Discovery/Development of Anticancer Agents from Plants

该项目的目标是发现和开发具有固体肿瘤活性的新的抗癌药物。 从植物中获得的铅，考虑到抗癌活性物质的缺乏，对这种物质的需求是巨大的。 针对过去5年来人类的主要实体肿瘤，近4000种植物粗提物，来自 亚利桑那大学约瑟夫·霍夫曼博士的实验室已经对实体瘤进行了评估 现供职于约瑟芬·福特癌症中心的弗雷德·瓦莱里奥特博士发表了这些研究的结果 我为该项目提供了30个优先的主要命中，以继续进行分离(通过生物测定- 定向分馏)和未来5年从这些植物中分离和鉴定活性化合物(S) 为了实现这些目标，将根据需要进行批量收集或种植植物 为体外和体内扩展测试提供足够材料的试验场地块 材料将通过气培/水培系统产生，特别是当根部材料是 活性化合物的主要来源(S)此外，每年将收集200株新植物与新的 而每年优先考虑的旧线索将有六个优先工厂计划每年完工，以产生 至少6种活性化合物的体外和体内测试将更加重视新的 具有新的或已知抗癌活性的化合物抗癌药物 研发组件将在约瑟芬·福特癌症中心进行，纯化合物 进入配方、药理学和疗效评估领域，有三个基本组成部分 以体内药理检测为基础的化学分析方法的新发展 化合物，通过生物制药措施开发合适的IV制剂，以及初步 将对药物清除和分配剂量以及目标药物浓度进行药理学测试 在体外建立的小鼠将携带双侧肿瘤，在开始治疗之前，这些肿瘤已经生长到100到300个Ram3 在0 2毫升容量内注射的每种制剂的剂量估计如下 根据体外药理学调整的传统剂量需求和剂量结果方法学 试验剂量达到最大耐受量的化合物对肿瘤的治疗效果研究 带瘤小鼠(同基因小鼠肿瘤或异种移植)

The goal of this project is the discovery and development of new anticancer agents with solid tumor activity from leads obtained from plants The need for this is significant given the paucity of anticancer agents active against the major solid tumors of man During the past 5 years, nearly 4000 crude plant extracts, from the laboratory of Dr Joseph Hoffmann at the University of Arizona, have been evaluated for solid tumor selectivity by Dr Fred Valeriote, now at the Josephine Ford Cancer Center The results of these studies have provided this project with 30 prioritized, primary hits to continue with isolation (through bioassay- directed fractionation) and identification of the active compound(s) from these plants over the next 5 years In order to accomplish the objectives, bulk collections will be made as needed or plants will be grown in experimental field plots to provide sufficient material for expanded testing both in vitro and in vivo Additional material will be generated through aeroponic/hydroponic systems, especially when root material is the primary source of the active compound(s) Also, 200 new plants will be collected each year with the new and old leads prioritized annually Six priority plants will be targeted for completion each year to generate at least 6 active compounds for both in vitro and in vivo testing Greater emphasis will be placed on novel compounds over known compounds with either new or known anticancer activity The anticancer drug development component will be carried out at the Josephine Ford Cancer Center The pure compound moves into formulation, pharmacology and therapeutic assessment There are three essential components to in vivo pharmacology testing development of analytical methods for chemical analysis of the new compounds, development of a suitable IV formulation through biopharmaceutical measures, and preliminary pharmacology testing for drug clearance and distribution Doses and target drug concentrations will be established in vitro Mice will bear bilateral tumors that have grown to 100 to 300 ram3 prior to initiation of dosing Doses of each agent contained in 0 2 ml volume for parenteral administration will be estimated from traditional dosage demands and dosages adjusted for in vitro pharmacology results The methodology for the study on therapeutic efficacy to test doses of compound, up to the maximum tolerated dose, in tumor- bearing mice (syngeneic with a murine tumor or xenografted wit