TY - JOUR
T1 - Cidofovir
T2 - A novel antitumor agent for glioblastoma
AU - Hadaczek, Piotr
AU - Ozawa, Tomoko
AU - Soroceanu, Liliana
AU - Yoshida, Yasuyuki
AU - Matlaf, Lisa
AU - Singer, Eric
AU - Fiallos, Estefania
AU - James, C. David
AU - Cobbs, Charles S.
N1 - Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2013/12/1
Y1 - 2013/12/1
N2 - 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 CD Valone 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.
AB - 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 CD Valone 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.
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U2 - 10.1158/1078-0432.CCR-13-1121
DO - 10.1158/1078-0432.CCR-13-1121
M3 - Article
C2 - 24170543
AN - SCOPUS:84890285277
VL - 19
SP - 6473
EP - 6483
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 23
ER -