DISCOVERY OF NEW ANTICANCER AGENTS FROM NATURAL PRODUCTS

本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。 将有大约3，000种提取物、馏分和纯化合物 每年检查。 这些将主要是从以下来源获得的提取物： 培养的真核微藻和野外采集的海洋生物 由夏威夷大学的理查德摩尔博士和他的 合作者 探索工作将针对普通的 人类耐药上皮肿瘤：结肠、肺和胰腺; 发展努力的基础是二次评价和机制， 行动研究 测试的第一阶段是体外圆盘 扩散试验，用于评估试验的差异活性 小鼠L1210白血病与耐药实体瘤之间的化合物 （鼠结肠38和胰腺02）和人耐药细胞系 （结肠CX-1和肺H-125）。 这些实体瘤选择性提取物将 分离并鉴定活性物质。 分数和 将在体内测试纯化的化合物的活性。 的提取物 在初步体外试验中具有同等活性的药物将在 继发性肿瘤/正常细胞体外测定，以确定肿瘤选择性 剂. 将对候选物进行分级、纯化和鉴定， 在体内检查。 将进行广泛的体内二次评价 在纯化的化合物上，包括： 其他肿瘤，B）各种给药途径的活性，c）最佳 时间表，和d）主机恢复时间以及急性和慢性 毒性 在体内有活性的药剂将进入作用机制 研究包括宿主和细胞药代动力学，对 大分子合成，DNA结合，DNA损伤和修复动力学，以及 剂量反应、年龄反应和增殖的细胞研究， 依赖性细胞毒性。 根据这些结果，将作出决定。 进行模拟搜索和合成的特定类别的 化合物.

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.