Discovery/Development of Anticancer Agents from Plants

描述（申请人提供）：该项目的目标是从植物中获得的先导化合物中发现和开发具有实体瘤活性的新型抗癌药物。在过去的5年里，来自亚利桑那大学约瑟夫·霍夫曼博士实验室的近4000种植物粗提取物已经被现在约瑟芬福特癌症中心的弗雷德·瓦莱里奥特博士评估了实体瘤的选择性。这些研究的结果为该项目提供了30个优先的主要命中点，以继续进行隔离（通过生物测定定向分级分离）和在未来5年内从这些植物中鉴定活性化合物。为了实现目标，将根据需要进行大量收集，或者将植物生长在实验田间地块中，以提供足够的材料用于体外和in vivo. 额外的材料将通过气培/水培系统产生，特别是当根材料是活性化合物的主要来源时。 此外，每年将收集200株新植物，每年优先考虑新的和旧的线索。 每年将有六个优先工厂完成，以产生至少6种活性化合物用于体外和体内测试。 与具有新的或已知的抗癌活性的已知化合物相比，将更加重视新化合物。 抗癌药物开发部分将在约瑟芬福特癌症中心进行。 纯化合物进入配方，药理学和治疗评估。体内药理学有三个基本组成部分：新化合物化学分析的分析方法的测试开发，通过生物制药措施开发合适的IV制剂，以及药物清除和分布的初步药理学测试。 将在体外确定剂量和目标药物浓度。 小鼠将带有在开始给药前已生长至100至300 mm 3的双侧肿瘤。 将根据传统剂量需求和根据体外药理学结果调整的剂量估计胃肠外给药的0.2 ml体积中所含的每种药物的剂量。 用于在荷瘤小鼠（与鼠肿瘤同源或与鼠肿瘤异种移植）中测试化合物剂量直至最大耐受剂量的治疗功效研究的方法学。

DESCRIPTION (provided by applicant): 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 mm3 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.