PDF file - 508K, Figure S1. CDV treatment inhibits viral gene expression in a primary GBM, endogenously infected with HMCV. Figure S2. Control to viability of U87MG after infection with HCMV. Figure S3. Treatment with Cidofovir inhibits global HCMV gene expression. Figure S4. SF7796 primary derived GBM (used for in vivo experiments) is endogenously infected with HCMV. Figure S5. Treatment of normal and tumor cells with CDV in vitro. Figure S6. CDV treatment significantly suppresses the expression of HCMV in established human SF7796 xenografts in vivo.
ARTICLE ABSTRACT
Purpose: 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.Experimental Design: 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.Conclusion: 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. Clin Cancer Res; 19(23); 6473–83. ©2013 AACR.
