Human adipose tissue-derived mesenchymal stem cells expressing yeast cytosinedeaminase::uracil phosphoribosyltransferase inhibit intracerebral rat glioblastoma
Human adipose tissue-derived mesenchymal stem cells expressing yeast cytosinedeaminase::uracil phosphoribosyltransferase inhibit intracerebral rat glioblastoma
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DOI：
10.1002/ijc.26278
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发表时间：
2012-05-15
影响因子：
6.4
通讯作者：
Altaner, Cestmir
中科院分区：
文献类型：
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作者：
Altanerova, Veronika;Cihova, Marina;Altaner, Cestmir
以肿瘤为靶点的间充质干细胞(MSCs)用于肿瘤前药基因治疗是一种诱人的工具，可直接在肿瘤内激活前药，从而避免全身毒性。在本研究中，我们检测了表达自杀基因胞嘧啶脱氨酶：尿嘧啶磷酸核糖转移酶的人脂肪组织来源的MSCs治疗大鼠脑内C6胶质母细胞瘤的可行性和有效性。实验旨在通过将治疗性干细胞直接注射到肿瘤中来模拟未来高级别胶质母细胞瘤治疗的临床应用条件。经5-氟胞嘧啶(5-FC)治疗后，基因修饰的治疗性干细胞在远距离颅内注射后仍具有肿瘤趋向性，并能有效地抑制胶质母细胞瘤的生长。C6细胞和治疗性干细胞与延迟的5-FC治疗联合应用，以治疗性干细胞剂量依赖的方式提高存活率，并在相当数量的动物中诱导肿瘤完全消退。用渗透压泵持续脑室注射5-FC减少了相同疗效所需的前药剂量，并随着治疗性干细胞的重复应用而延长了生存时间。脑内注射治疗性干细胞和5-FC治疗没有显示任何可检测到的不良反应。结果支持了开始治疗高级别脑瘤的临床研究的论点。
Prodrug cancer gene therapy by mesenchymal stem cells (MSCs) targeted to tumors represents an attractive tool to activate prodrugs directly within the tumor mass, thus avoiding systemic toxicity. In this study, we tested the feasibility and efficacy of human adipose tissue-derived MSCs, engineered to express the suicide gene cytosine deaminase::uracil phosphoribosyltransferase to treat intracranial rat C6 glioblastoma. Experiments were designed to simulate conditions of future clinical application for high-grade glioblastoma therapy by direct injections of therapeutic stem cells into tumor. We demonstrated that genetically modified therapeutic stem cells still have the tumor tropism when injected to a distant intracranial site and effectively inhibited glioblastoma growth after 5-fluorocytosine (5-FC) therapy. Coadministration of C6 cells and therapeutic stem cells with delayed 5-FC therapy improved the survival in a therapeutic stem cell dose-dependent manner and induced complete tumor regression in a significant number of animals. Continuous intracerebroventricular delivery of 5-FC using osmotic pump reduced the dose of prodrug required for the same therapeutic effect, and along with repeated administration of therapeutic stem cells increased the survival time. Intracerebral injection of therapeutic stem cells and treatment with 5-FC did not show any detectable adverse effects. Results support the arguments to begin clinical studies for treatment of high-grade brain tumors.