Agard C, Ligeza C, Dupas B, Izembart A, El Kouri C, Moullier P, Ferry N
Laboratoire de Thérapie Génique, CHU Hotel-Dieu, Nantes, France.
Cancer Gene Ther. 2001 Feb;8(2):128-36. doi: 10.1038/sj.cgt.7700281.
Gene transfer of the herpes simplex virus thymidine kinase (HSV-tk) gene sensitizes tumor cells to the toxic effect of ganciclovir (GCV). The toxic effect of GCV extends to nontransduced surrounding cells by a metabolic process known as the bystander effect. A distant bystander effect, which involves anatomically separated tumors, has been reported in vivo. Our aim was to evaluate and characterize such distant effect in a rat model of colorectal tumors implanted in the liver using adenovirus to carry the HSV-tk gene. Two colorectal tumors were implanted in two distinct liver lobes of the liver. One of the tumor was transduced with an adenoviral vector containing HSV-tk gene. The volumes of the tumors were monitored after GCV treatment. Implication of the immune system was studied histologically and after in vivo manipulations. After GCV administration, the nontransduced distant tumor regressed partially or completely in the experimental group. Immunohistochemical analysis revealed the presence of CD8+ lymphocytes in the distant lesion. HSV-tk/GCV-induced immune response against tumors was evidenced by an adoptive transfer assay (Winn assay) and the distant bystander effect was blunted after CD8+ lymphocytes depletion. However, the survival rates for treated animals were not improved. These findings demonstrate that an immune-mediated effective distant bystander effect can be obtained after limited adenoviral-mediated transfer of the HSV-tk gene.
单纯疱疹病毒胸苷激酶（HSV-tk）基因的基因转移使肿瘤细胞对更昔洛韦（GCV）的毒性作用敏感。GCV的毒性作用通过一种称为旁观者效应的代谢过程扩展到未转导的周围细胞。体内已报道了涉及解剖学上分离的肿瘤的远距离旁观者效应。我们的目的是在使用腺病毒携带HSV-tk基因的肝内植入结直肠癌大鼠模型中评估和表征这种远距离效应。在肝脏的两个不同肝叶中植入两个结直肠癌肿瘤。其中一个肿瘤用含有HSV-tk基因的腺病毒载体进行转导。在GCV治疗后监测肿瘤体积。通过组织学和体内操作后研究免疫系统的影响。给予GCV后，实验组中未转导的远距离肿瘤部分或完全消退。免疫组织化学分析显示远距离病变中存在CD8 +淋巴细胞。过继转移试验（Winn试验）证明了HSV-tk/GCV诱导的抗肿瘤免疫反应，并且在CD8 +淋巴细胞耗竭后远距离旁观者效应减弱。然而，治疗动物的存活率没有提高。这些发现表明，在腺病毒介导的HSV-tk基因有限转移后，可以获得免疫介导的有效的远距离旁观者效应。
