DISCOVERY OF NEW ANTICANCER AGENTS FROM NATURAL PRODUCTS

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The goal of the 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 5,000 extracts, fractions and pure compounds will be examined per year. These extracts will be obtained from both marine organisms and plants. The discovery effort will be directed against the common human drug resistant epithelial tumors: Colon, breast, 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 Mammary 17/Adr) and human drug resistant cell lines (Colon H-116, Breast MX-1 and Lung H-125). The solid tumor selective extracts will be fractionated and the active species identified. 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 gents. Candidates will be fractionated, purified and identified, and then examined in vivo. Extensive in vivo secondary evaluation will be carried out on purified compounds including: a) breadth of activity against other human 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 and host and cellular pharmokinetics. Depending upon these results, a decision will be made to pursue analog search and synthesis for specific compounds.