Severe hepatic dysfunction after adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene and ganciclovir administration
Severe hepatic dysfunction after adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene and ganciclovir administration
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DOI：
10.1038/sj.gt.3300637
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发表时间：
1998-04-01
期刊：
影响因子：
5.1
通讯作者：
Hoeben, RC
中科院分区：
文献类型：
--
作者：
van der Eb, MM;Cramer, SJ;Hoeben, RC
使用所谓的“自杀”基因来激活前药在几种实体肿瘤类型的动物模型中是有效的，目前正在进行I期和II期临床试验。我们利用腺病毒载体（Ad）转移和表达单纯疱疹病毒胸苷激酶（HSVtk）基因，使大鼠结直肠肝转移对抗疱疹药物更昔洛韦（GCV）敏感。在大鼠结肠肿瘤细胞原位转导和门脉内给药载体Ad.CMV.TK后，检测了该酶-前药联合用药的疗效和毒性。我们的研究结果证明了该方法的有效性，但也揭示了HSVtk的肝脏表达，无论是在荷瘤大鼠还是无瘤大鼠中，在GCV给药后都会引起严重的肝功能障碍和死亡。这些数据表明，与通常的假设相反，通常非有丝分裂组织也可以受到腺病毒介导的HSVtk转移和随后的GCV治疗的影响。考虑到系统给药的2型和5型腺病毒衍生载体的嗜肝性，在所有涉及HSVtk基因腺病毒载体的基因治疗试验中，监测患者的肝功能是必要的。
The use of so-called 'suicide' genes to activate prodrugs has been effective in animal models for several solid tumor types and is now in phase I and II clinical trials. We have exploited adenovirus vectors (Ad) for transfer and expression of the herpes simplex virus thymidine kinase (HSVtk) gene to render rat colorectal liver metastases sensitive to the anti-herpetic agent ganciclovir (GCV). The efficacy and toxicity of this enzyme-prodrug combination were tested after in situ transduction of rat colorectal tumor cells and after intraportal administration of the vector Ad.CMV.TK. Our results demonstrate the validity of the approach but reveal that hepatic expression of HSVtk, both in tumor bearing and tumor-free rats, provokes severe liver dysfunction and mortality upon GCV administration. These data show, that in contrast to the common assumption, normally non-mitotic tissues too, can be affected by adenovirus-mediated HSVtk transfer and subsequent GCV treatment. Given the hepatotropic nature of systemically administered adenovirus type 2- and 5-derived vectors, it will be essential to monitor liver functions of patients included in all gene therapy trials involving adenoviral vectors with the HSVtk gene.