1. ¹Programa Gens i Malaltia, Centre de Regulació Genòmica-CRG, UPF, Parc de Recerca Biomèdica de Barcelona-PRBB, Barcelona, Spain
2. ²Laboratori de Recerca Translacional, IDIBELL- Institut Català d'Oncologia, Barcelona, Spain
3. ³Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain

Correspondence: Dr C Fillat, Centre de Regulació Genòmica-CRG, Edifici Parc de Recerca Biomèdica de Barcelona, Dr Aiguader, 88, 08003 Barcelona, Spain. E-mail: cristina.fillat@crg.es

Received 20 March 2007; Revised 16 July 2007; Accepted 17 July 2007; Published online 23 August 2007.

Abstract

Replication-competent adenoviruses carrying the herpes simplex thymidine kinase (TK) gene have shown contradictory evidence with regard to their antitumoural efficacy in combination with ganciclovir (GCV) treatment. We generated a replication-competent adenovirus carrying Tat8-TK, a modified form of the TK gene, under the control of the adenoviral major late promoter (AdRGDTat8-TK-L). Pancreatic cancer cell lines with different sensitivity to the TK/GCV system were infected with AdRGDTat8-TK-L, both in the presence and absence of GCV, and tested for treatment efficacy. We observed that, although the presence of GCV reduced viral replication in all infected cell lines, in three out of four GCV significantly enhanced the efficacy of the virotherapy. Interestingly, the cytotoxicity of the AdRGD-Tat8-TK-L/GCV was found more potent than that of a first generation AdTK/GCV system. In tumour xenografts from BxPC-3 and NP-18 pancreatic cells, both AdRGDTat8-TK-L and AdRGDTat8-TK-L/GCV treatment showed antitumoural activity. In BxPC-3 tumours scheduling of virus and prodrug was a key factor to determine the outcome of the therapy. Importantly, the addition of GCV enhanced the antitumoural effect of AdRGDTat8-TK-L only when applied in two rounds of virus+GCV. Interestingly, in spite of interfering with viral replication in vitro, GCV treatment of NP-18 tumours did not compromise the antitumoural efficacy of the AdRGDTat8-TK-L adenovirus. Thus, our results show that the combination therapy of a replicative adenovirus and the Tat8-TK/GCV suicide system can prove beneficial, when the appropriate regimen of virus and GCV is applied.