ANTITUMOR AGENTS FROM BLUE-GREEN ALGAE

蓝绿藻的抗肿瘤剂

• 批准号: 2330660
• 负责人: RICHARD E MOORE
• 金额: $ 30.12万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-08-01 至 1998-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2330660
• 关键词: Cyanophyta; antineoplastics; biological products; chemical structure; cytotoxicity; drug interactions; drug metabolism; drug screening /evaluation; laboratory mouse; microorganism culture; multidrug resistance; paclitaxel; tissue /cell culture; vinblastine

The longterm goal of this project is to discover new antitumor drugs from blue-green algae (cyanobacteria). The research will be concerned primarily with searching for and finding cytotoxins that are significantly active against slow-growing solid tumors which account for approximately 85% of all cancer deaths in the United States. Not only will it be important to discover new agents that are effective against solid tumors, but ones which are capable of overcoming two major problems that develop in cancer patients undergoing chemotherapy, viz. multiple drug resistance (MDR) and immunosuppression. Two types of anti-MDR drugs are needed: (1) ones that are equally efficacious toward drug-sensitive and drug-resistant tumors and (2) ones that are able to potentiate the cytotoxicity of standard antitumor drugs like vinblastine and adriamycin toward drug-resistant cells, i.e. reverse multiple drug resistance. Using disk diffusion assays to screen a large number of extracts of cultured blue-green algae for selective cytotoxicity, it has been found that 0.8% of the extracts are more cytotoxic toward murine and/or human solid tumor cells than leukemia cells, i.e. solid tumor selective, and an additional 0.8% of the extracts are more cytotoxic toward tumor (leukemia) cells than normal cells such as CFU-GM, the stem cell of murine hematopoietic tissue. The first task of this project is to isolate, identify, and evaluate in vivo the solid tumor selective cytotoxins in the following 11 blue-green algae: Aulosira fertillisima DO-8-1, Calothrix gloeocola DT-21 -1, Hapalosiphon hibernicus DU-56-1, Tolypothrix scytonematoides HZ-48-1, Scytonema hofmanni HZ-50-1, T. byssoidea IA-5-1, Plectonema radiosum IA-82-2 and IC-70-1, P. phormidioides ID-66-1, Scytonema fremyii IA-90-1 and Stigonema sp. II-1. P. radiosum IC-70-1 has the highest priority since the hydrophilic, solid tumor selective extract of this cyanophyte shows a taxol-like mode of action (i.e. inhibition of microtubule depolymerization) equal cytotoxicity towards drug-sensitive and drug-resistant tumors, and greater cytotoxicity towards leukemia cells than normal cells, i.e. tumor selectivity. The next tasks are to isolate, identify, and evaluate tumor selective cytotoxins in 12 additional cyanophytes, non-selective taxol- like cytotoxins in five other blue-green algae, and multiple-drug- resistance-reversing agents in still another 18 cyanophytes. The last task is to isolate, identify, and evaluate the potent cytotoxins in eight more cyanophytes, four of which show vinblastine-like activity (inhibition of tubulin polymerization into microtubules). Concurrently with the tasks described above, new isolates of blue-green algae (about 125/yr) will be obtained from freshwater, terrestrial, and marine environments and grown in culture for antitumor evaluation and isolation and identification of drugs from positive leads.

该项目的长期目标是从癌症中发现新的抗肿瘤药物。 蓝绿藻（蓝藻）。研究将主要关注 寻找和发现那些具有显著活性的细胞毒素， 针对缓慢生长的实体瘤，其占约85%的 在美国所有的癌症死亡。不仅重要的是 发现有效对抗实体瘤的新药物， 它能够克服癌症中的两个主要问题 接受化疗的患者，即多药耐药（MDR）， 免疫抑制需要两种类型的抗MDR药物：（1） 对药物敏感和耐药肿瘤同样有效 和（2）能够增强标准品细胞毒性的化合物 长春碱和阿霉素等抗肿瘤药物 细胞，即逆转多药耐药性。 使用纸片扩散试验 筛选大量培养蓝藻的提取物， 选择性细胞毒性，已发现0.8%的浸提液 对鼠和/或人实体瘤细胞的细胞毒性大于白血病 细胞，即实体瘤选择性，以及另外0.8%的提取物 对肿瘤（白血病）细胞的细胞毒性大于正常细胞， CFU-GM是小鼠造血组织的干细胞。的首要任务 本项目旨在分离、鉴定和评价体内实体瘤， 以下11种蓝绿藻中的选择性细胞毒素： fertillisima DO-8-1、Calothrix gloeocola DT-21 - 1、Hapalosiphon hibernicus DU-56-1、拟蓝线单歧藻HZ-48-1、霍夫曼蓝线藻HZ-50-1、 T. byssoidea IA-5-1、辐射刺丝藻Plectonema radiosum IA-82-2和IC-70-1; phormidioides ID-66-1，Scytonema fremyii IA-90-1和Stigonema sp. II-1。 P. radiosum IC-70-1具有最高优先级，因为其亲水性、固体 这种蓝藻的肿瘤选择性提取物显示出紫杉醇样模式， 作用（即抑制微管解聚）等同 对药物敏感和耐药肿瘤的细胞毒性， 对白血病细胞的细胞毒性高于正常细胞，即肿瘤 选择性 接下来的任务是分离、识别和评估肿瘤 另外12种蓝藻中的选择性细胞毒素，非选择性紫杉醇， 比如其他五种蓝绿藻中的细胞毒素， 在另外18种蓝藻中发现了抗性逆转剂。 最后一 任务是分离，鉴定和评估八种有效的细胞毒素 更多的蓝藻，其中四个显示长春碱样活性（抑制 微管蛋白聚合成微管）。 与任务同时进行 如上所述，新的蓝绿藻分离物（约125/年）将被 从淡水、陆地和海洋环境中获得， 在培养物中用于抗肿瘤评价以及分离和鉴定 毒品的线索