RADIATION SENSITIZERS AND BIOREDUCTIVE DRUGS

辐射增敏剂和生物还原药物

• 批准号: 3186681
• 负责人: GERALD E ADAMS
• 金额: $ 8.57万
• 依托单位: MEDICAL RESEARCH COUNCIL
• 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/3186681
• 关键词: antineoplastics; cytotoxicity; drug adverse effect; drug resistance; hypoxia; laboratory mouse; radiation sensitivity; radiosensitizer; tissue /cell culture

This is one of a trilogy of applications 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 anti-cancer drugs that can function as hypoxic cell radiation sensitizers, as differential cytotoxic agents for oxygen-deficient cells in tumours and as potentiators of other anti-cancer drugs. These compounds are based on the principles of 'dual function' shown by the lead compound RSU 1069, a 2-nitroimidazole 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 anti-cancer drugs activated bio-reductively. The basic rationale for this collaborative programme is to synthesize new compounds of this type, examine their effectiveness as radiation sensitizers, chemo-sensitizers and differential cytotoxic agents for oxygen-deficient cells in a variety of cell lines in culture, in multi-cellular spheroids and in experimental tumours 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 10T 1/2 and balb 3T3 cells. An important part of the combined programme will be to examine therefore the transforming ability of the new compounds in a structure-activity study. This will be aimed at assessing the importance of factors such as electron-affinity, the degree of activation of the aziridinyl group and other mono-functional alkylating moieties, lipophilic properties and relationships, if any, between transforming ability, aerobic and hypoxic cytotoxicity and radiation-sensitizing effectiveness.

这是具有共同主题的应用程序三部曲之一。 它们涉及 合成、体内外试验及评价 新一代生物还原抗癌药物的作用机制 可以作为低氧细胞辐射增敏剂， 用于肿瘤中缺氧细胞的细胞毒性剂和增效剂 其他抗癌药物。 这些化合物基于以下原理： 先导化合物RSU 1069（2-硝基咪唑）显示的“双重功能” 在1-取代的侧链中含有氮丙啶官能团。 这 化合物引起大量的辐射和化学敏化， 剂量比米索硝唑所需的剂量小一个数量级。 此外，对缺氧细胞的差异毒性极高 显示了这类化合物用作抗癌剂的潜力 药物被生物还原激活。 基本原理是 合作计划是合成这种类型的新化合物， 检查它们作为辐射增敏剂、化学增敏剂和 用于各种缺氧细胞的差异细胞毒性剂 培养中、多细胞球体中和实验中的细胞系 已经在申请人的皮肤中建立的不同类型的肿瘤 laboratories. 此外，机制研究将包括调查 结构活性关系，因为它已经表明， RSU 1069和类似类型化合物的化学改性可 深刻地影响体外和体内细胞毒性， 影响敏化能力。 对于RSU 1069， 低氧细胞毒性是由于其转化为高反应性的 双功能厌氧还原剂。 这样会增加 DNA链断裂和交联。 RSU 1069也是 对需氧细胞的毒性比米索硝唑大得多， 未照射的C3 H 10 T 1/2和balb 3 T3细胞的致癌转化。 因此，合并方案的一个重要部分将是审查 新化合物在构效关系中的转化能力 study. 这将旨在评估下列因素的重要性： 电子亲和性、氮丙啶基的活化程度和 其它单官能烷基化部分、亲脂性和 转化能力、有氧和低氧之间的关系，如果有的话， 细胞毒性和辐射增敏效果。