title: The combination of the antiviral agent cidofovir and anti-EGFR antibody cetuximab exerts an antiproliferative effect on HPV-positive cervical cancer cell lines' in-vitro and in-vivo xenografts.
abstract: Cervical carcinoma remains a leading cause of female mortality worldwide and over 90% of these tumors contain the human papillomavirus (HPV) genome. Cross-talk between the epidermal growth factor receptor and HPV has been reported and is implicated in tumor progression. The combination of the antiviral compound cidofovir (Cd) with the monoclonal antibody antiepidermal growth factor receptor cetuximab (Cx) was evaluated. HPV-positive (HeLa and Me180) and HPV-negative (C33A, H460 and A549) human cancer cell lines were incubated with Cd (1-10 μg/ml) and/or Cx (10 or 50 μg/ml). The antitumor effect of the combination was assessed in vitro using a clonogenic survival assay, cell cycle analysis, and phospho-H2AX level. Tumor growth delay was assayed in vivo using xenograft models. A pan-genomic analysis was carried out to identify the genes expressed differentially in untreated HeLa HPV-positive cells versus cells treated by the Cd-Cx combination. The Cd-Cx combination inhibited proliferation in all the cell lines tested. The association of Cd and Cx exerted a synergistic activity on HPV-positive but not on HPV-negative cell lines. The combination delayed tumor growth of HPV-positive tumors in vivo; however, no efficacy was reported on HPV-negative C33A xenografts nor on cell lines treated by single-drug therapy. The combination induced an S-phase arrest associated with an enhanced level of the double-strand break in Me180 and HeLa cell lines. Gene profiling assays showed a significant differential modulation of genes in HeLa cell lines treated with the combination involving the EGR-1 transcription factor. The current data support a synergistic antiproliferative action of the Cd-Cx combination on HPV-related cervical tumors.
authors.affiliation: INSERM U1030, Molecular Radiotherapy, Paris XI University, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Deberne
authors.forename: Antonin
authors.initials: A
authors.lastname: Levy
authors.forename: Michele
authors.initials: M
authors.lastname: Mondini
authors.forename: Philippe
authors.initials: P
authors.lastname: Dessen
authors.forename: Sonia
authors.initials: S
authors.lastname: Vivet
authors.forename: Ajitha
authors.initials: A
authors.lastname: Supiramaniam
authors.forename: Marie-Catherine
authors.initials: MC
authors.lastname: Vozenin
authors.forename: Eric
authors.initials: E
authors.lastname: Deutsch
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D000068818:Cetuximab; D000077404:Cidofovir; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D063065:Organophosphonates / Q000008:administration & dosage / Q000494:pharmacology*; D027383:Papillomaviridae / Q000187:drug effects*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D063065:Organophosphonates; D003596:Cytosine; D000077404:Cidofovir; D000068818:Cetuximab