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铅中发现和开发具有固体肿瘤活性的新的抗癌药物。考虑到抗人类主要实体肿瘤的抗癌药物的稀缺性，对此的需求是显著的。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种植物粗提物经过了现供职于约瑟芬·福特癌症中心的弗雷德·瓦莱里奥特博士的固体肿瘤选择性评估。这些研究的结果为该项目提供了30个优先的、初步的命中，以便在未来5年内继续从这些植物中分离(通过生物测定指导的分离)和鉴定活性化合物(S)。为了实现这些目标，将根据需要进行大量收集，或者在试验田种植植物，为扩大体外和体内测试提供足够的材料。更多的物质将通过气培/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时(S)。此外，每年将收集200个新工厂，每年优先处理新旧线索。每年将有6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。将更加重视新化合物，而不是具有新的或已知抗癌活性的已知化合物。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、药理和疗效评估。体内药理学有三个基本组成部分：测试新化合物化学分析的分析方法的发展，通过生物药学措施开发合适的静脉注射制剂，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。小鼠将携带双侧肿瘤，在开始给药前已增长到100至300mm3。用于非肠道给药的0.2毫升容量中包含的每种药物的剂量将根据传统剂量需求和根据体外药理学结果调整后的剂量进行估计。在荷瘤小鼠(与小鼠同基因移植或异种移植)中测试化合物剂量至最大耐受量的疗效研究的方法学。

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.