By the addition of further DNA damage, such as irradiation therapy, it can be hypothesized that cellular apoptotic response to CDV would increase. Indeed, combining CDV with irradiation both in vitro and in engrafted nude mice resulted in a marked radio-sensitization in HPV-positive cells, which was not observed in HPV-uninfected cells ( Abdulkarim et al., 2002). The synergistic effect of CDV and radiation in HNSCC cells was associated with p53 accumulation. It has also been shown that the combination of CDV and radiation had a potent anti-angiogenic

effect, inducing inhibition of E6 expression, restoration of p53, and reduction of the pro-angiogenic phenotype of HPV18 positive cells associated with VEGF (vascular endothelial growth factor) inhibition ( Amine et al., 2006). CDV also GSK2656157 supplier enhanced the radiation-induced apoptosis in EBV-positive cells and in EBV-related cancer xenografts ( Abdulkarim et al., 2003). CDV induced a downregulation

of the EBV oncoprotein LMP1 associated with a decrease in expression of the anti-apoptotic Bcl-2 protein and an increase of the pro-apoptotic Bax protein in Raji (Burkitt lymphoma) and C15 (nasopharyngeal carcinoma) cells ( Abdulkarim et al., 2003). The antitumor effect of CDV was also evaluated in combination with radiation therapy against glioblastoma (Hadaczek et al., 2013). In vitro, a dramatic increase (over 21-fold) of phosphorylated H2AX, an indicator of DNA damage/instability, after exposure to both CDV and ionizing radiation was observed. Furthermore, this combination resulted in reduced Ceritinib datasheet tumor growth in a model of human glioblastoma-derived intracranial xenografts in mice leading to increased animal survival. On the other hand, the combination of cidofovir with chemotherapeutics presenting a different mode of antitumor action may be expected to result in synergistic antitumor activity. In line with this assumption, Deberne and colleagues investigated the combination of cidofovir

with the anti-epidermal growth factor receptor monoclonal antibody cetuximab in vitro (using a clonogenic survival assay, cell cycle analysis, and phospho-H2AX levels) and in vivo (using selleck chemical xenograft models) ( Deberne et al., 2013). This combination was assessed considering the cross-talk between epidermal growth factor receptor and HPV that is implicated in tumor progression. The CDV-cetuximab combination inhibited the growth of the different cell lines tested, including HPV-positive (HeLa and Me 180) and HPV-negative (C33A, H460 and A549) cells, with synergistic activity on HPV-positive but not on HPV-negative cells. The CDV-cetuximab combination also delayed tumor growth of HPV-positive tumors in vivo but no efficacy was reported on HPV-negative C33A xenografts.