title: Reduced tumorigenicity and pathogenicity of cervical carcinoma SiHa cells selected for resistance to cidofovir.
abstract: BACKGROUND
  Insights into the mechanisms associated with chemotherapy-resistance are important for implementation of therapeutic strategies and for unraveling the mode of action of chemotherapeutics. Although cidofovir (CDV) has proven efficacious in the treatment of human papillomavirus (HPV)-induced proliferation, no studies concerning the development of resistance to CDV in HPV-positive tumor cells have been performed yet.
  
  
  METHODS
  From the cervical carcinoma SiHa cells (SiHaparental), which are HPV-16 positive, cidofovir-resistant cells (SiHaCDV) were selected, and differential gene expression profiles were analyzed by means of microarrays. We examined in vitro phenotyping of resistant cells compared to parental cells as well as tumorigenicity and pathogenicity in a mouse-xenograft model.
  
  
  RESULTS
  SiHaCDV had a resistant phenotype and a reduced growth both in vitro and in vivo. A markedly diminished inflammatory response (as measured by production of host- and tumor-derived cytokines and number of neutrophils and macrophages in spleen) was induced by SiHaCDV than by SiHaparental in the xenograft model. Gene expression profiling identified several genes with differential expression upon acquisition of CDV-resistance and pointed to a diminished induction of inflammatory response in SiHaCDV compared to SiHaparental.
  
  
  CONCLUSIONS
  Our results indicate that acquisition of resistance to cidofovir in SiHa cells is linked to reduced pathogenicity. The present study contributes to our understanding on the antiproliferative effects of CDV and on the mechanisms involved, the inflammatory response playing a central role.
authors: Tim
authors: T
authors: De Schutter
authors: Graciela
authors: G
authors: Andrei
authors: Dimitri
authors: D
authors: Topalis
authors: Sophie
authors: S
authors: Duraffour
authors: Tania
authors: T
authors: Mitera
authors: Joost
authors: J
authors: van den Oord
authors: Patrick
authors: P
authors: Matthys
authors: Rega Institute, Laboratory of Virology and Chemotherapy, KU Leuven, Leuven, Belgium. robert.snoeck@rega.kuleuven.be.
authors: Robert
authors: R
authors: Snoeck
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D024882:Drug Resistance, Viral; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation; D051379:Mice; D008819:Mice, Nude; D063065:Organophosphonates / Q000494:pharmacology*; D010641:Phenotype; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D063065:Organophosphonates; D003596:Cytosine; D000077404:Cidofovir