RADIATION SENSITIZERS AND BIOREDUCTIVE DRUGS

这是具有共同主题的应用程序三部曲之一。他们关心的是 三聚氰胺的合成、体内外测试及评价 一代生物还原抗癌药物的作用机制 可作为低氧细胞辐射敏感剂，作为差异性 肿瘤中缺氧细胞的细胞毒剂和增强剂 其他抗癌药物。这些化合物是基于以下原理的 先导化合物RSU 1069--2-硝基咪唑表现出的“双重功能” 在1-取代侧链中含有氮杂环丙烷官能团。这 化合物在以下条件下会引起实质性的辐射和化学敏化 剂量比咪唑硝唑所需剂量小一个数量级。 此外，对低氧细胞的差异性毒性极高。 显示了这类化合物作为抗癌药物的潜力 药物以生物还原的方式激活。这样做的基本理由是 合作项目是合成这种类型的新化合物， 检查其作为辐射增敏剂、化学增敏剂和 不同种类的细胞毒剂对缺氧细胞的毒性作用 细胞系在培养中、在多细胞球体中和在实验中 申请人已确诊的不同类型的肿瘤 实验室。此外，机械学研究将包括调查 结构活性关系，因为已经表明 RSU 1069和类似类型的化合物的化学修饰可以 在体外和体内都深刻地影响细胞毒性，而不是很大 影响敏化能力。对于RSU 1069，高差值 低氧的细胞毒性是由于它转化为高活性的 厌氧还原的双功能药剂。这导致了 DNA中的链断裂和交联。然而，RSU 1069也是 对需氧细胞的毒性比米索硝唑大得多，导致 未照射的C3H10T1/2和Balb 3T3细胞的致癌转化 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 学习。这将旨在评估以下因素的重要性 电子亲和力、氮杂环的活化度和 其他单官能团烷基化部分、亲脂性和 转化能力、有氧和低氧之间的关系(如果有) 细胞毒性和辐射增敏效果。

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.