Namba H, Tagawa M, Iwadate Y, Kimura M, Sueyoshi K, Sakiyama S
Division of Neurological Surgery, Chiba Cancer Center Hospital, Japan.
Hum Gene Ther. 1998 Jan 1;9(1):5-11. doi: 10.1089/hum.1998.9.1-5.
Transfer of the herpes simplex virus-thymidine kinase (HSV-tk) gene, followed by administration of ganciclovir (GCV), generates the "bystander effect," in which HSV-tk-negative wild-type cells, as well as HSV-tk-expressing cells, are killed by GCV. To eradicate an intracranial tumor by this bystander effect, we injected the tumor cells transduced with the HSV-tk gene (TK cells) in the vicinity of the preimplanted wild-type tumor and then administered GCV. Wild-type 9L-gliosarcoma cells (1 x 10[5]) were implanted into the brain of syngeneic Fisher rats. On the next day, rats were injected with TK cells (1 x 10(5) or 3 x 10[5]) or medium alone at the same brain coordinate and then treated with GCV or saline. Administration of GCV significantly prolonged the survival of the rats injected with TK cells compared with that injected with medium alone (p < 0.01). Reduction in tumor size and retardation of tumor growth were observed by serial magnetic resonance imaging in the rats that received the combination of TK cells and GCV. The results show that the bystander effect is also achieved in vivo even when TK cells and wild-type cells are not simultaneously implanted. This treatment modality circumvents potential risks accompanied with in vivo gene transfer. Because there remained substantially no HSV-tk-positive cells in the recurrent tumors, this modality offers a "safe" therapeutic strategy against human malignant gliomas.
单纯疱疹病毒胸苷激酶（HSV-tk）基因的转移，随后给予更昔洛韦（GCV），会产生“旁观者效应”，即HSV-tk阴性的野生型细胞以及表达HSV-tk的细胞都会被GCV杀死。为了通过这种旁观者效应根除颅内肿瘤，我们将转导了HSV-tk基因的肿瘤细胞（TK细胞）注射到预先植入的野生型肿瘤附近，然后给予GCV。将野生型9L-胶质肉瘤细胞（1×10⁵）植入同基因Fisher大鼠的脑内。第二天，在相同脑坐标处给大鼠注射TK细胞（1×10⁵或3×10⁵）或仅注射培养基，然后用GCV或生理盐水进行处理。与仅注射培养基的大鼠相比，给予GCV显著延长了注射TK细胞的大鼠的生存期（p<0.01）。通过连续磁共振成像观察到，接受TK细胞和GCV联合治疗的大鼠肿瘤体积减小且肿瘤生长受到抑制。结果表明，即使TK细胞和野生型细胞不同时植入，体内也能实现旁观者效应。这种治疗方式规避了体内基因转移所伴随的潜在风险。由于复发性肿瘤中基本上没有HSV-tk阳性细胞，这种方式为治疗人类恶性胶质瘤提供了一种“安全”策略。
