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

到目前为止，我们发现了3个与阿昔洛韦（ACV）和更昔洛韦（GCV）具有协同抗疱疹活性的化合物。特别是，在这些药物中，两种二萜，scopadulciol （SDC）和ponicidin (PND)，在单纯疱疹病毒1型（HSV-1）胸苷激酶（TK）表达细胞中增强了ACV和GCV的细胞杀伤活性。本文从一种植物Gallicarpa japonica中分离得到天然黄酮5,6,7- iri甲氧基黄酮（TMF），并对其进行了抗病毒实验。该制剂对HSV- 1有抑制作用。研究了从植物龙蒿中分离的ponicidin（PND）的抗hsv活性，结果表明TMF和ACV具有协同作用。对ACV和GCV的抗病毒活性，发现该化合物优先激活HSV- 1特异性TK，而不是细胞激酶。在转染了HSV- 1tk基因的培养人癌细胞中，PND显著增强了ACV和GCV的细胞毒性。当测定PND在小鼠血液中生物活性的稳定性时，该物质对GCV的抗疱疹和细胞毒活性具有持久的增强作用。另一种二萜类化合物SDC也在体外实验模型中被证明是ACV和GCV的抗疱疹和细胞杀伤活性增强剂。这些数据表明，PND或SDC与ACV/GCV联合使用将是有效的癌症基因治疗，因为它们能更快、更强地消除肿瘤。

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.