SPIROHYDANTOIN MUSTARD: MECHANISM OF ACTION

螺乙内酰脲芥末：作用机制

基本信息

批准号：
3169307
负责人：
WILLIAM J SULING
金额：
$ 8.87万
依托单位：
SOUTHERN RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
1981
资助国家：
美国
起止时间：
1981-07-01 至 1990-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3169307
关键词：
DNA RNA antineoplastics aziridines brain neoplasms central nervous system neoplasms disease /disorder model drug metabolism ependymoma human therapy evaluation hydantoins laboratory mouse macromolecule phenobarbital spirane thin layer chromatography tritium unspecific monooxygenase

项目摘要

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.

Spirohydantoin芥末（SHM）报告了对鼠的活性脑膜状膜细胞瘤，目前处于I期临床上试验。小鼠肝脏混合功能氧化酶在体外代谢SHM （MFO）到单氯乙基-SHM和螺旋氢二氨酸（Shaz）。两个都代谢产物具有烷基化和诱变活性，因此可能充当SHM抗肿瘤活性的介体。因此，拟议的研究是研究代谢物的重要性 SHM达到药物对鼠的作用机理脑膜状膜细胞瘤。提出了以下研究鼠内脑膜膜状细胞瘤模型并建立方法论：（1）SHM的化学合成，单一氯乙基-SHM和 Shaz（H3标记和未标记）；（2）与 MFO诱导剂或SKF 525a和MFO抑制剂的苯巴比妥 SHM的抗肿瘤活性；（3）抗肿瘤效应的相关性在血清中SHM和代谢物的处置的预处理上方，大脑和肿瘤（TLC，Radiosay），以及大分子脑和肿瘤中H3标记的结合（蛋白质，RNA DNA）作为A H3-SHM剂量的功能；（4）比较抗肿瘤活性的与SHM的Monodechloreothyl-Shm和Shaz一起评估每种代谢物对SHM的抗肿瘤活性的相对贡献；（5）比较单一氯乙基-SHM和SHAZ与血清，大脑和肿瘤中的SHM以及大分子结合（蛋白质，RNA，DNA）在脑和肿瘤中，作为H3-SHM剂量的函数， H3-MonodeChloreothyl-Shm或H3-Shaz。后一项研究的目的是将三种药物的肿瘤与脑组织特异性相关联治疗特异性。拟议的研究涉及基本的药理学和生化问题，对于获得更好的问题很重要了解SHM的作用机理和第二具有改善活性的代理。