) This is a first competitive renewal of NCDDG grant CA 67786, which was awarded in September 1995. The goal of the project remains unchanged and is to discover and develop novel anticancer agents from a variety of natural products sources. The underlying theme of this program is to integrate discovery of novel biologically-active natural products from organisms that inhabit unique ecological niches with mechanism-directed cancer biology. The composition of the core group remains essentially the same as in the original application although the corporate partner has changed names. Lederle labs of American Cyanimid is now Wyeth-Ayerst Research (W-AR). There has been some turnover in personnel at WAR, and a Medicinal Chemistry group has been added to facilitate drug development studies. Additionally, four new subcontracts have been added to facilitate access to a greater diversity of organisms. Significant progress has been made in the first grant period towards the goal of identifying candidates for drug development and clinical study. In the first three years, extracts of more than 4,900 organisms were screened for activity in assays at W-AR. Investigation of these extracts in secondary assays, including in vivo animal models, resulted in designation of three projects as discover leads. These are the hemiasterlins from the sponge Cymbastela sp., the autocystins from the fungus Aspergillus ustus, and the makaluvamines from the sponge Zyzzya fuliginasa. The hemiasterlins have been designated a development project at W-AR and a team of medicinal chemists has been assigned to the project. The austocystins and makaluvamines are undergoing further in vivo testing before designation as development projects. Detailed discussions of these projects are presented in the progress report sections.
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