ANTICANCER LEADS FROM MARINE MACROORGANISMS AND THEIR ASSOCIATED MICROORGANISMS

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While effective therapeutic agents for the treatment of leukemias and lymphomas are available, little progress has been made in the development of new drugs that are useful for the treatment of clinically important tumors, such as breast, colon, lung, ovarian, and prostate. The lack of success in this area can be traced to the absence of effective assay models or screening technologies for the discovery of such agents. However, recent advances in our knowledge of cancer biology have catalyzed the development of innovative new methods.for the detection of compounds that affect biochemical targets such as oncogene products, tumor suppressor gene products, proteins involved in various signal transduction pathways, and proteins involved in apoptosis. We believe that compounds which have a mechanism of action involving one of these areas will be active against the important solid tumors listed above. To fully exploit the arsenal of new screens provided by Sandoz Pharmaceuticals, we will endeavor to provide compounds and extracts resulting from the widest possible diversity of biosynthetic pathways. Therefore, we will not only investigate marine sponges and ascidians, which are well proven sources of an array of unique secondary metabolites, we will also access the microbial fauna (i.e., bacteria and actinomycetes) present on the surfaces or within the tissues of these invertebrates. In this way we will maximize our resources and utilize the research specimens to their fullest potential. The overall goal of this segment of the NCNPDDG proposal is the discovery of new compounds produce by marine invertebrates, particularly sponges and ascidians, or their-associated microorganisms that will serve as new anticancer chemotherapeutic leads. To succeed in satisfying this goal, we propose to do the following: (a) obtain marine sponges and ascidians to serve both as a pool of biologically active compounds as well as a unique nutrient-rich source of microorganisms; (b) culture marine bacteria and actinomycetes from the surfaces and interior spaces of the collected invertebrates; (c) employ mechanism-based assays to uncover extracts containing new chemical agents which act on important biochemical targets; (d) optimize fermentation conditions for those marine isolates which produce active metabolites; (e) efficiently isolate active metabolites, guided by rapid primary biochemical assays; (f) elucidate the chemical structures of active compounds using spectrochemical methods; (g) initiate recollection or scale-up fermentation and re-isolation of those compounds selected for further pharmacological study or preclinical investigation; (h) prepare semi- synthetic analogs of active compounds for investigation of structure- activity relationships; and (i) obtain patent coverage for promising antitumor natural products and their derivatives.