ANTITUMOR AGENTS FROM BLUE-GREEN ALGAE

该项目的长期目标是发现新的抗肿瘤药物 蓝藻(蓝藻)。这项研究将主要关注 通过搜索和寻找具有显著活性的细胞毒素 抗生长缓慢的实体瘤，约占85% 美国所有死于癌症的人。不仅重要的是 发现对实体瘤有效的新药物，但 它们能够克服在癌症中发展起来的两个主要问题 接受化疗的患者，即。多重耐药(MDR)和 免疫抑制。需要两种类型的抗MDR药物：(1) 对药物敏感和耐药肿瘤同样有效 以及(2)能够增强标准品的细胞毒性的化合物 长春花碱、阿霉素等抗肿瘤药物耐药 细胞，即逆转多重耐药。使用纸片扩散法 对大量养殖蓝藻提取物进行筛选 选择性细胞毒性研究发现，0.8%的提取物是 对小鼠和/或人实体瘤细胞的细胞毒作用强于白血病 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)细胞的杀伤作用比正常细胞更强，如 CFU-GM，小鼠造血组织的干细胞。的第一项任务 本项目旨在分离、鉴定和评价体内实体瘤。 以下11种蓝藻的选择性细胞毒素：Aulosira Fertillisima DO-8-1，Calothrix loeocola DT-21-1，Hapalosiphon hiberNicus DU-56-1、Slypothrix Sytonematoides HZ-48-1、Scytonema hofmanni HZ-50-1、 B.byssoidae IA-5-1，辐射扁藻IA-82-2和IC-70-1，P. PhormidioidesID-66-1、Scytonema fremyii IA-90-1和Stigonema sp.II-1。 P.Radiosum IC-70-1具有最高的优先级，因为它具有亲水性、固体 这种蓝藻的肿瘤选择性提取物显示出紫杉醇样的模式 作用(即抑制微管解聚)相等 对药物敏感和耐药肿瘤的细胞毒性更大 对白血病细胞的细胞毒作用高于正常细胞，即肿瘤 选择性。下一步的任务是分离、鉴定和评估肿瘤 其他12种蓝藻中的选择性细胞毒素，非选择性紫杉醇- 就像其他五种蓝藻中的细胞毒素一样，以及多种药物- 在另外18种蓝藻中加入了抗逆剂。最后 任务是分离、鉴定和评估8种有效的细胞毒素 更多的蓝藻，其中四种表现出长春花碱样的活性(抑制 微管蛋白聚合成微管)。与任务同时进行 如上所述，新的蓝藻分离株(约125株/年)将 从淡水、陆地和海洋环境中获取并种植 在用于抗肿瘤评价和分离鉴定的培养中 有积极线索的毒品。

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.