van der Eb M M, Cramer S J, Vergouwe Y, Schagen F H, van Krieken J H, van der Eb A J, Borel Rinkes I H, van de Velde C J, Hoeben R C
Department of Surgery, Leiden University Medical Center, The Netherlands.
Gene Ther. 1998 Apr;5(4):451-8. doi: 10.1038/sj.gt.3300637.
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 in 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.
使用所谓的“自杀”基因来激活前体药物在多种实体瘤类型的动物模型中已取得成效，目前正处于I期和II期临床试验阶段。我们利用腺病毒载体（Ad）来转移和表达单纯疱疹病毒胸苷激酶（HSVtk）基因，以使大鼠结直肠癌肝转移灶对抗疱疹药物更昔洛韦（GCV）敏感。在大鼠结直肠肿瘤细胞原位转导以及门静脉注射载体Ad.CMV.TK后，对这种酶-前体药物组合的疗效和毒性进行了测试。我们的结果证明了该方法的有效性，但也揭示出，无论是在荷瘤大鼠还是无瘤大鼠中，HSVtk在肝脏中的表达都会在给予GCV后引发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，正常情况下不进行有丝分裂的组织也会受到腺病毒介导的HSVtk转移及随后GCV治疗的影响。鉴于全身给药的2型和5型腺病毒载体具有嗜肝性，在所有涉及携带HSVtk基因的腺病毒载体的基因治疗试验中，监测患者的肝功能将至关重要。
