Discovery of Anticancer Drugs from Cyanobacteria

从蓝藻中发现抗癌药物

• 批准号: 7221876
• 负责人: FREDERICK Augustus VALERIOTE
• 金额: $ 37.48万
• 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 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7221876
• 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）：本项目的总体目标是从海洋蓝藻中获得的先导化合物中发现和开发具有实体瘤选择性的新型抗癌药物。鉴于对人类主要实体瘤有活性的药物的缺乏，对新的抗癌药物的需求是显着的。我们筛选策略的基本假设是，它将产生对主要实体瘤（如肺和结肠）有活性的药物，这些实体瘤目前还没有得到有效治疗。海洋蓝细菌是丰富的自由生活和共生的热带生物，并有相应的丰富和多样的次生代谢。我们建议每年从实地收集和培养的热带海洋微藻（主要是蓝藻）中提取1000至1500种提取物，重点关注那些天然生物量低或与海洋无脊椎动物共生的微藻，如海绵和被囊动物，并描述“高产”海洋蓝藻菌株的特征。提取物也将从丛状形成的海洋蓝细菌和浮游/薄粘液形成的海洋蓝细菌的集合中获得，以用于培养，以及在天然产物诱导条件下从无脊椎动物宿主分离的培养蓝细菌。我们将使用一种独特的体外纸片扩散试验来鉴定提取物中的实体瘤选择性，并指导推定抗癌剂的分离。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和其他光谱信息相结合来确定。如有必要，我们将扩大培养或选择选择性菌种，以提供足够的药物进行临床前研究。第一步需要约20 mg药物，并将来自实体瘤体外浓度-存活克隆形成研究的信息与药代动力学信息（血清和肿瘤药物水平）结合。该药物首先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。如果为阳性，则将在至少一种异种移植模型中进行荷瘤小鼠的疗效试验。治疗活性药物将在本申请之外进行。