Discovery of Anticancer Drugs from Cyanobacteria

从蓝藻中发现抗癌药物

• 批准号: 7356378
• 负责人: FREDERICK Augustus VALERIOTE
• 金额: $ 37.66万
• 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 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7356378
• 关键词: Algae; Antineoplastic Agents; Biological; Biological Assay; Biological Factors; Biomass; Characteristics; Collection; Colon; Condition; Cyanobacterium; Data; Detection; Development; Diffusion; Dose; Drug Formulations; Drug Kinetics; Ensure; Fractionation; Gel Chromatography; Genus Cola; Goals; High Pressure Liquid Chromatography; Human; In Vitro; Lead; Life; Liquid Chromatography; Lung; Marine Invertebrates; Marines; Mass Spectrum Analysis; Maximum Tolerated Dose; Metabolism; Methods; Molecular Structure; Monitor; Mus; Numbers; Organism; Pharmaceutical Preparations; Pharmacology; Physiologic pulse; Porifera; Principal Investigator; Procedures; Pulse taking; Research; Schedule; Screening procedure; Serum; Solid Neoplasm; Spectrometry; Staging; Structure; Symbiosis; Techniques; Testing; Therapeutic Studies; Therapy Clinical Trials; TimeLine; Tissues; Treatment Efficacy; Tumor Volume; Urochordata; Vacuum; Work; Xenograft Model; base; drug structure; efficacy trial; in vivo; innovation; intravenous administration; invertebrate host; man; pre-clinical; preclinical study; programs; scale up; tumor

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中获得的铅中发现和开发具有实体肿瘤选择性的新型抗癌药物。鉴于对人类主要实体肿瘤有效的药物缺乏，对新的抗癌药物的需求是显著的。我们筛选策略的一个基本假设是，它将产生对目前没有有效治疗的主要实体肿瘤（如肺和结肠）有活性的药物。海洋蓝藻是丰富的自由生活和共生热带生物，具有相应丰富多样的次生代谢。我们建议每年从野外采集和培养的热带海洋微藻（主要是蓝藻）中生产1000到1500种提取物，重点是那些天然生物量低或与海洋无脊椎动物（如海绵和被囊动物）共生的藻类，并表征“超级生产”的海洋蓝藻菌株。提取物还将从丛状形成的海洋蓝藻和浮游/薄泥形成的海洋蓝藻中获得，用于培养，以及在自然产物诱导条件下从无脊椎动物宿主中分离出来的培养蓝藻。我们将使用一种独特的体外圆盘扩散试验来确定提取物对实体瘤的选择性，并指导推定的抗癌剂的分离。药物结构将通过使用和开发创新的核磁共振脉冲序列并将其与质谱和其他光谱信息相结合来确定。如果有必要;我们将扩大培养或回收选择性物种，以提供足够的药物，以推进临床前研究。第一步需要大约20毫克的药物，并结合实体瘤的体外浓度-生存克隆原性研究的药代动力学信息（血清和肿瘤药物水平）。该药物首先用于静脉注射，并开发了一种高效液相色谱法来监测血清和组织水平。对克隆/药代动力学信息进行分析，以确定是否应该进行更昂贵的体内治疗试验。如果阳性，则将在荷瘤小鼠中进行至少一种异种移植模型的疗效试验。治疗活性药物将在此应用程序之外进行研究。