CORE--IN VITRO TESTING OF AGT INHIBTORS

核心——AGT抑制剂的体外测试

• 批准号: 6347330
• 负责人: ANTHONY E PEGG
• 金额: $ 9.81万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2001-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6347330
• 关键词: alkylating agents; alkyltransferase; biomedical facility; carmustine; drug metabolism; drug resistance; enzyme activity; enzyme inhibitors; neoplastic cell; prodrugs; tissue /cell culture

Core B will test compounds for the ability to inactivate AGT and to render tumor cells in culture sensitive to killing by BCNU. The three types of assay that will be carried out are: (a) new potential inhibitors of AGT will be tested for AGT inactivating potential using purified recombinant human AGT. Compounds designed as pro-drugs will also be tested in the presence of activating enzymes/ (b) the ability of the potential AGT inhibitors to inactive the AGT in HT29 colon carcinoma cells in culture will be determined; and (c) The ability of the AGT inhibitors to sensitize lung, colon, breast and prostate tumor cells to killing by BCNU will be measured. The compounds to be assayed include those produced during the first period of support, compounds designed based on data generated in the first period of support and compounds designed based on the studies in Program 1. Useful inhibitors which are identified in this core will be made available to all programs in the proposal either directly or via core C. These studies will indicate whether compounds have inherent ability to inactivate the AGT and whether they are active in cells thus providing preliminary information on uptake and metabolic conversion to more active or less active species. The compounds to be tested will be designed to provide compounds that are more potent or resistant to metabolism than BG, compounds that act as prodrugs generating AGT inhibitors in tumors, compounds likely to inactivate the BG-resistant mutants and compounds that would be suitable for regional therapy by virtue of a high potency and a rapid rate of metabolism.

核心B将测试化合物，以使AGT失活和渲染的能力 培养物中对被BCNU杀死敏感的肿瘤细胞。 这三种类型的 将进行的测定是：（a）AGT的新潜在抑制剂 将使用纯化的重组测试AGT灭活电位 人类Agt。 设计为亲毒品的化合物也将在 激活酶的存在/（b）电势AGT的能力 HT29结肠癌细胞中无活性AGT的抑制剂培养物 将确定； （c）AGT抑制剂敏化的能力 肺，结肠，乳腺癌和前列腺肿瘤细胞被BCNU杀死 测量。 要测定的化合物包括第一阶段产生的化合物 支持，基于第一阶段生成的数据设计的化合物 基于程序1中的研究设计的支持和化合物。 将在此核心中鉴定的有用抑制剂可用 直接或通过核心C中的提案中的所有程序。 这些研究将表明化合物是否具有固有的能力 使AGT失活以及它们是否活跃在细胞中 有关摄取和代谢转换为更活跃的初步信息 或不太活跃的物种。 要测试的化合物将设计为 提供比BG更有效或对代谢具有更有效或具有抗性的化合物 充当前药产生AGT抑制剂的化合物， 可能使BG耐药突变体和化合物失活的化合物 由于高效力和A 代谢的快速率。