Discovery of Anticancer Drugs from Cyanobacteria

从蓝藻中发现抗癌药物

• 批准号: 6865627
• 负责人: FREDERICK Augustus VALERIOTE
• 金额: $ 37.67万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6865627
• 关键词: SCID mouse; antineoplastics; aquatic organism; bioassay; biological products; biotechnology; biotherapeutic agent; chemical structure; drug design /synthesis /production; drug discovery /isolation; drug screening /evaluation; gel filtration chromatography; high performance liquid chromatography; laboratory mouse; mass spectrometry; microorganism culture; neoplasm /cancer pharmacology; nuclear magnetic resonance spectroscopy; pharmacokinetics; photosynthetic bacteria; saltwater environment; spectrometry; xenotransplantation

DESCRIPTION (provided by applicant): The overall goal of this project is the discovery and development of new anticancer agents with solid tumor selectivity from leads obtained from marine cyanobacteria. The need for new anticancer drugs is significant given the paucity of agents active against the major solid tumors of man. An underlying hypothesis of our screening strategy is that it will generate drugs active against the major solid tumors (such as lung and colon), which are not effectively treated at present. Marine cyanobacteria are abundant as both free-living and symbiotic tropical organisms, and have a correspondingly rich and diverse secondary metabolism. We propose to produce between 1000 and 1500 extracts per year from field collected and cultured tropical marine microalgae, mainly cyanobacteria, with a focus on those of low natural biomass or found in symbiosis with marine invertebrates, such as sponges and tunicates and to characterize "super-producing" marine cyanobacterial strains. Extracts will also be obtained from collections of tuft-forming marine cyanobacteria and planktonic/thin slime forming marine cyanobacteria for culture as well as cultured cyanobacteria isolated from invertebrate hosts under natural product-eliciting conditions. We will use a unique in vitro disk diffusion assay to both identify solid tumor selectivity in the extracts and to direct the isolation of putative anticancer agent. Drug structure will be determined by using and developing innovative NMR pulse sequences and integrating this with MS and other spectroscopic information. If necessary; we will scale-up the culture or recollect selective species to provide sufficient drug to advance to preclinical studies. The first step requires about 20 mg of drug and incorporates information from in vitro concentration-survival clonogenic studies on a solid tumor with pharmacokinetic information (serum and tumor drug levels). The drug is first formulated for intravenous administration and an HPLC assay is developed to monitor serum and tissue levels. The clonogenic/pharmacokinetic information is analyzed to determine whether the more expensive in vivo therapeutic trial should be undertaken. If positive, then an efficacy trial in tumor-bearing mice will be carried out in at least one xenograft model. Therapeutically active drugs will be pursued outside of this application.

描述（由申请人提供）：该项目的总体目标是从从海洋蓝细菌获得的铅中发现和开发具有实体肿瘤选择性的新抗癌药。鉴于对人类主要实体瘤的药物很少，对新抗癌药物的需求很大。我们筛查策略的一个基本假设是，它将针对主要实体瘤（例如肺和结肠）产生活性的药物，目前尚未有效治疗。海洋蓝细菌既有自由生活和共生的热带生物，并且具有相应丰富且多样的次要代谢。我们建议每年从收集的和培养的热带海洋微藻（主要是蓝细菌）中生产1000至1500种提取物，重点是天然生物量低，或与海洋无脊椎动物的共生中发现，例如spec虫和图犬，例如spec虫，并表征“超级生产”海洋cyanocerial cyanobactaccerial selains selains。提取物还将从簇生的海洋蓝细菌和浮游/薄粘液中获得，形成海洋蓝细菌，用于培养物以及在自然产物吸引条件下从无脊椎动物宿主中分离出来的培养的蓝细菌。我们将使用独特的体外磁盘扩散测定法来识别提取物中的实体肿瘤选择性，并指导假定的抗癌剂的分离。药物结构将通过使用和开发创新的NMR脉冲序列并将其与MS和其他光谱信息整合在一起来确定。如有必要；我们将扩大培养物或回忆选择性物种，以提供足够的药物来发展临床前研究。第一步需要大约20毫克的药物，并在具有药代动力学信息的实体瘤（血清和肿瘤药物水平）上包含了体外浓度 - 生存的克隆生成研究。该药物首先是用于静脉内给药的配方，并开发了HPLC测定法以监测血清和组织水平。分析克隆/药代动力学信息，以确定是否应进行更昂贵的体内治疗试验。如果阳性，则在至少一个异种移植模型中将进行耐肿瘤小鼠的功效试验。在本申请中将采用治疗活性的药物。