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 蓝绿色藻类（蓝细菌）。这项研究将主要关注 搜索并找到明显活跃的细胞毒素 反对增长的实体瘤，约占约85％ 美国所有癌症死亡。不仅重要 发现对实体瘤有效的新药物，但是 能够克服癌症中出现的两个主要问题 接受化疗的患者，即。多种耐药性（MDR）和 免疫抑制。需要两种类型的抗MDR药物：（1） 对药物敏感和耐药性肿瘤同样有效 （2）能够增强标准细胞毒性的人 抗肿瘤药物，例如vinblastine和adrimycin to抗药性药物 细胞，即反向多种耐药性。 使用磁盘扩散测定 要筛选大量培养的蓝绿色藻类提取物 选择性细胞毒性，已经发现0.8％的提取物为 与白血病相比，对鼠和/或人类实体瘤细胞的细胞毒性更多 细胞，即实体瘤的选择性，另外0.8％的提取物 比正常细胞（例如 CFU-GM，鼠造血组织的干细胞。第一个任务 该项目是在体内隔离，识别和评估实体瘤 在以下11个蓝绿色藻类中，选择性细胞毒素：aulosira 肥料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和IC-70-1，P。 Phormidioides ID-66-1，Scytonema Fremyii IA-90-1和Stigonema sp。 II-1。 P. adiosum IC-70-1自亲水，固体以来的优先级最高 该氰植物的肿瘤选择性提取物显示出类似紫杉醇的模式 作用（即抑制微管解聚）相等 对药物敏感和耐药性肿瘤的细胞毒性，更大 对白血病细胞的细胞毒性比正常细胞，即肿瘤 选择性。 下一个任务是隔离，识别和评估肿瘤 选择性细胞毒素在12种其他蓝植物中，非选择性紫杉醇 - 像其他五种蓝绿色藻类中的细胞毒素一样，多药 在另外18种氰基植物中抗性逆转剂。 最后 任务是在八个中隔离，识别和评估有效的细胞毒素 更多的蓝植物，其中四个显示长葡萄蛋白样活性（抑制作用 小管蛋白聚合成微管）。 与任务同时 上面描述的是，蓝绿色藻类的新分离株（约125/年）将是 从淡水，陆地和海洋环境中获得 培养抗肿瘤评估，隔离和鉴定 阳性铅的药物。