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.
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