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

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。

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.