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.

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