SPIROHYDANTOIN MUSTARD: MECHANISM OF ACTION

螺乙内酰脲芥末：作用机制

• 批准号: 3169304
• 负责人: WILLIAM J SULING
• 金额: $ 11.22万
• 依托单位: SOUTHERN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-07-01 至 1989-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3169304
• 关键词: DNA; RNA; aziridines; brain neoplasms; disease /disorder model; drug metabolism; ependymoma; human therapy evaluation; hydantoins; macromolecule; phenobarbital; spirane; thin layer chromatography; unspecific monooxygenase

Spirohydantoin mustard (SHM) has reported activity against the murine intracerebral ependymoblastoma and is currently in Phase I clinical trials. SHM is metabolized in vitro by mouse liver mixed function oxidases (MFO) to monodechloroethyl-SHM and spirohydantoin aziridine (SHAZ). Both metabolites possess alkylating and mutagenic activity and may, therefore act as mediators of SHM antitumor activity. Consequently, the objective of the proposed research is to investigate the significance of the metabolites of SHM to the mechanism of action of the drug against the murine intracerebral ependymoblastoma. The following studies are proposed using the murine intracerebral ependymoblastoma tumor model and established methodologies: (1) chemical synthesis of SHM, monodechloroethyl-SHM, and SHAZ (H3-labeled and unlabeled); (2) the effect of pretreatment with phenobarbital, an MFO inducer, or SKF 525A, and MFO inhibitor, on the antitumor activity of SHM; (3) correlation of the antitumor effect of the above pretreatments with the disposition of SHM and metabolites in serum, brain, and tumor (TLC, radioassay), and also with the macromolecular binding (protein, RNA DNA) of the H3-label in brain and tumor, as a function of dose of H3-SHM; (4) a comparison of the antitumor activity of monodechloreothyl-SHM and SHAZ with that of SHM as a means of assessing the relative contribution of each metabolite to the antitumor activity of SHM; (5) a comparison of the disposition of monodechloroethyl-SHM and SHAZ with that of SHM in serum, brain, and tumor, and also macromolecular binding (protein, RNA, DNA) in brain and tumor, as a function of dose of H3-SHM, H3-monodechloreothyl-SHM, or H3-SHAZ. The objective of the latter study is to correlate tumor versus brain tissue specificity of the three drugs with therapeutic specificity. The proposed studies address basic pharmacologic and biochemical questions which are important in gaining a better understanding of the mechanism of action of SHM and the design of second generation agents with improved activity.

螺乙内酰脲芥末 (SHM) 已报告对小鼠有活性 脑内室管膜母细胞瘤，目前处于临床 I 期 试验。 SHM 在体外由小鼠肝脏混合功能氧化酶代谢 (MFO) 转化为单去氯乙基-SHM 和螺乙内酰脲氮丙啶 (SHAZ)。 两个都 代谢物具有烷化和诱变活性，因此可能 作为 SHM 抗肿瘤活性的介质。 因此，目标是 拟议的研究是为了调查代谢物的意义 SHM对药物抗小鼠作用机制的影响 脑内室管膜母细胞瘤。 建议使用以下研究 小鼠脑内室管膜母细胞瘤模型的建立 方法学：（1）SHM、单去氯乙基-SHM的化学合成，以及 SHAZ（H3 标记和未标记）； (2)预处理效果 苯巴比妥（一种 MFO 诱导剂）或 SKF 525A 和 MFO 抑制剂 SHM的抗肿瘤活性； (3) 抗肿瘤作用的相关性 上述预处理与血清中SHM和代谢物的处置， 脑、肿瘤（TLC、放射测定），以及大分子 大脑和肿瘤中 H3 标记的结合（蛋白质、RNA DNA），作为 H3-SHM剂量的函数； (4) 抗肿瘤活性比较 单脱氯乙基-SHM 和 SHAZ 以及 SHM 作为评估方法 每种代谢物对 SHM 抗肿瘤活性的相对贡献； (5)单去氯乙基-SHM和SHAZ的处置比较 血清、脑和肿瘤中的 SHM 以及大分子结合 大脑和肿瘤中的（蛋白质、RNA、DNA），作为 H3-SHM 剂量的函数， H3-单氯乙基-SHM，或H3-SHAZ。 后一项研究的目的是 将三种药物的肿瘤特异性与脑组织特异性相关联 治疗特异性。 拟议的研究涉及基本药理学 和生化问题对于获得更好的结果非常重要 了解SHM的作用机制和第二个设计 具有改进活性的生成剂。