权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

螺乙内酰脲芥（SHM）已报道了针对小鼠的活性。脑内室管膜母细胞瘤，目前处于I期临床审判 SHM在体外经小鼠肝混合功能氧化酶代谢 (MFO)一脱氯乙基-SHM和螺乙内酰脲氮丙啶（SHAZ）。两代谢物具有烷基化和诱变活性，因此，作为SHM抗肿瘤活性的介质。因此，拟议的研究是调查代谢物的意义， SHM的作用机制的药物对小鼠脑内室管膜母细胞瘤以下研究建议使用小鼠脑室内管膜母细胞瘤模型的建立方法：（1）化学合成SHM，一氯乙基-SHM，和 SHAZ（H3标记和未标记）;（2）用H3预处理的效果苯巴比妥，一种MFO诱导剂，或SKF 525 A，和MFO抑制剂， SHM的抗肿瘤活性;（3）SHM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，脑和肿瘤（TLC，放射性测定），以及大分子 H3标记在脑和肿瘤中的结合（蛋白质，RNA DNA）， H_3-SHM的抗肿瘤活性与剂量的关系单脱氯乙基-SHM和SHAZ与SHM作为评估的手段，各代谢产物对SHM抗肿瘤活性的相对贡献; (5)一脱氯乙基-SHM和SHAZ的处置与 SHM在血清、脑和肿瘤中的作用，以及大分子结合（蛋白质，RNA，DNA）在脑和肿瘤，作为剂量的H3-SHM的函数， H3-单脱氯乙基-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与治疗特异性拟议的研究涉及基础药理学和生物化学问题，这些问题对于获得更好的了解SHM的作用机制和第二个具有改进活性的生成剂。