Discovery of Anticancer Drugs from Cyanophytes

项目描述（由申请人提供）：本项目的总体目标是从收集和培养的海洋蓝藻和海洋微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。鉴于对人体主要实体瘤有效的抗癌药物缺乏，对新型有效抗癌药物的需求至关重要。在这项资助的过程中，450个分类上不同的样本被提议作为新的天然产物的来源。将对其中一组样品采用微激发培养方法，以彻底查询其次级代谢组。从每种生物中提取9个馏分和粗提取物用于抗癌筛选（每年超过900个测试样本）。我们采用了一种独特的、新颖的圆盘扩散试验来确定初始提取物对实体瘤的选择性，并指导推定的抗癌剂的分离。该试验已扩展到在体外和体内检查7种主要实体肿瘤类型。我们预计每年能在功能和结构上识别出大约6种实体肿瘤选择性化合物。虽然许多引线将是新的结构，但一些引线可能是已知化合物或已知化合物的类似物；然而，这些化合物中很少有在体内或体外进行抗癌活性评估。我们希望将所有先导化合物通过药物开发模式，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-生存克隆性研究；体内最大耐受剂量和药代动力学信息（血浆和肿瘤水平）。该药物用于静脉注射，并开发了一种高效液相色谱测定法来监测血清和组织水平。我们预计每年发现的所有6种体外铅化合物将在这个药理学阶段进行检查。将对这些数据进行分析，以确定是否应该在荷瘤小鼠中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，以获得足够的材料，估计为50 - 200毫克。我们希望每年能发现一种对异种移植物模型有效的化合物，并将通过简单类似物的合成和天然产物的合成改性对这种先导结构进行化学探索。治疗活性药物将进一步在临床前和临床开发之外的应用。公共卫生相关性：抗癌药物先导物将被发现，其结构将被确定，并在组织培养和动物模型中发展到对生物技术或制药公司具有吸引力的阶段，以继续向临床发展。鉴于缺乏针对主要实体瘤的有效抗癌药物，特别是对于转移性疾病，我们的线索可以对癌症患者产生重大的积极影响。

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.