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海洋蓝藻获得的先导物中发现和开发具有实体瘤选择性的新型抗癌药物。鉴于缺乏有效对抗人类主要实体瘤的药物，对新抗癌药物的需求非常大。我们筛选策略的一个基本假设是，它将产生针对目前尚未有效治疗的主要实体瘤（例如肺和结肠）的活性药物。海洋蓝藻作为自由生活和共生的热带生物体数量丰富，并且具有相应丰富多样的次生代谢。我们建议每年从现场收集和培养的热带海洋微藻（主要是蓝藻）中生产 1000 至 1500 种提取物，重点关注天然生物量低或与海绵和被囊类等海洋无脊椎动物共生的微藻，并表征“超级微藻”。 -生产”海洋蓝藻菌株。提取物也将从用于培养的簇形成海洋蓝藻和浮游/稀粘液形成海洋蓝藻的集合中获得，以及在天然产物引发条件下从无脊椎动物宿主分离的培养蓝藻。我们将使用独特的体外纸片扩散测定来鉴定提取物中的实体瘤选择性并指导假定的抗癌剂的分离。将通过使用和开发创新的 NMR 脉冲序列并将其与 MS 和其他光谱信息相结合来确定药物结构。如有需要；我们将扩大培养规模或重新收集选择性物种，以提供足够的药物以推进临床前研究。第一步需要约 20 毫克药物，并结合实体瘤体外浓度-生存克隆形成研究的信息以及药代动力学信息（血清和肿瘤药物水平）。该药物首先被配制用于静脉内给药，并开发了 HPLC 测定法来监测血清和组织水平。分析克隆形成/药代动力学信息以确定是否应该进行更昂贵的体内治疗试验。如果呈阳性，则将在至少一种异种移植模型中对荷瘤小鼠进行疗效试验。将在本申请之外寻求治疗活性药物。