Cidofovir: a novel antitumor agent for glioblastoma.
Cidofovir: a novel antitumor agent for glioblastoma.
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DOI：
10.1158/1078-0432.ccr-13-1121
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发表时间：
2013-12-01
期刊：
影响因子：
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通讯作者：
Cobbs CS
中科院分区：
文献类型：
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作者：
Hadaczek P;Ozawa T;Soroceanu L;Yoshida Y;Matlaf L;Singer E;Fiallos E;James CD;Cobbs CS
西多福韦（CDV）是FDA批准的核苷类抗病毒药，用于治疗严重的人巨细胞病毒（HCMV）感染。到目前为止，没有明确的治疗效果的CDV已报告以外的病毒感染的设置，包括CDV作为一个潜在的作用，治疗脑肿瘤的抗肿瘤剂。我们研究了CDV对胶质母细胞瘤（GBM）细胞，U87 MG和原代SF 7796，在体外和体内，使用颅内异种移植模型的细胞毒性。采用细胞培养、免疫组织化学、Western印迹和实时PCR的标准技术。通过Kaplan-Meier方法分析用CDV单独或与放射组合治疗的携带GBM肿瘤的无胸腺小鼠（每组n= 8-10）的存活率，并用双侧对数秩检验进行评价。CDV对HCMV感染的GBM细胞具有强的抗病毒活性。这种活性与HCMV基因表达的抑制和细胞凋亡的激活有关。令人惊讶的是，我们还确定CDV在没有HCMV感染的情况下诱导GBM细胞死亡。CDV被掺入肿瘤细胞DNA中，促进双链DNA断裂并诱导凋亡。在电离辐射治疗（RT）（人类GBM的标准治疗）的背景下，CDV增强了辐射诱导的DNA损伤并进一步促进肿瘤细胞死亡。联合CDV和RT治疗显著延长了携带颅内GBM肿瘤的小鼠的存活期。我们已经鉴定了FDA批准的药物CDV的新的抗神经胶质瘤特性，其提高了RT细胞毒性作用，这是GBM的护理疗法的标准。
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. 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. 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. 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.