Sera of older mice showed lower and stable concentrations of cytokines (data not shown), pointing to an effect of immune maturation on cytokine levels rather than an effect of housing or experimental conditions
Sera of older mice showed lower and stable concentrations of cytokines (data not shown), pointing to an effect of immune maturation on cytokine levels rather than an effect of housing or experimental conditions. inflammatory response in SiHaCDVcompared to SiHaparental. == Conclusions == Our results indicate that acquisition of resistance to cidofovir in SiHa cells is usually linked to reduced pathogenicity. PLX5622 The present study contributes to our understanding around the antiproliferative effects of CDV and on the mechanisms involved, the inflammatory response playing a central role. Keywords:Cidofovir, Cervical cancer, Human papillomavirus, Xenografts, Inflammatory response, Microarrays == Background == Three acyclic nucleoside phosphonate analogues (ANPs), i.e. tenofovir (PMPA), adefovir (PMEA) and cidofovir (CDV), are approved for the treatment of viral infections [1,2]. Tenofovir and adefovir are active against retroviruses and hepadnaviruses, their oral prodrug forms being approved for therapy of HIV (PMPA) and of chronic hepatitis B virus infections (PMPA and PMEA). Although CDV is usually formally licensed for treatment of cytomegalovirus retinitis in AIDS patients, it is often used off-label for the management of diseases caused by several DNA viruses, including adeno-, pox-, papilloma-, polyoma-, and herpesviruses others than cytomegalovirus [3-6]. Besides their well-recognized antiviral properties, some ANPs have shown anticancer potency. For instance, PMEA, PMEDAP, PMEG, and prodrugs of PMEG [i.e. cPr-PMDEDAP, GS-9219 and GS-9191] showed marked cytotoxic propertiesin vitro[7-9]. Additionally,in vivoantitumor activities for these compounds have been described in different animal models: GS-9219 in a pet dog model of non-Hodgkin’s lymphoma [10] and cPr-PMEDAP in a rat choriocarcinoma tumor model [11]. A close correlation between the cytostatic activities of PME derivatives and the inhibitory effects of their active metabolites (diphosphate forms) on cellular DNA polymerases , , and has been established. In these studies, PMEG-diphosphate (PMEGpp) emerged as the most potent chain-terminating inhibitor of cellular DNA polymerases [12,13]. The utility of PMEG as an anticancer agent is limited by poor cellular permeability and toxicity [13,14] and prodrugs, such as GS-9191 and GS-9219, were designed to increase the permeability and accumulation of PMEGpp in the cells [10,13]. Cidofovir represents also an ANP with marked antiproliferative effects but unlike PMEG, the effects of CDV-diphosphate (CDVpp) on cellular DNA polymerization are weak [inhibition constant (Ki) of CDVpp for cellular DNA polymerase- of 51 Mversus0.55 M for PMEGpp]. In addition, CDVpp is not an obligate chain terminator [12,13] and, in contrast to PMEG, CDV has been used to manage human papillomavirus (HPV)-induced benign and malignant hyperproliferation with minimal if any side-effects, as described in several case reports and some phase II/III clinical trials [15-20]. Recently, a phase II clinical trial was conducted in Belgium to evaluate the safety and efficacy of CDV in the treatment of high grade cervical lesions (NCT01303328). Full data analysis of this Phase II clinical trial will be provided during the next months. Cidofovir antitumor properties were also demonstrated in different animal models of tumors related to transforming viruses, including Epstein-Barr virus-associated nasopharyngeal carcinoma [21] Rabbit Polyclonal to MITF and HPV-induced cervical carcinoma [22-24] xenografts in athymic-nude mice, polyomavirus-induced hemangiomas in rats [25] and hemangiosarcoma development in mice [26]. Also, CDV proved effective against cottontail rabbit papillomavirus in the domestic rabbit model [27]. We have recently shown that PLX5622 besides inhibition of tumor growth, intratumoral CDV administration had a beneficial effect on the pathology associated with the growth of cervical carcinoma cells in athymic nude mice as exhibited by a favorable effect on body weight gain, reduced splenomegaly and lower inflammatory state in animals that received the compoundversusthe placebo-treated group [24]. Furthermore, a whole genome gene expression profiling performed on CDV-treated malignant cells and normal keratinocytes allowed us to identify unique signatures in tumor cells compared PLX5622 to normal keratinocytes pointing to a selective drug effect [28]. Among the functions that were.