Cool V, Pirotte B, Gérard C, Dargent J L, Baudson N, Levivier M, Goldman S, Hildebrand J, Brotchi J, Velu T
IRIBHN, Erasme Hospital, Free University of Brussels (ULB), Belgium.
Hum Gene Ther. 1996 Mar 20;7(5):627-35. doi: 10.1089/hum.1996.7.5-627.
The transfer of the gene coding for the thymidine kinase of the herpes simplex virus (HSV-tk), followed by ganciclovir (GCV) administration, has been described for the treatment of several types of cancer, especially brain tumors. We further studied the efficacy of this approach by using the 9L rat gliosarcoma model, and cells producing 5 x 10(3), 9 x 10(4), 3 x 10(5) HSV-tk retroviral particles per milliliter. Their stereotactic injection in 9L brain tumors and GCV treatment did not result in any increase of survival. To study a model of optimal in vivo transduction, we examined the survival of rats with tumors growing from 9L cells that had been previously transduced in vitro with the HSV-tk vectors (9LTk cells). We observed that GCV administration cured 26% (n = 42) of the animals with 9LTk brain tumors, with most of the relapsing tumors remaining HSV-tk positive. The increase of either the dose or the duration of GCV treatment did not improve the survival rate. But the cerebral localization of the tumor played an important role, because this survival rate reached 67% (n = 12) when similar tumors were growing subcutaneously. No or only marginal antitumoral responses were induced by the presence of a selectable marker gene in the HSV-tk vectors. These results demonstrate that in vitro HSV-tk gene transfer in 9L tumor cells, but not in vivo gene transfer, followed by GCV treatment, is able to cure rats at a rate that is higher for subcutaneous than for intracerebral tumors.
单纯疱疹病毒胸苷激酶（HSV - tk）编码基因的转移，随后给予更昔洛韦（GCV），已被用于治疗多种类型的癌症，尤其是脑肿瘤。我们通过使用9L大鼠胶质肉瘤模型进一步研究了这种方法的疗效，所用细胞每毫升可产生5×10³、9×10⁴、3×10⁵个HSV - tk逆转录病毒颗粒。将它们立体定向注射到9L脑肿瘤中并进行GCV治疗，并未使生存率提高。为了研究最佳的体内转导模型，我们检测了由先前用HSV - tk载体（9LTk细胞）体外转导的9L细胞形成肿瘤的大鼠的生存率。我们观察到，给予GCV可使26%（n = 42）患有9LTk脑肿瘤的动物治愈，大多数复发肿瘤仍为HSV - tk阳性。增加GCV治疗的剂量或持续时间并未提高生存率。但肿瘤的脑内定位起着重要作用，因为当类似肿瘤在皮下生长时，生存率达到了67%（n = 12）。HSV - tk载体中存在选择标记基因未诱导出或仅诱导出边缘性的抗肿瘤反应。这些结果表明，9L肿瘤细胞的体外HSV - tk基因转移，而非体内基因转移，随后进行GCV治疗，能够治愈大鼠，皮下肿瘤的治愈率高于脑内肿瘤。
