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Research on the potentiators of HSV-specific thymidine kinase for the purpose of their application to gene therapy and antiviral therapy

HSV特异性胸苷激酶增强剂的研究及其在基因治疗和抗病毒治疗中的应用

基本信息

批准号：
09672276
负责人：
HAYASHI Kyoko
金额：
$ 1.92万
依托单位：
Toyama Medical and Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

So far, we found three compounds which exerted synergistic antiherpetic activities with acyclovir (ACV) and ganciclovir(GCV). Especially, of these agents, two diterpenoids, scopadulciol (SDC) and ponicidin (PND), potentiated the cell-killing activity of ACV and GCV in herpes simplex virus type 1(HSV-1) thymidine kinase (TK)-expressing cells. We report about these in detail as follows A naturally occuring flavone, 5,6,7-irimethoxyflavone (TMF), isolated from a plant Gallicarpa japonica, was subjected to antiviral assays . The agent exhibited inhibitory effects on HSV- 1 . TMF and ACV were synergic in their anti-HSV activities, During the evaluation of the effect of ponicidin(PND), which was isolated from a plant Rabdosia ternifolia . on the antiviral activities of ACV and GCV, the compound was found to preferentially activate HSV- 1 -specific TK but not cellular kinases. ln cultured human cancer cells transfected with HSV- 1 TK gene, cytotoxicities of ACV and GCV was strongly potentiated by PND.When the stability of the bioactivity of PND in the blood of mice was determined, the substance showed long-lasting effects on the potentiation of antiherpetic and cytotoxic activities of GCV.Another diterpenoid, SDC isolated from Scoparia dulcis, was also demonstrated as a potentiator of antiherpetic and cell-killing activities of ACV and GCV in in vilro experimental models. These data suggest that combined use of PND or SDC with ACV/GCV will be effective for cancer gene therapy because of more rapid and enhanced tumor elimination.

迄今为止，我们发现三个化合物与阿昔洛韦（ACV）和更昔洛韦（GCV）具有协同抗疱疹活性。特别是，这些代理商，两个二萜类化合物，东莨菪碱（SDC）和ponicidin（PND），加强ACV和GCV在单纯疱疹病毒1型（HSV-1）胸苷激酶（TK）表达细胞的细胞杀伤活性。我们详细报道如下：一种天然存在的黄酮，5，6，7-三甲氧基黄酮（5，6，7-trimethoxyflavone，5-trimethoxyfl该试剂对HSV- 1表现出抑制作用。从三叶香茶菜中提取的Ponicidin（PND）对HSV的抑制作用与ACV有协同作用。在ACV和GCV的抗病毒活性上，发现该化合物优先激活HSV- 1特异性TK，但不激活细胞激酶。在体外培养的转染HSV- 1 TK基因的人癌细胞中，PND能显著增强ACV和GCV的细胞毒作用，PND在小鼠血液中的生物活性稳定性测定表明，PND对GCV的抗疱疹和细胞毒作用具有持久的增强作用。在体外实验模型中，也证明了作为ACV和GCV的抗疱疹和细胞杀伤活性的增强剂。这些数据表明，联合使用PND或SDC与ACV/GCV将是有效的癌症基因治疗，因为更快速和增强的肿瘤消除。