Studies in Chemical Carcinogenesis

化学致癌研究

• 批准号: 7547246
• 负责人: Paul FERNANDO Thomson
• 金额: $ 2.59万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7547246
• 关键词: 10p; 2' -deoxyadenosine; Address; Adenine; Affect; Aromatic Polycyclic Hydrocarbons; Automobile Exhaust; B-DNA; Benzo(a)pyrene; Biochemical; Biological; Breast Cancer Cell; Burn injury; Carcinogens; Causations; Collaborations; Coupled; Cyclization; DNA; DNA Adducts; DNA Alkylation; DNA Binding; DNA Damage; DNA Modification Process; DNA Repair; DNA Sequence; DNA Structure; DNA biosynthesis; DNA chemical synthesis; Data; Databases; Deoxyadenosines; Deoxyguanosine; Development; Environment; Epoxy Compounds; Event; Excision Repair; Exposure to; Glean; Glycol; Goals; Guanine; High Pressure Liquid Chromatography; Housing; Human; Investigation; Isomerism; Link; MCF7 cell; Malignant Neoplasms; Measurement; Mediating; Metabolic Activation; Metabolism; Metals; Methods; Mismatch Repair; Molecular; Molecular Conformation; Mutation; Nucleosides; Oregon; Palladium; Pathway interactions; Process; Reaction; Research; Research Personnel; Roentgen Rays; Route; Site; Societies; Structure; System; Temperature; Tumorigenicity; Universities; Work; adduct; base; benzo(c)phenanthrene; chemical carcinogenesis; cigarette smoking; deoxyadenosine; enantiomer; exposed human population; interest; metaplastic cell transformation; novel; programs; repaired; research study; tumorigenesis

DESCRIPTION (provided by applicant): Polycyclic aromatic hydrocarbons (PAH) are widely prevalent in the environment and they are products of activities of a modern society. Human exposure to these is unavoidable and many of these compounds are implicated in cancer causation. The work proposed is aimed at studying DNA insult by these compounds and the biological results of the insult. The research is aimed at developing novel synthetic methods for site-specific modification of DNA as well as for the synthesis of novel PAH derivatives for studies in chemical carcinogenesis. For goal one, we anticipate the stereo and regioselective synthesis of a PAH amino triol that will be coupled with fluoro nucleosides to yield the carcinogen-nucleoside conjugates. These will be suitably manipulated and incorporated into specific sites of biologically relevant ras DNA sequences. These modified DNA will be used for physical studies such as thermal denaturation and temperature-dependent CD. Duplexes will involve normal complementary strands as well as mismatch incorporated strands. The data will be analyzed for structural information that can be used in concert with the NMR experiments that will be done in order to ascertain unambiguously the structures of the damaged DNA. Subsequently, the modified DNA will be used for structural assessment by NMR and for biochemical experimentation such as DNA excision repair (these will be done collaboratively). It is also anticipated that a new route to angularly fused PAH metabolites will be developed that hinges on a novel metal-mediated cyclization. Overall, it is anticipated that the studies proposed will help in better understanding the basis and steps involved in cellular transformation by an environmentally present carcinogen leading to cancer causation.

描述（申请人提供）： 多环芳烃（PAH）在环境中广泛存在，是现代社会活动的产物。人类接触这些化合物是不可避免的，其中许多化合物与癌症有关。拟议的工作旨在研究这些化合物对 DNA 的损伤以及损伤的生物学结果。该研究旨在开发新的合成方法，用于 DNA 的位点特异性修饰以及用于化学致癌研究的新型 PAH 衍生物的合成。对于目标一，我们预计 PAH 氨基三醇的立体和区域选择性合成将与氟核苷偶联以产生致癌物-核苷缀合物。这些将被适当地操作并整合到生物学相关的ras DNA序列的特定位点中。这些修饰的 DNA 将用于物理研究，例如热变性和温度依赖性 CD。双链体将涉及正常的互补链以及错配的掺入链。将对数据进行分析以获取结构信息，这些信息可与核磁共振实验配合使用，以便明确确定受损 DNA 的结构。随后，修饰后的 DNA 将用于通过 NMR 进行结构评估以及 DNA 切除修复等生化实验（这些将共同完成）。还预计将开发一种新的角度融合 PAH 代谢物途径，该途径取决于新型金属介导的环化。总体而言，预计所提出的研究将有助于更好地理解环境中存在的致癌物导致癌症发生的细胞转化的基础和步骤。