RADIATION SENSITIZERS AND BIOREDUCTIVE DRUGS II

辐射增敏剂和生物还原药物 II

• 批准号: 3186691
• 负责人: ERIC J HALL
• 金额: $ 25.03万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-30 至 1990-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3186691
• 关键词: aziridines; bleomycin; brain neoplasms; cis platinum compound; contrast media; cytotoxicity; drug adverse effect; drug design /synthesis /production; fibroblasts; gamma radiation; hypoxia; imidazole; ionizing radiation; laboratory mouse; lung neoplasms; neoplasm /cancer chemotherapy; radiation dosage; radiation sensitivity; radiopharmacology; radiosensitizer; relative biological effectiveness; tissue /cell culture; vinblastine

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.

这是具有共同主题的应用程序三部曲之一。 它们涉及合成、体外和体内测试以及 一代生物作用机制的评估 还原性抗癌药物，可以作为低氧 致敏剂，作为缺氧的差异细胞毒性剂 肿瘤中的细胞以及作为其他抗癌药物的增效剂。 这些化合物是基于“双重功能”的原则 由先导化合物RSU 1069表示，2-硝基咪唑 在1-取代的侧链中含有氮丙啶官能团。 这种化合物会产生大量的辐射和化疗 致敏剂量的数量级低于那些 需要米索硝唑。 此外，不同的毒性 对缺氧细胞的反应非常高， 用作抗癌药物的这类化合物激活了生物活性， 还原性地。 这个合作项目的基本原理是 为了合成这种新的化合物，检查它们的 作为辐射增敏剂、化学增敏剂和 用于缺氧细胞的差异细胞毒性剂 培养物中、多细胞球体中和细胞中的各种细胞系 不同类型的实验性肿瘤， 在申请人的实验室里。 此外，本发明还提供了一种方法， 机理研究将包括结构活性的研究 因为它已经表明，化学 RSU 1069和类似类型化合物的改性物可 在体外和体内都深刻地影响细胞毒性， 大大影响了敏化能力。 对于RSU 1069， 不同的低氧细胞毒性是由于其转化为一种 高活性双功能试剂通过厌氧还原。 这 导致DNA链断裂和交联的增加。 然而，RSU 1069的毒性也比 米索硝唑需氧细胞，导致致癌转化， 未照射的C3 H 10 T1/2和Balb 3 T3细胞。 一个重要组成部分 因此，合并方案的目的将是审查 新化合物在结构-活性方面的转化能力 study. 这将旨在评估因素的重要性， 例如电子亲和性， 氮丙啶基团和其它单官能烷基化部分， 亲脂性和关系，如果有的话， 转化能力，有氧和缺氧细胞毒性， 辐射增敏效果。