RADIATION SENSITIZERS AND BIOREDUCTIVE DRUGS II

这是具有共同主题的应用程序三部曲之一。 它们涉及到合成、体外和体内测试以及 一代生物制剂作用机理的评价 可起到缺氧作用的还原抗癌药物 增敏剂作为缺氧性细胞毒性的鉴别药物 肿瘤中的细胞和其他抗癌药物的增强剂。 这些化合物是基于“双重功能”的原则。 如先导化合物RSU 1069所示，是一种2-硝基咪唑 在1-取代侧链中含有氮杂环丙烷官能团。 这种化合物会产生大量的辐射-和化学- 致敏剂量比 米索硝唑所需的。此外，不同的毒性 对低氧细胞的抵抗力极高，显示出 这类化合物用作抗癌药物活化了生物活性 简单化的。这个协作计划的基本原理是 为了合成这种类型的新化合物，研究它们的 作为辐射增敏剂、化学增敏剂和 不同的细胞毒剂对缺氧细胞的作用 在培养中、在多细胞球体中和在 不同类型的实验性肿瘤已经 在申请者实验室建立。此外, 力学研究将包括对构造活动的研究 关系，因为已经证明了化学物质 RSU 1069和类似类型的化合物的修饰可以 在体外和体内都能深刻地影响细胞毒性 对敏化能力有很大影响。对于RSU 1069，最高 不同的缺氧性细胞毒性是由于其转化为 厌氧还原高活性双功能助剂。这 导致DNA中的链断裂和交联增加。 然而，RSU 1069的毒性也比 咪唑对好氧细胞的作用，导致细胞发生致癌转化 未照射的C3H10T1/2和Balb 3T3细胞。一个重要的部分 因此，合并后的方案将审查 新化合物在构效关系中的转化能力 学习。这将旨在评估因素的重要性。 如电子亲和力、分子的活化度等 氮丙烷基团和其他单官能团烷基化部分， 亲油性和亲油性之间的关系(如果有) 转化能力、有氧和低氧细胞毒性以及 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 sensitizers, as differential cytotoxic agents of oxygen-deficient cells in tumors 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-subtituted 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 program 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 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 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 aziridinel group and other mono-functional alkylating moieties, lipophilic properties and relationships, if any, between transforming ability, aerobic and hypoxic cytotoxicity and radiation-sensitizing effectiveness.