Chemical and Biological Mechanisms of Leinamycin

莱纳霉素的化学和生物学机制

• 批准号: 7663837
• 负责人: Kent S Gates
• 金额: $ 25.87万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-12 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7663837
• 关键词: Accounting; Alkylating Agents; Antineoplastic Agents; Biochemical; Biological; Biological Factors; Cancer cell line; Cells; Chemicals; Communities; DNA; DNA Damage; Depurination; Development; Drug usage; Generations; Glutathione; Guanine; Hela Cells; Human; Inhibitory Concentration 50; Lead; Malignant Neoplasms; Medicine; Oxidative Stress; Pharmacologic Substance; Positioning Attribute; Production; Property; Reaction; Reactive Oxygen Species; Route; Site; Source; Stress; Sulfhydryl Compounds; Testing; Thinking; Translating; Work; adduct; anticancer activity; base; cancer cell; cell killing; crosslink; design; leinamycin; novel; persulfides; research study; response; statistics

DESCRIPTION (provided by applicant): Historically, natural products have proven a rich source of anticancer drugs. A recent review estimated that 74% of the clinically used drugs in this field of medicine are natural products or are derived from natural product lead compounds. This statistic suggests that it is important for the cancer community to continue studies of novel anticancer agents isolated from natural sources. The work described in this proposal is designed to characterize the chemical and biological mechanisms of the antineoplastic, DNA- damaging natural product leinamycin. Leinamycin displays very potent activity against human cancer cell lines (e.g. IC50 of 0.014 ng/mL - this translates to an IC50 of 27 nM - against HeLa cells) and is currently in development as a potential anticancer agent at Kyowa Hakko Kogyo Pharmaceuticals. Exposure of duplex DNA to leinamycin leads to production of a rapid "burst" of apurinic sites (AP sites). In addition, reaction with leinamycin converts the attacking thiol residue into a persulfide (RSSH) species that has the potential to cause oxidative stress in cells. Leinamycin does not generate DNA-crosslinks or double-strand breaks, but displays biological activity comparable to clinically used agents that do. Thus, the unusual DNA-damaging properties of leinamycin may represent a new biochemical route to potent anticancer activity. Experiments described in this proposal are designed to relate leinamycin's unique biochemical properties to its potent activity against cancer cell lines. We will test the hypothesis that leinamycin's ability to simultaneously generate a burst of AP sites along with oxidative stress account for its very potent biological activity. The work is divided into the following five Specific Aims: 1. Test the Hypothesis That the Rapid Generation of AP Sites Is Central to Leinamycin's Cancer Cell Killing Properties. 2. Explore the Chemical Basis for the Exceedingly Rapid Depurination of the Leinamycin-Guanine Adduct in Duplex DNA. 3. Test the Hypothesis That Leinamycin Causes Oxidative Stress In Human Cancer Cell Lines. 4. Explore the Chemical Mechanisms by Which Leinamycin Generates Reactive Oxygen Species Under Physiologically Relevant Conditions. 5. Characterize Cellular Responses to Leinamycin.

描述（由申请人提供）：历史上，天然产物已被证明是抗癌药物的丰富来源。最近的一项综述估计，该医学领域中临床上使用的药物中有74%是天然产物或由天然产物先导化合物衍生而来。这一统计数据表明，癌症界继续研究从天然来源中分离出来的新型抗癌药物是很重要的。本提案所描述的工作旨在描述抗肿瘤、破坏DNA的天然产物leinamycin的化学和生物学机制。Leinamycin对人类癌细胞系显示出非常有效的活性（例如，对HeLa细胞的IC50为0.014 ng/mL -这意味着IC50为27 nM），目前Kyowa Hakko Kogyo Pharmaceuticals正在开发一种潜在的抗癌剂。双链DNA暴露于leinamycin导致无嘌呤位点（AP位点）的快速“爆发”。此外，与leinamycin的反应可将攻击硫醇残基转化为过硫化物（RSSH），该物质有可能引起细胞氧化应激。莱那霉素不产生dna交联或双链断裂，但显示出与临床使用的药物相当的生物活性。因此，leinamycin不寻常的dna损伤特性可能代表了一种新的生化途径，具有强大的抗癌活性。本提案中描述的实验旨在将leinamycin独特的生化特性与其对癌细胞系的有效活性联系起来。我们将验证leinamycin同时产生AP位点爆发和氧化应激的能力，这是其非常有效的生物活性的原因。