Miyatake S, Martuza R L, Rabkin S D
Department of Neurosurgery, Georgetown University Medical Center, Washington, DC 20007, USA.
Cancer Gene Ther. 1997 Jul-Aug;4(4):222-8.
Viral vectors used for cancer gene therapy have usually been either replication-incompetent vectors expressing a gene product that leads to the destruction of the tumor or replication-competent vectors that are inherently cytotoxic to the tumor cells. We have sought to combine the attributes of these different approaches using a defective herpes simplex virus (HSV) vector that consists of a defective particle, containing tandem repeats of the HSV thymidine kinase (TK) gene, and a replication-competent, non-neurovirulent HSV mutant as a helper virus. HSV-TK activity in defective vector-infected cells was significantly greater than that in helper virus-infected cells which contained a single copy of HSV-TK. Infection of cells with this defective vector renders them, as well as surrounding uninfected cells, sensitive to killing by ganciclovir. Ganciclovir treatment of C57BL/6 mice bearing TK-defective vector/helper virus-infected subcutaneous GL261 gliomas resulted in significantly decreased tumor size.
用于癌症基因治疗的病毒载体通常要么是表达导致肿瘤破坏的基因产物的复制缺陷型载体，要么是对肿瘤细胞具有固有细胞毒性的复制型载体。我们试图利用一种缺陷型单纯疱疹病毒（HSV）载体来结合这些不同方法的特性，该载体由一个缺陷颗粒组成，包含HSV胸苷激酶（TK）基因的串联重复序列，以及一种复制型、非神经毒性的HSV突变体作为辅助病毒。缺陷型载体感染的细胞中HSV-TK活性显著高于辅助病毒感染的细胞，后者仅含有单拷贝的HSV-TK。用这种缺陷型载体感染细胞会使其以及周围未感染的细胞对更昔洛韦杀伤敏感。对携带TK缺陷型载体/辅助病毒感染的皮下GL261胶质瘤的C57BL/6小鼠进行更昔洛韦治疗，可显著减小肿瘤大小。
