DISCOVERY OF NEW ANTICANCER AGENTS FROM NATURAL PRODUCTS

NCNPDDG的目标是发现和开发新的 具有实体瘤活性的抗癌剂， 天然产品。 考虑到缺乏这方面的资源， 对人的主要实体瘤有活性的抗癌剂。 大约5,000种提取物、馏分和纯化合物将被 每年检查。 这些提取物将从两种海洋生物中获得 生物和植物。 探索工作将针对 常见的人类耐药上皮肿瘤：结肠、乳腺、肺和 胰腺：发展努力是基于二次评估， 作用机制研究。 测试的第一阶段是在 体外纸片扩散试验，其评估 小鼠L1210白血病与耐药实体之间的测试化合物 肿瘤（鼠结肠38和乳腺17/Adr）和人耐药细胞 行（结肠H-116、乳腺MX-1和肺H-125）。 述实体瘤 选择性提取物将被分馏， 鉴定 将在体内测试纯化的化合物的活性。 在初步体外试验中具有同等活性的浸提液将 在继发性肿瘤/正常细胞体外测定中检查以定义肿瘤- 选择性氧化 候选人将被分馏，纯化， 鉴定，然后在体内检测。 广泛的体内继发性 将对纯化的化合物进行评价，包括：a） 抗其它人肿瘤的活性宽度，B）各种肿瘤的活性， 给药途径，c）最佳时间表，和d）宿主恢复时间 以及急性和慢性毒性。 体内活性剂将 继续进行作用机制研究， 药物动力学 将根据这些结果作出决定 来进行特定化合物的类似物搜索和合成。

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.