ROLE OF CARBAMOYLATING ACTIVITY FROM ANTINEOPLASTIC SULFONYLHYDRAZINES & NITROSO

抗肿瘤磺酰肼的氨基甲酰化活性的作用

• 批准号: 8167707
• 负责人: KEVIN M RICE
• 金额: $ 13.76万
• 依托单位: MOUNT DESERT ISLAND BIOLOGICAL LAB
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167707
• 关键词: Acute Myelocytic Leukemia; Antineoplastic Agents; Cell Death; Chemicals; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; DNA Interstrand Crosslinking; Enzymes; Exposure to; Funding; Gene Expression; Glioma; Grant; In Situ; Institution; Investigation; Lead; Nitrosourea Compounds; Process; Prodrugs; Research; Research Personnel; Resources; Role; Signal Pathway; Source; United States National Institutes of Health; base; clinical effect; cytotoxic; cytotoxicity; methyl isocyanate; neoplastic cell; pre-clinical

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project focuses on the mechanism of action of Laromustine, a sulfonylhydrazine anticancer prodrug currently in clinical trials for acute myelogenous leukemia and glioma multiforme. The activity of Laromustine is a function of two reactive electrophiles that are generated upon base-catalyzed activation in situ: a 2-chloroethylating species and methylisocyanate. The 2-chloroethylating species ultimately forms cytotoxic, interstrand DNA crosslinks, and the carbamoylating activity of methylisocyanate synergizes with the 2-chloroethylating activity, resulting in significant cytotoxicity to neoplastic cells. These in situ chemical processes are similar to those of other anticancer compounds, including nitrosoureas. This project involves an investigation of several enzymes as targets likely to be modified with a carbamoyl group from methylisocyanate so as to explain the synergistic cytotoxicity. In addition, the effects of exposure to studied agents on gene expression, signaling pathways, and cell death mechanisms will be elucidated. The research will greatly enhance the understanding of the relationship between the chemical reactivity of these compounds and their observed pre-clinical and clinical effects, which potentially could lead to more effective chemotherapeutic strategies.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 该项目重点研究拉莫司汀的作用机制，拉莫司汀是一种磺酰肼抗癌前药，目前正在进行急性髓性白血病和多形性胶质瘤的临床试验。 拉莫司汀的活性是两种反应性亲电子试剂的函数，这两种试剂是在原位碱催化活化时产生的：2-氯乙基化物质和甲基异氰酸酯。 2-氯乙基化物质最终形成细胞毒性的链间DNA交联，并且甲基异氰酸酯的氨基甲酰化活性与2-氯乙基化活性协同作用，从而对肿瘤细胞产生显着的细胞毒性。 这些原位化学过程与其他抗癌化合物（包括亚硝基脲）的化学过程相似。 该项目涉及对几种酶作为可能被甲基异氰酸酯的氨基甲酰基修饰的靶标进行研究，以解释协同细胞毒性。 此外，还将阐明暴露于所研究的药物对基因表达、信号通路和细胞死亡机制的影响。 该研究将极大地增强对这些化合物的化学反应性与其观察到的临床前和临床效果之间关系的理解，这可能会导致更有效的化疗策略。