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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 (SiHa  parental  ), which are HPV-16 positive, cidofovir-resistant cells (SiHa  CDV  ) 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  SiHa  CDV   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 SiHa  CDV   than by SiHa  parental   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 SiHa  CDV   compared to SiHa  parental  .    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.

Reduced tumorigenicity and pathogenicity of cervical carcinoma SiHa cells selected for resistance to cidofovir