Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.
Gene Ther. 2010 Nov;17(11):1363-71. doi: 10.1038/gt.2010.88. Epub 2010 Jun 3.
Glioblastoma multiforme (GBM) is one of the most formidable brain tumors with a mean survival period of approximately 12 months. To date, a combination of radiotherapy and chemotherapy with an oral alkylating agent, temozolomide (TMZ), has been used as first-line therapy for glioma. However, the efficacy of chemotherapy for treating GBM is very limited; this is partly because of the high activity levels of the DNA repair protein O⁶-methylguanine-DNA methyltransferase (MGMT) in tumor cells, which creates a resistant phenotype by blunting the therapeutic effect of alkylating agents. Thus, MGMT may be an important determinant of treatment failure and should be considered as a suitable target for intervention, in an effort to improve the therapeutic efficacy of TMZ. In this study, we showed that small-interfering RNA (siRNA)-based downregulation of MGMT could enhance the chemosensitivity of malignant gliomas against TMZ. Notably, TMZ-resistant glioma-initiating cells with increased DNA repair and drug efflux capabilities could be efficiently transduced with MGMT-siRNA by using a novel liposome, LipoTrust. Accordingly, such transduced glioma-initiating cells could be sensitized to TMZ in both in vitro and in vivo tumor models. Taken together, this study provides an experimental basis for the clinical use of such therapeutic combinations.
多形性胶质母细胞瘤（GBM）是最具挑战性的脑肿瘤之一，平均生存周期约为 12 个月。迄今为止，放疗和化疗联合口服烷化剂替莫唑胺（TMZ）已被用作治疗神经胶质瘤的一线疗法。然而，化疗治疗 GBM 的疗效非常有限；部分原因是肿瘤细胞中 DNA 修复蛋白 O⁶-甲基鸟嘌呤-DNA 甲基转移酶（MGMT）的高活性水平，通过削弱烷化剂的治疗效果，产生耐药表型。因此，MGMT 可能是治疗失败的重要决定因素，应被视为干预的合适靶点，以提高 TMZ 的治疗效果。在这项研究中，我们表明，基于小干扰 RNA（siRNA）的 MGMT 下调可以增强恶性胶质瘤对 TMZ 的化疗敏感性。值得注意的是，具有增强的 DNA 修复和药物外排能力的 TMZ 耐药神经胶质瘤起始细胞可以通过新型脂质体 LipoTrust 有效地转导 MGMT-siRNA。因此，在体外和体内肿瘤模型中，这种转导的神经胶质瘤起始细胞可以对 TMZ 敏感。总之，这项研究为临床应用这种治疗组合提供了实验依据。
