title: Cidofovir: a novel antitumor agent for glioblastoma.
abstract: OBJECTIVE
  Cidofovir (CDV) is an U.S. Food and Drug Administration (FDA)-approved nucleoside antiviral agent used to treat severe human cytomegalovirus (HCMV) infection. Until now, no clear therapeutic effects of CDV have been reported outside of the setting of viral infection, including a potential role for CDV as an antineoplastic agent for the treatment of brain tumors.
  
  
  METHODS
  We investigated the cytotoxicity of CDV against the glioblastoma cells, U87MG and primary SF7796, both in vitro and in vivo, using an intracranial xenograft model. Standard techniques for cell culturing, immunohistochemistry, Western blotting, and real-time PCR were employed. The survival of athymic mice (n = 8-10 per group) bearing glioblastoma tumors, treated with CDV alone or in combination with radiation, was analyzed by the Kaplan-Meier method and evaluated with a two-sided log-rank test.
  
  
  RESULTS
  CDV possesses potent antineoplastic activity against HCMV-infected glioblastoma cells. This activity is associated with the inhibition of HCMV gene expression and with activation of cellular apoptosis. Surprisingly, we also determined that CDV induces glioblastoma cell death in the absence of HCMV infection. CDV is incorporated into tumor cell DNA, which promotes double-stranded DNA breaks and induces apoptosis. In the setting of ionizing radiotherapy, the standard of care for glioblastoma in humans, CDV augments radiation-induced DNA damage and, further, promotes tumor cell death. Combination therapy with CDV and radiotherapy significantly extended the survival of mice bearing intracranial glioblastoma tumors.
  
  
  CONCLUSIONS
  We have identified a novel antiglioma property of the FDA-approved drug CDV, which heightens the cytotoxic effect of radiotherapy, the standard of care therapy for glioblastoma.
authors.affiliation: Authors' Affiliations: California Pacific Medical Center Research Institute; and Department of Neurological Surgery, Helen Diller Cancer Center, University of California, San Francisco, California, Swedish Neuroscience Institute, Seattle, WA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Hadaczek
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ozawa
authors.forename: Liliana
authors.initials: L
authors.lastname: Soroceanu
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Lisa
authors.initials: L
authors.lastname: Matlaf
authors.forename: Eric
authors.initials: E
authors.lastname: Singer
authors.forename: Estefania
authors.initials: E
authors.lastname: Fiallos
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.forename: Charles S
authors.initials: CS
authors.lastname: Cobbs
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D053903:DNA Breaks, Double-Stranded; D004261:DNA Replication; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D063065:Organophosphonates / Q000378:metabolism / Q000494:pharmacology*; D018874:Spheroids, Cellular / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D063065:Organophosphonates; D003596:Cytosine; D000077404:Cidofovir