NATURAL PRODUCTS WHICH CIRCUMVENT MULTIDRUG RESISTANCE

规避多重耐药性的天然产品

• 批准号: 2107744
• 负责人: CHARLES D. SMITH
• 金额: $ 18.13万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-02-01 至 1997-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2107744
• 关键词: P glycoprotein; antineoplastics; biological products; calmodulin dependent protein kinase; chemical synthesis; cytotoxicity; drug design /synthesis /production; enzyme inhibitors; fibroblasts; gene expression; methylcholanthrene; multidrug resistance; neoplasm /cancer pharmacology; phosphorylation; photosynthetic bacteria; porphyrins; protein kinase; protein kinase C

The development of tumor cell resistance to natural product anti-cancer drugs is widely recognized as a major limiting factor in patient responsiveness to chemotherapy programs. A common mechanism for the acquisition of tumor cell multi-drug resistance (MDR) is through increased activity of P-glycoprotein, which acts as an energy-dependent drug efflux pump. It is therefore likely that the identification of compounds which circumvent this mechanism of resistance will enhance the successfulness of cancer chemotherapy. We have established a program to identify such anti-MDR compounds. In a collection of extracts from different species of cyanobacteria, two classes of compounds which circumvent P-glycoprotein-mediated MDR have been identified. Firstly, certain members of a family of macrolides called scytophycins have been found to demonstrate equivalent cytotoxicities toward normal cells and MDR cells, i.e. they do not appear to be transported by P-glycoprotein. Secondly, a family of novel porphyrins which chemosensitize P-MDR cells has been isolated. We have also recently found that closely structurally related cytochalasins interact very differently with P-glycoprotein. Studies conducted under the present proposal will characterize the biochemical and pharmacological anti-MDR properties of these natural products. The effects of each chemosensitizing compound on P-glycoprotein activity (drug binding and transport), P-glycoprotein expression (both protein and mRNA) and MDR cell chemosensitivity will be established. Cellular responses to longterm exposure to these agents will be examined. Additional active compounds in these extracts are currently being isolated, and their pharmacological properties will be similarly characterized. These studies may lead to the identification of new compounds which either inhibit P-glycoprotein activity or which elude the Pglycoprotein mechanism of resistance. Such compounds may allow new approaches to the chemotherapy of drug-resistant cancers.

肿瘤细胞对天然产物抗癌的耐药性的发展 药物被广泛认为是患者的主要限制因素 对化学疗法计划的反应。 一种常见的机制 肿瘤细胞多药耐药性（MDR）的获取是通过增加 P-糖蛋白的活性，该蛋白充当能量依赖性药物外排 泵。 因此，很可能识别化合物 规避这种抵抗机制将增强 癌症化学疗法。 我们已经建立了一个程序来识别此类抗MDR化合物。 在 收集不同种类蓝细菌的提取物，两个 围绕P-糖蛋白介导的MDR的化合物类别 已确定。 首先，大花环家族的某些成员 已经发现称为Scytophophcins表现出等效的 对正常细胞和MDR细胞的细胞毒性，即它们没有出现 通过P-糖蛋白运输。其次，一个小说家族 化学敏化P-MDR细胞的卟啉已被分离。 我们有 最近还发现，结构上相关的细胞松裂蛋白密切 与P-糖蛋白的相互作用非常不同。 研究下进行的研究 目前的建议将表征生化和药理学 这些天然产物的抗MDR特性。 每个的影响 P-糖蛋白活性的化学敏化化合物（药物结合和 传输），P-糖蛋白表达（蛋白质和mRNA）和MDR细胞 将建立化学敏感性。 细胞对长期的反应 将检查这些药物的暴露。其他活性化合物 这些提取物目前正在隔离，它们的药理学 属性将类似地表征。 这些研究可能导致鉴定新化合物 抑制P-糖蛋白活性或抑制PG糖蛋白机制 阻力。 这样的化合物可能允许新的方法进入 耐药性癌症的化学疗法。