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。 来自蓝绿藻(蓝藻)。这项研究将会受到关注 主要是搜索和寻找细胞毒素 对生长缓慢的实体肿瘤有显著的积极作用，这是 美国大多数癌症死亡病例。它不仅会成为 重要的是发现对固体有效的新制剂 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生，即。多种药物-- 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)能够增强 长春花碱、阿霉素等标准抗癌药物的细胞毒性 转向耐药细胞，即逆转多药耐药。使用圆盘扩散 大量培养蓝藻提取液的筛选方法 在选择性细胞毒性方面，已发现0.8%的 提取物对实体瘤具有选择性，即对小鼠有更强的细胞毒性 和/或人类实体瘤细胞，白血病细胞，以及 另外0.8%的提取物对肿瘤具有选择性，即更多 对肿瘤(如白血病)细胞的杀伤作用优于正常细胞 CFU-GM，小鼠造血组织的干细胞。几个固体 肿瘤选择性和肿瘤选择性细胞毒素已经被 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。这一项目的第一项任务是 几种天然和半合成类似物的体内评价 单胞藻中的坦他唑、咪巴唑、镰刀菌素和咪草亚胺E Mirabilary by-8-1和假霍曼氏假单胞菌BC-1-2和奥洛西拉唑 Aulosira fertillissima Do-8-1.下一个任务是隔离， 该固体的结构测定和药理评价 角叉尾轮藻DT-21-1的肿瘤选择性细胞毒素 Hibernicus DU-56-1、Tolypothrix Sytonematoides HZ-48-1、Scytonema Hofmanni HZ-50-1、白纹伊蚊IA-5-1、辐射扁藻IA-82-2、 Scytonema fremyii IA-90-1和Stigonema sp.II-1与肿瘤 林巴氏振荡杆菌atcc 27935的选择性细胞毒素 Lagerheimii atcc 29125，Ctenocladus Cincinnatus BN-11-1，发菜。 BR-8-2，Phormidium tenue CB-1-1，Calothrix viguieri CCAP 1410/6， 汉斯吉林扁藻CN-2-2、放射状扁藻DT-65-1、铁锈菌Phormidium Rubroterricola DV-8-1，Phormidium bohneri IC-58-1，Nostoc sp.IE-87-1 和IE-87-3，公证紫虹吸菌UTEX 1816。接下来的任务是 黄连的分离、鉴定及药理评价 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，还有一种耐多药逆转剂 17个蓝绿色的。最后一项任务是隔离、识别和 费氏拟青霉DU-18-1和Aulosira fertillisima DU-18-1高效细胞毒素的鉴定 五种蓝藻中有效的杀菌细胞毒素。

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.