Cidofovir: A Novel Antitumor Agent for Glioblastoma
Menée sur des lignées cellulaires et à l'aide de xénogreffes de glioblastome, cette étude évalue l'activité antitumorale du cidofovir, un agent autorisé pour le traitement d'une infection au cytomégalovirus humain
Purpose: Cidofovir (CDV) is a 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. Experimental Design: We investigated CDV cytotoxicity against glioblastoma (GBM) cells, U87MG and primary SF7796, 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 GBM 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 GBM cells. This activity is associated with inhibition of HCMV gene expression and with activation of cellular apoptosis. Surprisingly, we also determined that CDV induces GBM 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 radiation treatment (RT), the standard of care for GBM in humans, CDV augments radiation-induced DNA damage and further promotes tumor cell death. Combined CDV and RT treatment significantly extended the survival of mice bearing intracranial GBM tumors. Conclusions: We have identified a novel anti-glioma property of the FDA approved drug CDV, which heightens RT cytotoxic effect, the standard of care therapy for GBM.