DISCOVERY OF NEW ANTICANCER AGENTS FROM NATURAL PRODUCTS

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The goal of this NCNPDDG is the DISCOVERY and DEVELOPMENT of new anticancer agents with solid tumor activity from leads obtained from natural products. The need for this is significant given the paucity of anticancer agents active against the major solid tumors of man. Approximately 3,000 extracts, fractions and pure compounds will be examined per year. These will be primarily extracts obtained from cultured eucaryotic microalgae and field-collected marine organisms supplied by Dr. Richard Moore at the University of Hawaii and his collaborators. The discovery effort will be directed against the common human drug resistant epithelial tumors: colon, lung and pancreas; the developmental effort is based on secondary evaluation and mechanism of action studies. The first phase of the testing is an in vitro disk diffusion assay which assesses the differential activity of the test compound between murine L1210 leukemia and drug resistant solid tumors (murine colon 38 and pancreatic 02) and human drug resistant cell lines (colon CX-1 and lung H-125). These solid tumor selective extracts will be fractionated and the active species identified. Both fractions and the purified compound will be tested in vivo for activity. Extracts which are equally active in the primary in vitro assay will be examined in a secondary tumor/normal cell in vitro assay to define tumor-selective agents. Candidates will be fractionated, purified and identified, and examined in vivo. Extensive in vivo secondary evaluation will be carried out on purified compounds and include: a) breadth of activity against other tumors, b) activity by various routes of administration, c) optimal schedule, and d) host recovery time as well as acute and chronic toxicities. Agents active in vivo will proceed to mechanism of action studies including host and cellular pharmokinetics, effects on macromolecular synthesis, DNA binding, DNA damage and repair kinetics, and cellular studies of dose-response and age-response and proliferation- dependent cytotoxicity. Depending upon these results, a decision will be made to pursue analog search and synthesis for specific categories of compounds.