RADIATION SENSITIZERS AND BIOREDUCTIVE DRUGS

辐射增敏剂和生物还原药物

• 批准号: 3186687
• 负责人: ROBERT M SUTHERLAND
• 金额: $ 21.1万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-06-15 至 1990-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3186687
• 关键词: antineoplastics; drug adverse effect; drug metabolism; human therapy evaluation; hypoxia; imidazole; laboratory mouse; nervous system carcinoma; radiation sensitivity; radiosensitizer; tissue /cell culture

This is one of a trilogy of applications of collaborative research with a common theme. They concern the synthesis, testing in vitro and in vivo and the evaluation of mechanisms of action, of a generation of bio-reductive anticancer drugs that can function as hypoxic cell radiation sensitizers, as differential cytotoxic agents for oxygendeficient cells in tumors and as potentiators of other anticancer drugs. These compounds are based on the principles of "dual function" shown by the lead compound RSU 1069, a 2nitroimidazole containing an aziridine function in the 1- substituted side chain. This compound gives rise to substantial radiation and chemo-sensitization at doses an order of magnitude less than those required for misonidazole. Further, the differential toxicity towards hypoxic cells is extremely high showing the potential of this class of compound for use as anticancer drugs activated bioreductively. The basic rationale for this collaborative program is to synthesize new compounds of this type, examine their effectiveness as radiation sensitizers, chemosensitizers and differential cytotoxic agents for oxygendeficient cells in a variety of cell lines in culture, in multicellular spheroids and in experimental tumors of different types that are already established in the applicants' laboratories. In addition, mechanistic studies will include investigation of structure activity relationships since it has already been shown that chemical modifications of RSU 1069 and similar types of compounds can profoundly affect cytotoxicity both in vitro and in vivo without greatly influencing sensitizing ability. For RSU 1069, the high differential hypoxic cytotoxicity is due to its conversion to a highly reactive bifunctional agent by anaerobic reduction. This leads to an increase in strand breakage and cross- linking in DNA. However, RSU 1069 which is also considerably more toxic than misonidazole to aerobic cells, causes oncogenic transformation in unirradiated C3H 10T1/2 and balb 3T3 cells. An important part of the combined program will be to examine therfore the transforming ability of the new compounds in a structureaimed activity study. This will be aimed at assessing the importance of factors such as electronaffinity, the degree of activation of the aziridinyl group and other monofunctional alkylating moieties, lipophilic properties and relationships, if any, between transforming ability, aerobic and hypoxic cytotoxicity and radiationsensitizing effectiveness.

这是合作研究的应用三部曲之一 一个共同的主题。 它们涉及合成，测试， 体外和体内研究以及作用机制的评价， 产生生物还原性抗癌药物， 低氧细胞辐射增敏剂，作为差别细胞毒性剂 作为肿瘤中缺氧细胞的增效剂， 抗癌药 这些化合物是基于 在铅化合物RSU 1069所示的“双重功能”中， 在1-甲基环上含有氮丙啶官能团的2-硝基咪唑 取代的侧链 该化合物产生大量的 辐射和化学致敏剂量的数量级 少于米索硝唑所需的量。 此夕h 对缺氧细胞的不同毒性非常高 显示了这类化合物用作 生物还原性激活的抗癌药物。 的基本理由 这个合作项目的目的是合成新的化合物 这种类型，检查它们作为辐射敏化剂的有效性， 化学增敏剂和差异细胞毒性剂， 缺氧细胞在培养的各种细胞系中， 多细胞球体和不同的实验性肿瘤 已在申请人的实验室中建立的类型。 此外，机制研究将包括调查 结构化活动关系，因为它已经显示 RSU 1069和类似类型的化学修饰 化合物可以在体外和体内深刻地影响细胞毒性。 而对致敏能力无明显影响。 就受限制股份单位 1069，高差异缺氧细胞毒性是由于其 通过厌氧转化为高活性双功能试剂 还原 这导致链断裂和交叉- 连接在DNA上 然而，RSU 1069也相当大， 对需氧细胞的毒性比米索硝唑大， 在未照射的C3 H10 T1/2和balb 3 T3细胞中的转化。 一个 合并计划的重要组成部分将是检查 因此，新化合物在一种 构效关系研究 目的是评估 电子亲合性， 氮丙啶基和其它单官能基的活化 烷基化部分，亲脂性和关系，如果有的话， 转化能力、有氧和低氧细胞毒性 and radiationsensitizing辐射sensitizing敏感effectiveness有效性.