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.
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