SPIROHYDANTOIN MUSTARD: MECHANISM OF ACTION

据报道，螺旋海因芥末具有抗小鼠的活性。 脑室管膜母细胞瘤，目前处于I期临床 审判。SHM在体外被小鼠肝脏混合功能氧化酶代谢 (MFO)到一氯乙基-SHM和螺内酯氮丙啶(Shaz)。两者都有 代谢物具有烷基化和诱变活性，因此 作为SHM抗肿瘤活性的介体。因此，目标是 拟议的研究是为了调查代谢物的意义。 三七总皂苷对药物抗小鼠作用机制的影响 脑室管膜母细胞瘤。建议进行以下研究，使用 小鼠脑内室管膜母细胞瘤模型的建立 方法：(1)SHM、一氯乙基-SHM的化学合成； SHAZ(H3标记的和未标记的)；(2) 苯巴比妥，MFO诱导剂或SKF 525A，以及MFO抑制剂 SHM的抗肿瘤活性；(3)SHM抗肿瘤作用的相关性 上述前处理与SHM和代谢物在血清中的处置， 脑和肿瘤(TLC，放射分析)，也与大分子 脑和肿瘤中H3标记的结合(蛋白质，RNA，DNA)，作为一种 H3-SHM的剂量作用；(4)抗肿瘤活性的比较 一氯代谢物-SHM和Shaz，并将其作为评估 各代谢物对SHM抗肿瘤活性的相对贡献； (5)一氯乙基-SHM和沙士的处理效果比较 SHM在血清、脑和肿瘤中的结合以及大分子结合 (蛋白质，RNA，DNA)在脑和肿瘤中，作为H3-SHM剂量的函数， H3-单氯氰菊酯-SHM或H3-Shaz。后一个研究的目标是 将三种药物的肿瘤与脑组织的特异性与 治疗的特异性。拟议的研究涉及基础药理学 以及生化问题，这些问题对于获得更好的 对SHM作用机理的理解及二次设计 具有更高活性的世代制剂。

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.