GENOTOXICITY OF DNA-DIRECTED ANTINEOPLASTIC AGENTS

DNA 定向抗肿瘤药物的基因毒性

• 批准号: 3180856
• 负责人: Lawrence F Povirk
• 金额: $ 12.3万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-08-01 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3180856
• 关键词: CHO cells; DNA damage; DNA repair; DNA replication; Xenopus oocyte; adduct; adenine; adenine phosphoribosyltransferase; antineoplastics; bleomycin; chemical binding; chemical carcinogen; chemical models; computer simulation; gene deletion mutation; guanine; melphalan; molecular site; mutagen testing; mutagens; neocarzinostatin; nucleic acid structure; podophyllin; transfection; transfection /expression vector

Many of the most effective drugs used in cancer chemotherapy are DNA- damaging agents. However, long-term survivors of treatment with at least some of these drugs have a substantially increased risk of developing second, unrelated malignancies, presumably as a result of the mutagenic effects of these drugs. The ultimate goal of the proposed studies is to understand the mechanisms by which certain antitumor drugs exert their mutagenic and carcinogenic effects, in order to facilitate the selection and development of more effective and less carcinogenic chemotherapeutic agents and protocols. For drugs which induce DNA double-strand breaks, including the radiomimetics bleomycin and neocarzinostatin and the topoisomerase II inhibitors m-AMSA and teniposide, the relationship between double-strand break repair and deletion mutagenesis will be investigated. Defined repair substrates which incorporate a unique site- specific double-strand break, with termini characteristic of particular drug-induced breaks, will be constructed. These substrates will be introduced into various mammalian and other eukaryotic cells, and repaired products will be recovered and analyzed in an attempt to develop models to explain how the double-strand breaks were repaired, how the blocked termini were processed, and whether any specific blocked termini were particularly prone to cause deletions during repair. In order to determine whether similar repair events occur in endogenous genes, mutations induced by these same drugs in the aprt gene in CHO cells will be sequenced. For the bifunctional alkylating agent melphalan, which has been strongly associated with second malignancies, sequences have been identified in CHO/aprt and in shuttle vector systems which are frequent sites of drug- induced base substitutions mutations. Both monofunctional and bifunctional adducts induced by the drug at these sequences will be identified in order to determine whether any adducts are specifically formed at these sites, and whether these adducts can be implicated in mutagenesis. Spectra of mutations induced by a monofunctional analogue of melphalan will be determined in CHO/aprt and in a shuttle vector system in order to determine the relative importance of monofunctional and bifunctional alkylation in mutagenesis. For all the drugs being studied, molecular computer graphics modeling will be employed in an attempt to explain in structural terms the types of DNA damage induced by each drug.

许多用于癌症化疗的最有效的药物都是 DNA- 破坏剂。然而，至少接受治疗的长期幸存者 其中一些药物的患病风险大大增加 第二，不相关的恶性肿瘤，可能是诱变的结果 这些药物的作用。拟议研究的最终目标是 了解某些抗肿瘤药物发挥作用的机制 有致突变和致癌作用，以利于选择 并开发更有效且致癌性更低的化疗药物 代理和协议。对于诱导DNA双链断裂的药物， 包括放射模拟物博来霉素和新制癌菌素以及 拓扑异构酶 II 抑制剂 m-AMSA 与替尼泊苷的关系 双链断裂修复和缺失诱变之间 调查了。定义的修复基材包含一个独特的位点- 特定的双链断裂，具有特定的末端特征 药物引起的断裂，将被构建。这些基材将 导入各种哺乳动物和其他真核细胞，并修复 产品将被回收和分析，以尝试开发模型 解释双链断裂是如何修复的，如何封闭的 处理了末端，以及是否有任何特定的封闭末端 特别容易在修复过程中导致删除。为了确定 类似的修复事件是否发生在内源基因、诱导突变中 通过这些相同药物对CHO细胞中的aprt基因进行测序。 双功能烷化剂美法仑，受到强烈关注 与第二种恶性肿瘤相关的序列已在 CHO/aprt 和穿梭载体系统是药物频繁作用的位点 诱导碱基取代突变。有单功能和双功能两种 将按顺序鉴定药物在这些序列处诱导的加合物 以确定是否在这些位点专门形成任何加合物， 以及这些加合物是否与诱变有关。 的光谱 由马法兰的单功能类似物诱导的突变将是 在 CHO/aprt 和穿梭载体系统中测定，以便 确定单功能和双功能的相对重要性 诱变中的烷基化。 对于所有正在研究的药物，分子 将采用计算机图形建模来尝试解释 结构术语 每种药物引起的 DNA 损伤类型。