Potentiation of ganciclovir toxicity in the herpes simplex virus thymidine kinase/ganciclovir administration system by ponicidin

Abstract

The herpes simplex virus thymidine kinase (HSV-TK)/ganciclovir (GCV) administration system is commonly used in gene therapy trials. We have evaluated the effect of ponicidin, a diterpenoid isolated from a plant, Rabdosia ternifolia, on the cell-killing activity of the anti-herpes drugs acyclovir (ACV) and GCV. Ponicidin preferentially activated HSV-1-specific TK but not cellular kinases. In HSV-infected cells, ponicidin significantly accumulated the phosphorylated metabolites of GCV and suppressed the extracellular release of GCV. These data suggested that the cytotoxicities of ACV and GCV in HSV-TK-expressing cells might be potentiated by ponicidin. After transfected with the HSV-1 TK gene, COS-1 and several human cancer cells became highly sensitive to the cytotoxic properties of the nucleoside analogs. When ponicidin at the concentration without antiviral activities (0.2 g/mL) was combined with ACV or GCV, the cytotoxic levels in HSV-TK-expressing cells were enhanced by 3-to 87-fold and 5-to 52-fold, respectively, compared with the nucleoside alone. When the stability of the bioactivity of ponicidin in the blood of mice was evaluated, the substance showed relatively long-lasting effects on the potentiation of the anti-herpetic and cytotoxic activities of GCV after intravenous administration. These data suggest that the combined use of ponicidin with GCV will be effective for cancer gene therapy, because high cytotoxicity in viral TK-expressing cells should yield more rapid and enhanced tumor elimination.

Suicide genes for cancer therapy

“…Several different chemicals have been found to promote synergistic tumour cellkilling when administered in combination with the HSVtk/GCV system, including topotecan (Wildner et al, 1999), UCN-01 (McMasters et al, 2000), termozolomide (Rainov et al, 2001), hydroxyurea (Boucher et al, 2002, ponicidin (Hayashi et al, 2000), cyclophosphamide (Fulci et al, 2006), difluoromethylornithine (Wahlfors et al, 2006), gemcitabine (Boucher and Shewach, 2005), scopadulciol (Hayashi et al, 2006) and several deacetylase inhibitors (Yamamoto et al, 2003b). The ability of radiation treatment to potentiate the therapeutic effects of the HSVtk/GCV suicide system, and vice versa, has also been demonstrated both in vitro and in vivo .…”

Expression of thymidine kinase driven by an endothelial-specific promoter inhibits tumor growth of Lewis lung carcinoma cells in transgenic mice

“…Improvement of TK/GCV efficacy may be obtained (i) by promoter engineering, that is, adding enhancer elements that will not compromise tissuespecificity, (ii) by coexpression with a herpes virus structural protein, which enhances intercellular trafficking of TK, 63 or (iii) through the administration of ponicidin, a plant diterpenoid, which increases TK activity. 64 Alternatively, TK/GCV therapy may be combined with conventional anticancer treatments. 27 For instance, several publications reported synergistic effects achieved with a combination of TK/GCV therapies and ionizing radiation.…”

“…27 For instance, several publications reported synergistic effects achieved with a combination of TK/GCV therapies and ionizing radiation. [64][65][66] As discussed by Jain, 67 in case of combination with standard chemotherapy, 'normalization' of vessel growth is preferable to angiogenic cell ablation in order to achieve drug delivery.…”

Electroporation-mediated and EBV LMP1-regulated gene therapy in a syngenic mouse tumor model

“…This suggests that continuous treatment or a combination with other agents is required for the full regression of tumor growth, consistent with previous reports. For example, ponicidin 49 and topotecan 50 were used to enhance killing and the bystander effect for tumor eradication.…”