Discovery of Anticancer Drugs from Cyanobacteria

描述(申请人提供)：这个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固体肿瘤选择性的新的抗癌药物。考虑到抗人类主要实体肿瘤的药物很少，对新的抗癌药物的需求是巨大的。我们筛查策略的一个基本假设是，它将产生对目前尚未有效治疗的主要实体肿瘤(如肺和结肠)有效的药物。海洋蓝藻是一种丰富的自由生活和共生的热带生物，具有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至1500种提取物，重点放在那些自然生物量较低或与海洋无脊椎动物共生的藻类，如海绵和被毛动物，并鉴定“超高产”海洋蓝藻菌株。此外，亦会从形成丛生的海洋蓝藻和形成浮游/细泥的海洋蓝藻，以及在自然环境下从无脊椎动物宿主分离出来的培养蓝藻中提取提取物。我们将使用一种独特的体外纸片扩散法来鉴定提取物中的实体肿瘤选择性，并指导可能的抗癌药物的分离。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MS和其他光谱信息相结合来确定。如果有必要，我们将扩大培养规模或重新收集有选择的物种，以提供足够的药物来推进临床前研究。第一步需要大约20毫克的药物，并结合来自固体肿瘤体外浓度-存活克隆形成研究的信息和药代动力学信息(血清和肿瘤药物水平)。该药物首次用于静脉给药，并开发了一种高效液相色谱法来监测血清和组织水平。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，则将在至少一个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研究。

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.