Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Department of Biology, Lund University, Lund, Sweden.
Cancer Gene Ther. 2015 Apr;22(3):130-7. doi: 10.1038/cgt.2014.76. Epub 2015 Jan 23.
Malignant gliomas (MGs) are the most common malignant primary brain tumors with a short life estimate accompanied by a marked reduction in the quality of life. Herpes Simplex virus-1 thymidine kinase ganciclovir (HSV-TK/GCV) system is the best characterized enzyme prodrug therapy in use. However, lipophobicity of GCV and low enzymatic activity of HSV-TK reduce the treatment efficacy. Tomato TK (ToTK) has shown high activity in combination with its specific substrate azidothymidine (AZT). The aim of this study was to evaluate whether ToTK/AZT could be used as an alternative to HSV-TK/GCV therapy. Both treatments demonstrated cytotoxicity in human MG cells in vitro. In vivo, both treatments decreased tumor growth and tumors were smaller in comparison with controls in mouse orthotopic MG model. Survival of ToTK/AZT-treated mice was significantly increased compared with control mice (*P<0.05) but not as compared with HSV-TK/GCV-treated mice. No significant differences were observed in clinical chemistry safety analyses. We conclude that both treatments showed a beneficial treatment response in comparison to controls on tumor growth and ToTK/AZT also on survival. There were no significant differences between these treatments. Therefore ToTK/AZT could be considered as an alternative treatment option for MG because of its favorable therapeutic characteristics.
恶性神经胶质瘤（MGs）是最常见的原发性恶性脑肿瘤，患者预期寿命短，生活质量显著下降。单纯疱疹病毒-1 胸苷激酶更昔洛韦（HSV-TK/GCV）系统是目前应用最广泛的酶前药治疗方法。然而，更昔洛韦的亲脂性差和 HSV-TK 的酶活性低降低了治疗效果。番茄胸苷激酶（ToTK）与它的特异性底物叠氮胸苷（AZT）结合显示出很高的活性。本研究旨在评估番茄胸苷激酶/叠氮胸苷（ToTK/AZT）是否可替代 HSV-TK/GCV 治疗。两种治疗方法均在体外对人 MG 细胞表现出细胞毒性。在体内，与对照组相比，两种治疗方法均能降低荷瘤小鼠的肿瘤生长速度，使肿瘤体积减小。与对照组相比，ToTK/AZT 治疗组的小鼠存活率显著提高（*P<0.05），但与 HSV-TK/GCV 治疗组相比无显著差异。临床化学安全性分析未观察到显著差异。我们的结论是，与对照组相比，两种治疗方法在肿瘤生长方面都显示出有益的治疗效果，ToTK/AZT 还能提高存活率。这两种治疗方法之间没有显著差异。因此，由于其良好的治疗特性，番茄胸苷激酶/叠氮胸苷（ToTK/AZT）可被视为治疗 MG 的一种替代治疗选择。
