The long term goal of this research is to discover natural products that will be useful in cancer chemotherapy but which will operate by mechanisms different from those of the currently used drugs. To achieve this goal we propose to screen extracts of marine invertebrates, bacteria and fungi against a group of biochemical and cellular assays to detect potential drugs and use these assays to direct isolation of pure active compounds. Some assays have been designed to detect antagonists of signal transduction, transcription factor and tumor repressor proteins that are oncogene products of defined tumor cell line. Another assay system will check for compounds which can transform tumor cells back to a non- malignant phenotype. Antagonists to the proteins Bcl-2 and Bcl-x which modulate apoptosis will also be sought Active compounds will be tested in cellular assays to confirm efficacy in inhibiting cell growth and then in animal models. Pure compounds will be isolated using modern chromatographic methods and Structures determined using an array of spectroscopic techniques. The pool of natural products to be used for this drug discovery effort will be comprised of extracts of cultured obligate and facultative halophilic or halotolerant anaerobic bacteria, marine fungi, and some marine invertebrates, primarily sponges and ascidians. Microorganisms will be isolated from marine sediments, terrestrial saline sediments such as salt plains, and marine invertebrate tissues. This project is directly related to the NCNPDDG objectives of discovering effective chemotherapies having new mechanisms of action from natural source& The unique contribution of this project will be the input of natural products from an underexplored resource, marine fungi and facultative and obligate marine bacteria. Our pharmaceutical partner, Sandoz, will provide novel primary and secondary bioassays to detect compounds which will affect selected elements in the positive and negative control machinery involved in cell proliferation. The biochemical targets are different from those on which the currently available drugs act.
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