MOLECULAR PHARMACOLOGY OF TUMOR AND VIRUS INHIBITORS

肿瘤和病毒抑制剂的分子药理学

• 批准号: 3164699
• 负责人: Arthur Patrick Grollman
• 金额: $ 33.22万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-01-01 至 1993-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3164699
• 关键词: DNA damage; DNA directed DNA polymerase; DNA repair; adduct; antineoplastic antibiotics; antineoplastics; antiviral agents; bacteria; bleomycin; chemical carcinogen; chemical carcinogenesis; chemical models; chemical structure; combination cancer therapy; crosslink; inhibitor /antagonist; ionizing radiation; molecular oncology; neoplasm /cancer radiation therapy; nuclear magnetic resonance spectroscopy; nucleotide analog; pharmacokinetics; site directed mutagenesis; tissue /cell culture

This research investigates the relationship of DNA damage to processes involved in chemical mutagenesis. nucleoside adducts, derived from chemical carcinogens, chemotherapeutic agents and products of ionizing radiation, will be incorporated, site-specifically, into synthetic oligodeoxynucleotides. The mutagenic spectra of these lesions will be determined in mammalian cells and bacteria. New protecting groups will be developed that will permit site-specific incorporation of alkali-sensitive adducts into oligodeoxynucleotides. Synthetic methods for introducing crosslinks and pre-selected positions in duplex DNA will be established. Chemically-modified oligodeoxynucleotides will be used to explore molecular mechanisms by which DNA polymerases copy damaged templates and to delineate the process of DNA replication and repair, with special reference to chemical mutagenesis. Experimental systems will be developed which allow chemically-modified DNA to be integrated into chromosomal DNA and subsequently rescue for mutational analysis. Damaged DNA will be examined for its ability to enhance homologous recombination. The precise relationship between the number and location of DNA lesions and the induction of the SOS response will be determined. Physical methods, including 2D-NMR and molecular model building, will be used to establish the three dimensional structure of chemically-modified oligodeoxynucleotides in solution. The mutagenicity of the radiomimetic agent, bleomycin, could arise from the abasic sites, 3-phosphoglycolate residues, and/or nucleoside base propenals produced when this antibiotic reacts with DNA. We will examine the mutagenicity of the two structural lesions and characterize the adducts formed when nucleoside base propenals react with DNA. The significance of this research lies in establishing a molecular basis for the mutagenic effects of various types of DNA damage and in demonstrating its relationship to DNA repair. These phenomena are fundamental to an understanding of the primary events involved in chemical carcinogenesis.

本研究探讨了DNA损伤与过程的关系 涉及化学诱变。 核苷加合物，衍生自 化学致癌物、化学治疗剂和电离产物 辐射，将被纳入，特定地点，到合成 寡脱氧核苷酸 这些病变的致突变谱将是 在哺乳动物细胞和细菌中测定。 将开发新的保护基团， 将碱敏感加合物掺入寡脱氧核苷酸中。 用于引入交联和预选位置的合成方法 将建立双链DNA。 化学修饰 寡脱氧核苷酸将用于探索分子机制， 哪些DNA聚合酶复制受损的模板， DNA复制和修复过程，特别是 化学诱变 将开发实验系统， 将DNA整合到染色体DNA中，并随后拯救 突变分析 受损的DNA将被检查其能力， 增强同源重组。 两者之间的精确关系 DNA损伤的数量和位置以及SOS反应的诱导 将被确定。 物理方法，包括2D-NMR和分子 模型的建立，将用于建立三维 化学修饰的寡脱氧核苷酸在溶液中的结构。 拟辐射剂博莱霉素的致突变性可能来自于 脱碱基位点、3-磷酸乙醇酸残基和/或核苷碱基 当这种抗生素与DNA反应时产生的丙烯。 我们将 检查两种结构病变的致突变性，并表征 当核苷基丙烯醛与DNA反应时形成的加合物。 这项研究的意义在于建立了分子基础 各种类型的DNA损伤的致突变作用， 证明了它与DNA修复的关系。 这些现象 对理解涉及的主要事件至关重要， 化学致癌作用