Midkine promoter-based adenoviral vector gene delivery for pediatric solid tumors.
Midkine promoter-based adenoviral vector gene delivery for pediatric solid tumors.
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发表时间：
2000-08
期刊：
影响因子：
11.2
通讯作者：
Y. Adachi;P. Reynolds;M. Yamamoto;W. E. Grizzle;K. Overturf;S. Matsubara;T. Muramatsu;D. Curiel-D.-Curi
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文献类型：
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作者：
Y. Adachi;P. Reynolds;M. Yamamoto;W. E. Grizzle;K. Overturf;S. Matsubara;T. Muramatsu;D. Curiel-D.-Curi
因此，开发一种能够在肿瘤细胞中表达治疗性基因的系统对于肿瘤基因治疗具有重要的意义。中期因子（MK）是一种新发现的肝素结合生长因子，在视黄酸诱导胚胎癌细胞分化的早期阶段瞬时表达。据报道，许多人类恶性肿瘤表达高水平的MK mRNA或蛋白。然而，在人或小鼠肝脏中未检测到MK表达。MK的这些有趣的特征使我们将MK启动子作为肿瘤特异性基因表达的候选者进行研究。因此，我们开发了新的重组腺病毒（Ad）载体含有荧光素酶报告基因（AdMKLuc）或单纯疱疹病毒胸苷激酶基因（AdMKTK）的人MK启动子的控制下。AdMKLuc在肾母细胞瘤（G-401）和神经母细胞瘤（SK-N-SH）细胞系中获得相对高的活性。此外，AdMKTK在这些相同的细胞系中诱导响应于更昔洛韦（GCV）的显著细胞死亡。相反，与巨细胞病毒启动子相比，在小鼠肝脏中观察到MK启动子的活性非常低。重要的是，AdMKTK + GCV不诱导肝毒性，而用AdCMVTK + GCV处理观察到实质性毒性。基于这些发现，我们得出结论，MK启动子是威尔姆斯瘤或神经母细胞瘤的候选肿瘤特异性启动子。
It is important to develop a system to express therapeutic genes in tumor cells with sufficient selectivity for cancer gene therapy. Midkine (MK) is a newly identified heparin-binding growth factor that is transiently expressed in the early stages of retinoic acid-induced differentiation of embryonal carcinoma cells. It has been reported that many human malignant tumors express high levels of MK mRNA or protein. However, no MK expression is detected in human or mouse liver. These interesting features of MK led us to examine the MK promoter as a candidate for tumor-specific gene expression. We thus developed new recombinant adenoviral (Ad) vectors containing either luciferase reporter gene (AdMKLuc) or herpes simplex thymidine kinase gene (AdMKTK) under the control of the human MK promoter. AdMKLuc achieved relatively high activity in Wilms' tumor (G-401) and neuroblastoma (SK-N-SH) cell lines. In addition, AdMKTK induced marked cell death in response to ganciclovir (GCV) in these same lines. Conversely, very low activity of the MK promoter was observed in mouse liver in vivo compared with the cytomegalovirus promoter. Importantly, AdMKTK + GCV did not induce liver toxicity, whereas substantial toxicity was seen with AdCMVTK + GCV treatment. On the basis of these findings, we conclude that the MK promoter is a candidate tumor-specific promoter for Wilms' tumor or neuroblastoma.