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ET-67SUICIDE GENE THERAPY FOR GLIOMA USING MULTILINEAGE-DEFFERENTIATING STRESS ENDURING (MUSE) CELLS

机译:ET-67自杀基因胶体细胞治疗多发性分化(小鼠)细胞的胶质瘤

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摘要

INTRODUCTION: We have been investigating cell-based glioma gene therapy using various kinds of stem cells transduced with the herpes simplex virus thymidine kinase gene (HSVtk). In our previous study, we used SSEA3/CD105 double-positive multilineage-differentiating stress-enduring (Muse) cells transduced with HSVtk (Muse-tk cells) as the vehicle for HSVtk/ganciclovir (GCV) gene therapy. We demonstrated a potent in vitro tumoricidal bystander effect for various glioma cells. In the present study, we examined the in vivo bystander effect between U87 human glioma cells and human Muse-tk cells. METHODS: Muse-tk cells were obtained by lentiviral transduction of HSVtk in human Muse cells. U87 cells transduced with the luciferase gene were used for the brain tumor model, in which tumor volume could be measured using a bioluminescence imaging system (IVIS 200). Nude mice were intracranially co-implanted at Muse-tk:U87 cell ratios of 1:4, 1:8, and 1:16 (U87 cell number: 1 × 105); GCV was intraperitoneally administered (100 mg/kg/day) for 10 days. RESULTS: Luminescence intensity progressively increased in the control mice implanted with U87 alone with or without GCV treatment, and in those implanted with Muse-tk and U87 but not treated with GCV. All control mice died because of the tumor by Day 51 post tumor implantation (no difference among the control groups). In contrast, no luminescence was observed in the mice implanted with Muse-tk and U87 (Muse-tk:U87 cell ratios of 1:4 and 1:8) from Day 14 onward. Almost all mice survived longer than 100 days and no mouse died as a result of the tumor. CONCLUSIONS: There was a potent in vivo bystander effect between human glioma and Muse-tk cells. The results of the present study suggest that HSVtk/GCV gene therapy using Muse-tk is a promising treatment strategy for malignant glioma.
机译:简介:我们一直在研究使用单纯疱疹病毒胸苷激酶基因(HSVtk)转导的各种干细胞进行的基于细胞的神经胶质瘤基因治疗。在我们以前的研究中,我们将SSEA3 / CD105双阳性多系分化应激持续性(Muse)细胞与HSVtk(Muse-tk细胞)转导,作为HSVtk /更昔洛韦(GCV)基因治疗的载体。我们证明了对各种神经胶质瘤细胞有效的体外肿瘤旁观者效应。在本研究中,我们研究了U87人神经胶质瘤细胞和人Muse-tk细胞之间的体内旁观者效应。方法:通过慢病毒转染人Muse细胞中的HSVtk获得Muse-tk细胞。使用萤光素酶基因转导的U87细胞用于脑肿瘤模型,其中肿瘤体积可使用生物发光成像系统(IVIS 200)进行测量。裸鼠颅内共植入Muse-tk:U87细胞比例为1:4、1:8和1:16(U87细胞数:1×10 5 );腹膜内给予GCV(100 mg / kg /天),持续10天。结果:单独或不使用GCV治疗的,单独植入U87的对照组小鼠以及未进行GCV的Muse-tk和U87植入的对照组小鼠的发光强度逐渐增加。在肿瘤植入后第51天,所有对照小鼠均因肿瘤而死亡(对照组之间无差异)。相反,从第14天开始,在植入Muse-tk和U87的小鼠中未观察到发光(Muse-tk:U87细胞比率为1:4和1:8)。几乎所有小鼠都存活超过100天,并且没有小鼠因肿瘤而死亡。结论:人脑胶质瘤和Muse-tk细胞之间存在有效的旁观者效应。本研究的结果表明,使用Muse-tk的HSVtk / GCV基因治疗是恶性神经胶质瘤的一种有前途的治疗策略。

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