Eradication of hepatocellular carcinoma xenografts by radiolabelled, lipiodol-inducible gene therapy
Eradication of hepatocellular carcinoma xenografts by radiolabelled, lipiodol-inducible gene therapy
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DOI：
10.1038/sj.gt.3302531
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发表时间：
2005-11-01
期刊：
影响因子：
5.1
通讯作者：
Yamashita, S
中科院分区：
文献类型：
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作者：
Kawashita, Y;Ohtsuru, A;Yamashita, S
早期生长反应-1（Egr-1）基因的启动子区域已被证明可被外部辐射激活，从而使选择性杀瘤作用成为可能。先前的一项实验表明，Egr-1启动子可以通过使用放射性同位素的内部辐射和外部辐射激活。使用I-131脂醇（I-131- lip）内照射已被确定为治疗肝癌最有效的策略之一。我们将Egr-1启动子连接到单纯疱疹病毒胸苷激酶（HSV-TK）基因上，并研究其与I-131-Lip联合治疗肝癌的疗效。荧光素酶测定显示，egr -1启动子活性在肝癌组织标本中以i -131剂量依赖性方式显著增加，而在其他器官中观察到该活性增加不到两倍。此外，碘-131的放射性在肿瘤组织标本中选择性积累。采用日本血凝病毒(HVJ)-脂质体载体转染裸鼠皮下肝癌异种移植物，研究fegrtk /更昔洛韦（GCV）基因在体内的治疗效果。所有转染egtk的肿瘤在治疗后42天联合I-131-Lip和GCV治疗后，肿瘤完全消退，无任何副作用（n = 8）。相比之下，所有对照小鼠（n = 10）的肿瘤继续生长。此外，联合治疗组血清甲胎蛋白水平下降，而对照组升高。综上所述，这些数据表明，基于Egr-1启动子的基因治疗联合内放疗对肝癌肿瘤具有选择性作用，同时体内疗效也有所提高。因此，这种联合疗法可能是一种有效的人类肝癌基因疗法，即使在晚期多发性病例中也是如此。
The promoter region of the early-growth response-1(Egr-1) gene has been shown to be activated by external radiation, thus making a selective tumoricidal effect possible. A previous experiment showed that the Egr-1 promoter can be activated by internal radiation using radioisotopes as well as external radiation. Internal radiation using I-131 lipiodol (I-131-Lip) has been established as one of the most useful therapeutic strategies against hepatoma. We herein linked the Egr-1 promoter to the herpes simplex virus-thymidine kinase (HSV-TK) gene, and investigated its efficacy in hepatoma gene therapy in combination with I-131-Lip. A luciferase assay showed the Egr-1-promoter activity to be markedly increased in hepatoma tissue specimens in an I-131-dosedependent manner, whereas a less than two-fold increase in this activity was observed in other organs. In addition, the radioactivity derived from I-131 was selectively accumulated in the tumor tissue specimens. To examine the efficacy ofEgrTK/ganciclovir (GCV) gene therapy in vivo, subcutaneous hepatoma xenografts in nude mice were transfected using a hemagglutinating virus of Japan (HVJ)-liposome vector. Complete tumor regression was observed in all the EgrTK-transfected tumors following combination treatment with I-131-Lip and GCV 42 days after treatment without any side effects (n = 8). In contrast, the tumors continued to grow in all control mice (n = 10). Furthermore, the serum alpha-fetoprotein levels decreased in the combination therapy group, while they increased in the controls. In conclusion, these data indicate that Egr-1 promoter-based gene therapy combined with internal radiation has a selective effect on hepatoma tumors while also showing an improved in vivo efficacy. This combination therapy might, therefore, be an effective human hepatoma gene therapy, even in advanced multiple cases.