ANTITUMOR AGENTS FROM BLUE-GREEN ALGAE

这项研究的长期目标是发现新的抗肿瘤药物 蓝绿藻（蓝藻）。 研究将关注 主要是寻找细胞毒素， 对缓慢生长的实体瘤具有显著活性， 美国大部分的癌症死亡。不仅会 重要是发现有效对抗固体的新药剂 肿瘤，但它能够克服两个主要问题， 在接受化疗的癌症患者中发展，即多药- 耐药（MDR）和骨髓抑制。 两种类型的抗MDR药物是 需要：（1）对药物敏感和 耐药肿瘤和（2）那些能够增强 长春碱和阿霉素等标准抗肿瘤药物的细胞毒性 针对耐药细胞，即逆转MDR。 使用磁盘扩散 筛选大量培养蓝藻提取物的试验 对于选择性细胞毒性，已经发现0.8%的 提取物是实体瘤选择性的，即对小鼠更具细胞毒性 和/或人实体瘤细胞，即白血病细胞，并且 另外0.8%的提取物是肿瘤选择性的，即， 对肿瘤（例如白血病）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。 几种实体 肿瘤选择性和肿瘤选择性细胞毒素已经 从这些提取物中分离和鉴定，但相对较少 已经在体内进行了评估。 该项目的第一个任务是在 几种天然的和半合成的类似物的体内评价 来自Scytonema的tantazoles、mirabazoles、scytophycins和mirabimide E mirabile BY-8-1和S. pseudohormanni BC-1-2和来自 肥沃管链藻DO-8-1。 下一个任务是隔离， 固体的结构测定和药理学评价 胶枝眉藻DT-21-1、八棱管藻的肿瘤选择性细胞毒素 越冬单歧藻DU-56-1、蓝线单歧藻HZ-48-1、蓝线藻 hofmanni HZ-50-1、T.丝藻IA-5-1，辐射丝藻IA-82-2， Scytonema fremyii IA-90-1和Stigonema sp. II-1与肿瘤 Foreaui颤藻ATCC 27935，鞘丝藻中的选择性细胞毒素 lagerheimii ATCC 29125、Ctenocladus cincinnatus BN-11-1、念珠藻属（Nostoc sp.） BR-8-2，纤细席藻CB-1-1，维氏眉藻CCAP 1410/6， 汉氏丛丝藻CN-2-2、放射丛丝藻DT-65-1、席藻 红地藻DV-8-1、博氏席藻IC-58-1、念珠藻IE-87-1 和IE-87-3，以及斑节藻UTEX 1816。 接下来的任务是 分离、鉴定和药理学评价 五种蓝藻中的紫杉醇类细胞毒素，非选择性细胞毒素 在另外九种蓝藻中，还有一种MDR逆转剂， 17蓝绿 最后一项任务是分离、识别和 评价Aulosira fertilisima DU-18-1和 在五种蓝藻中发现的强效杀真菌细胞毒素

The long term goal of this research 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 most of the cancer deaths in the United States. Not only will it be important to discover new agents that are effective against solid tumors, but one which are capable of overcoming two major problems that develop in cancer patients undergoing chemotherapy, viz. multiple-drug- resistance (MDR) and myelosuppression. 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 MDR. 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 percent of the extracts are solid tumor selective, i.e. more cytotoxic toward murine and/or human solid tumor cells that leukemia cells, and that an additional 0.8 percent of the extracts are tumor selective, i.e. more cytotoxic toward tumor (e.g. leukemia) cells than normal cells such as CFU-GM, the stem cell of murine hematopoietic tissue. Several solid tumor selective and tumor selective cytotoxins have already been isolated and identified from these extracts, but relatively few of them have been evaluated in vivo. The first task of this project in the in vivo evaluation of several natural and semi-synthetic analogs of tantazoles, mirabazoles, scytophycins and mirabimide E from Scytonema mirabile BY-8-1 and S. pseudohormanni BC-1-2 and aulosirazole from Aulosira fertillissima DO-8-1. The next task is the isolation, structure determination, and pharmacological evaluation of the solid tumor selective cytotoxins in 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, Scytonema fremyii IA-90-1, and Stigonema sp. II-1 and the tumor selective cytotoxins in Oscillatoria foreaui ATCC 27935, Lyngbya lagerheimii ATCC 29125, Ctenocladus cincinnatus BN-11-1, Nostoc sp. BR-8-2, Phormidium tenue CB-1-1, Calothrix viguieri CCAP 1410/6, Plectonema hansgirgi CN-2-2, Plectonema radiosum DT-65-1, Phormidium rubroterricola DV-8-1, Phormidium bohneri IC-58-1, Nostoc sp. IE-87-1 and IE-87-3, and Porphyrosiphon notarisii UTEX 1816. The next tasks are the isolation, identification and pharmacological evaluation of the taxol-like cytotoxins in five cyanophytes, the non-selective cytotoxins in nine more cyanophytes, and the MDR-reversing agents in still another 17 blue-greens. The last tasks are the isolation, identification and evaluation of the potent cytotoxin in Aulosira fertillisima DU-18-1 and the potent fungicidal cytotoxins in five cyanophytes.