DISCOVERY OF NEW ANTICANCER AGENTS FROM NATURAL PRODUCTS

NCNPDDG的目标是发现和发展新的 具有固体肿瘤活性的抗癌药，其来源为 天然产品。考虑到这一点的匮乏，对此的需求是巨大的 对人体主要实体肿瘤有效的抗癌药物。 大约5,000种提取物、馏分和纯化合物将被 每年检查一次。这些萃取物将从两个海洋 有机体和植物。发现的努力将针对 人类常见的耐药上皮性肿瘤：结肠、乳腺、肺和 胰腺：发育努力基于二次评估和 行动机制研究。测试的第一阶段是在 体外纸片扩散法评价黄曲霉毒素的差异活性 小鼠L1210白血病与耐药固体的试验化合物 肿瘤(小鼠结肠38和乳腺17/ADR)与人耐药细胞 品系(结肠H-116、乳腺MX-1和肺H-125)。实体瘤 选择性提取物将被分级，活性物种 已确认身份。纯化后的化合物将在体内进行活性测试。 在初级体外试验中同样有效的提取物将是 在继发性肿瘤/正常细胞体外试验中进行检查以确定肿瘤- 精挑细选的绅士。候选人将被分级，提纯和 进行鉴定，然后在体内进行检测。广泛的体内继发性 将对纯化的化合物进行评估，包括：a) 针对其他人类肿瘤的活动广度，b)各种不同的活动 管理路线，c)最佳计划，d)主机恢复时间 以及急性和慢性毒性。活体内活跃的药物将 继续进行作用机制研究和宿主与细胞 药代动力学。根据这些结果，将做出决定 对特定化合物进行类比搜索和合成。

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.