Plants have a traditionally been one of man's richest sources of biologically active materials and over 25% of all prescriptions dispensed in the U.S. contain a plant-derived active principle. In collaboration with the University of Illinois at Chicago (UIC) and Research Triangle Institute (RTI), Bristol-Myers Squibb (B-MS) plans to identify, isolate and characterize novel anti-cancer agents, derived from both plant secondary metabolites as well as microorganisms associated with plants. Bristol-Myers Squibb Pharmaceutical Research Institute is a part of one of the largest pharmaceutical companies in the world with strong commitment and resources dedicated to natural products screening. With respect to the UIC-RTI-B-MS NCNPDDG project, we plan to carry out the following specific aims. 1. To assay up 2,000 extracts per year for molecular interaction with specific oncogenes, hormonal pathways, angiogenic factors, as well as cytotoxicity assays and traditional targets relevant to cancer therapy. 2. To assist in selecting and prioritizing the most biologically significant leads. 3. To support bioassay-guided fractionation of the active constituents, either by performing the assays at B-MS or by transferring the high- throughput screening technology to UIC (Program 3) and RTI (Program 4). 4. To provide biological in vitro and in vivo development support to the lead compounds and selected plant extracts obtained. 5. To perform fermentation, isolation, and biological studies on micro- organisms (mainly actinomycetes and fungi) associated with certain of the plants collected as part of this project. 6. To conduct additional parameters such as lead optimization using combinatorial chemistry, pharmacokinetics, oral bioavailability, toxicology, and pharmaceutics, as needed. 7. To carry out the large-scale isolation and/or synthesis of candidate active compounds which match the B-MS preclinical lead criteria. B-MS has an outstanding track record in accomplishing this type of aim, having successfully brought to clinical trials several anti-cancer agents in recent years and have successfully solved the supply problem of the plant- derived drug, paclitaxel (Taxol).
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