RADIATION SENSITIZERS AND BIOREDUCTIVE DRUGS (III)

这是协作研究应用三部曲之一。 有着共同的主题。他们涉及到合成，测试在 体外和体内实验及作用机制的评价 生物还原抗癌药物的产生 低氧细胞辐射增敏剂，作为不同的细胞毒剂 对肿瘤中的缺氧性细胞和其他 抗癌药物。这些化合物是基于 先导化合物RSU 1069所示的“双重功能”，一个 2含1-氮杂环丙烷基团的硝基咪唑 取代侧链。这种化合物产生了大量的 剂量达数量级的辐射和化学增敏 低于咪唑类药物的要求。此外， 对低氧细胞的差异性毒性极高 显示了这类化合物用作 抗癌药物以生物还原方式激活。基本的理论基础 因为这个合作项目是合成新的化合物 这种类型，检查它们作为辐射敏感剂的有效性， 化疗增敏剂和不同的细胞毒剂 在培养中的各种细胞系中的缺氧细胞 多细胞球体及其在不同肿瘤实验中的表达 已经在申请人的实验室建立的类型。 此外，机械学研究将包括调查 构造活动关系，因为它已经显示 RSU 1069和类似类型的化学修饰 化合物在体外和体内都能深刻地影响细胞毒性。 体内对致敏能力影响不大。对于RSU 1069，其高分化低氧细胞毒性是由于其 厌氧转化为高活性双功能菌剂 还原。这会导致链断裂和交叉增加。 在DNA中连接。然而，RSU 1069也是相当大的 对需氧细胞的毒性比米索硝唑大，导致致癌 未照射的C3H10T1/2和Balb 3T3细胞的转化。一个 联合计划的重要部分将是审查 因此，新化合物在水溶液中的转化能力 结构性活动研究。这将旨在评估 重要的因素，如电子亲和力，程度 氮杂环丁基和其他单官能团的活化 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之间的关系 和辐射增敏效果。

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.