CARBAMOYLATING ACTIVITY FROM ANTINEOPLASTIC SULFONYLHYDRAZINES

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 本项目主要研究拉莫司汀的作用机制，拉莫司汀是一种磺酰肼类抗癌前药，目前正处于治疗急性髓系白血病和多形性胶质瘤的临床试验中。拉莫司汀的活性是碱催化原位活化产生的两个反应性亲电体的函数：2-氯乙基化物种和甲基异氰酸酯。2-氯乙基化物种最终形成细胞毒性的链间DNA交联物，甲基异氰酸酯的氨甲酰化活性与2-氯乙基化活性协同作用，对肿瘤细胞产生显著的细胞毒性。这些原位化学过程类似于其他抗癌化合物，包括亚硝脲。这个项目将涉及几种酶作为靶标的研究，这些酶很可能被甲基异氰酸酯的氨甲酰基修饰，以解释协同细胞毒性。此外，还将阐明暴露于所研究的制剂对基因表达、信号通路和细胞死亡机制的影响。拟议的研究将极大地加强对这些化合物的化学反应与其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。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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 will involve 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 proposed 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.