The very vigorous and sharply focused objective of the continuation research will be the accelerated discovery and preclinical development of new and structurally unique anticancer drug candidates for the U.S. National Cancer institute. Emphasis will continue to be devoted to small molecule anticancer constituents isolated from terrestrial arthropods, marine organisms, microorganisms and plants followed by structural determinations, syntheses and/or structural modifications. Special emphasis will be placed on new antineoplastic substances either isolated based on molecular target bioassays or subsequently displaying such potent antiangiogenesis, cancer vascular targeting, tubulin and/or various cancer-implicated kinase (cyclin-dependent, protein kinase C, tyrosine kinase and telomerase) properties as well as exceptionally strong antineoplastic activity. Additional emphasis will be placed on further research necessary to advancing the expanding clinical trials of the auristatins, bryostatin 1, the dolastatins, and others we discovered such as the powerful cancer antiangiogenesis and vascular targeting drugs in the combretastin (CA4P, CA1P) and other series. Only those leads from confirmed active extracts of arthropods, marine invertebrates, marine and terrestrial plants, and marine as well as terrestrial microorganisms that give maximum promise of yielding new drugs with potential clinical activity will be pursued. The proposed continuation research will provide great assistance to the DCTD/NCI in selecting new anticancer drugs candidates and speeding their development toward clinical trials. In summary, the proposed research will be sharply aimed at the discovery and very rapid development of new anticancer drugs for the NCI programs direct at improving human cancer treatments.
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