Discovery of Anticancer Drugs from Cyanophytes

从蓝藻中发现抗癌药物

• 批准号: 7849027
• 负责人: FREDERICK Augustus VALERIOTE
• 金额: $ 39.81万
• 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 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849027
• 关键词: Algae; Animal Model; Antineoplastic Agents; Applications Grants; Aquaculture; Biological Assay; Biological Factors; Biology; Biomass; Brain; Breast; California; Cancer Center; Cancer Patient; Characteristics; Chemical Structure; Chemicals; Chemistry; Clinic; Clinical; Collaborations; Collection; Coupled; Crude Extracts; Cyanobacterium; Data; Detection; Development; Diffusion; Disease; Dose; Drug Administration Schedule; Drug Kinetics; Epigenetic Process; Evaluation; Foundations; Fractionation; Gene Cluster; Genes; Goals; Grant; Health system; High Pressure Liquid Chromatography; In Vitro; Inhibitory Concentration 50; Institution; Laboratories; Lead; Malignant neoplasm of lung; Marines; Materials Testing; Maximum Tolerated Dose; Methods; Modification; Molecular; Monitor; Mus; Oceanography; Organism; Ovarian; Pancreas; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phylogenetic Analysis; Plasma; Program Development; Regulatory Pathway; Relative (related person); Research; Route; Sampling; Scheme; Screening procedure; Serum; Solid; Solid Neoplasm; Source; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Staging; Structure; Structure-Activity Relationship; System; Testing; Therapeutic; Tissues; Toxic effect; Treatment Efficacy; Universities; Water; Xenograft Model; analog; anticancer activity; base; cancer cell; cytotoxicity; drug development; drug discovery; efficacy trial; in vitro Assay; in vivo; innovation; interest; intravenous administration; marine natural product; microbial; novel; pre-clinical; programs; public health relevance; rectal; therapeutic effectiveness; tissue culture; tumor

DESCRIPTION (provided by applicant): The overall goal of this project is the discovery and development of new anticancer drugs with solid tumor selectivity from leads obtained from collected and cultured marine cyanobacteria and marine microalgae. The need for new and effective anticancer drugs is critical given the paucity of ones active against the major solid tumors in people. Over the course of this grant, 450 taxonomically diverse samples are proposed to be obtained as a source of novel natural products. Micro-elicitation culture methods will be employed on a set of these samples to thoroughly query their secondary metabolomes. Nine fractions plus crude extract are produced from each organism for the anticancer screen (over 900 test samples per year). We employ a unique and novel disk diffusion assay to both identify solid tumor selectivity in the initial extracts and also to direct the isolation of the putative anticancer agent. The assay has been expanded to examine the 7 major solid tumor types in vitro and then in vivo. We expect to both functionally and structurally identify about 6 solid tumor selective compounds per year. While many of the leads will be novel structures, some of the leads may be known compounds or analogues of known compounds; however, very few of these latter compounds will have been evaluated for anticancer activity either in vitro or in vivo. We expect to take all of our lead compounds through a drug development paradigm so as to determine whether they have clinical potential. The first step of drug development requires 15 mg of pure compound to produce in vitro IC50 values and concentration-survival clonogenic studies; and, in vivo maximum tolerated dose and pharmacokinetic information (plasma and tumor levels). The drug is formulated for intravenous administration and an HPLC assay is developed to monitor serum and tissue levels. We expect that all 6 of the yearly discovered in vitro lead compounds will be examined in this pharmacologic phase. These data will be analyzed to determine whether the more expensive efficacy trials in tumor-bearing mice should be undertaken. We expect 3 drugs per year will go to therapeutic efficacy trial in at least one xenograft model. Such a trial will likely require a further collection, culturing or synthetic efforts to gain sufficient material, estimated at 50 - 200 mg. We expect to find one compound per year that has efficacy in the xenograft models, and this lead structure will be chemically explored through synthesis of simple analogs and synthetic modification of the natural product. Therapeutically active drugs will be pursued further in preclinical and clinical development outside of this application. PUBLIC HEALTH RELEVANCE: Anticancer drug leads will be discovered, their structure determined and developed both in tissue culture and animal models to a stage where they should be attractive to either Biotech or Pharmaceutical companies to continue with their development towards the clinic. Given the lack of effective anticancer drugs for the major solid tumors, especially for metastatic disease, our leads can have a significant positive impact on the cancer patient.

描述(申请人提供)：该项目的总体目标是从收集和培养的海洋蓝藻和海洋微藻获得的铅中发现和开发具有固体肿瘤选择性的新的抗癌药物。考虑到对人类主要实体肿瘤有效的药物很少，对新的有效抗癌药物的需求是至关重要的。在这笔赠款的过程中，建议获得450个不同分类的样本，作为新天然产品的来源。将对一组样品采用微诱导培养方法，以彻底查询它们的次生代谢产物。为了抗癌筛查，每个生物体都产生了九个组分加粗提物(每年超过900个测试样本)。我们使用了一种独特而新颖的纸片扩散法来鉴定最初提取物中的实体肿瘤选择性，并指导假定的抗癌药物的分离。该方法已扩展到体外和体内检测7种主要实体瘤类型。我们希望每年从功能和结构上鉴定大约6种实体肿瘤选择性化合物。虽然许多先导化合物将是新的结构，但一些先导化合物可能是已知的化合物或已知化合物的类似物；然而，这些后一类化合物中很少有化合物在体外或体内被评估抗癌活性。我们希望将我们所有的先导化合物通过药物开发范例，以确定它们是否具有临床潜力。药物开发的第一步需要15毫克的纯化合物来产生体外IC50值和浓度-存活克隆研究；以及体内最大耐受剂量和药代动力学信息(血浆和肿瘤水平)。该药物用于静脉给药，并开发了一种高效液相色谱法来监测血清和组织水平。我们预计，每年发现的6种体外先导化合物都将在这个药理阶段进行检查。将对这些数据进行分析，以确定是否应该在荷瘤小鼠身上进行更昂贵的疗效试验。我们预计每年将有3种药物在至少一种异种移植模型中进行疗效试验。这样的试验可能需要进一步的收集、培养或合成努力才能获得足够的材料，估计为50-200毫克。我们希望每年能找到一种在异种移植模型中有效的化合物，这种铅结构将通过合成简单的类似物和对天然产物进行合成修饰来进行化学探索。在这一应用之外，治疗活性药物将在临床前和临床开发中进一步寻求。公共卫生相关性：抗癌药物先导药物将被发现，它们的结构将在组织培养和动物模型中确定和发展到一个阶段，在这个阶段，它们应该对生物技术或制药公司具有吸引力，以继续向临床发展。鉴于主要实体肿瘤，特别是转移性疾病缺乏有效的抗癌药物，我们的Leads可以对癌症患者产生重大的积极影响。