈兴趣，作为化学疗法靶标。然而，耐药性肿瘤细胞的出现限制了紫杉醇治愈疾病的能力。对紫杉醇的抗性主要是通过P-糖蛋白（PGP）的过表达和β-微管蛋白突变的存在来介导的。因此，虽然微管蛋白似乎是非常重要的化学疗法靶标，但越来越多的新型MT靶向剂在抗性细胞中具有活性。这样的药物是二甲甲甲甲苯（一种海洋海绵天然产品），与紫杉醇的作用机理相似，但具有几个独特的特征。二甲甲甲苯具有非Xaxane化学结构，并且对抗紫杉醇的细胞系具有活性，既可过表达PGP或携带β-微管蛋白突变的细胞。此外，doundermolide是迄今为止唯一与紫杉醇在各种人类癌细胞系中与紫杉醇协同作用的MT稳定药物。但是，目前尚不清楚这种协同相互作用的分子机制。为了更好地理解discoderlide和紫杉醇如何与其细胞内靶标微管蛋白相互作用，我们已经建立了对二甲甲甲苯；对二甲甲苯和甲状腺固醇和紫杉醇的协同组合的人类癌细胞系。我们提案的具体目的是：（a）阐明对二甲甲甲甲基抗性的分子机制或对药物选定的克隆中的discodermolide/taxol组合的抗性。 （b）对二甲甲苯类似物进行结构活性关系（SAR）研究，以确定生物活性的结构要求。我们还将对二甲甲甲苯蛋白结合（C）进行分子建模和结构研究（C）将特定的小管蛋白突变引入人类癌细胞中，以研究其对药物结合的影响。