Ablation of tumor cells in vivo by direct injection of HSV-thymidine kinase retroviral vector and ganciclovir therapy
Ablation of tumor cells in vivo by direct injection of HSV-thymidine kinase retroviral vector and ganciclovir therapy
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DOI：
10.1111/j.1749-6632.1999.tb09538.x
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发表时间：
1999-01-01
期刊：
影响因子：
--
通讯作者：
Fong, TC
中科院分区：
文献类型：
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作者：
Howard, BD;Kalthoff, H;Fong, TC
通过瘤内直接注射逆转录病毒载体将治疗性基因导入体内增殖性肿瘤细胞，为多种实体瘤的治疗提供了一种有效而有价值的途径。利用含有β-半乳糖苷酶(β-GAL)基因的逆转录病毒载体，通过直接注射的方法有效地原位转导肿瘤细胞。用含有单纯疱疹病毒胸苷激酶基因(HSV-TK)的逆转录病毒载体将TK基因导入小鼠结肠癌细胞系CT26进行体内消融治疗，将高滴度的HSV-TK逆转录病毒载体直接注射到肿瘤细胞接种部位，然后腹腔注射，实现对CT26肿瘤细胞的原位消融。与对照组动物相比，更昔洛韦(GCV)的这种基因治疗策略显示出明显较低的肿瘤进展速度，并有几次完全消退。我们还证明了对未修饰的CT26细胞的后续挑战的抵抗力和增强的细胞免疫反应与免疫活性动物的肿瘤消退有关。我们的结果证明了直接原位给药HSV-TK逆转录病毒载体治疗癌症的可行性，并提示这种治疗可能会引发细胞免疫反应。
The introduction of therapeutic genes into proliferating tumor cells in vivo by direct intralesional injection of retroviral vectors can provide an effective and valuable approach for the treatment of a variety of solid tumor types. Efficient transduction of tumor cells in situ by direct injection was demonstrated using a retroviral vector containing the beta-galactosidase (beta-gal) gene. Ablation therapy in vivo was demonstrated using a retroviral vector containing the Herpes simplex virus thymidine kinase gene (HSV-TK) to deliver the TK gene into the murine colorectal tumor cell line CT26, Ablation of CT26 tumor cells in situ was achieved by directly injecting high-titer HSV-TK retroviral vector preparations into the site of tumor cell inoculation followed by intraperitoneal (i.p.) delivery of ganciclovir (GCV), This gene therapy strategy demonstrated a markedly lower rate of tumor progression, with several complete regressions, compared to animals in control groups. We also demonstrated that resistance to subsequent challenges with unmodified CT26 cells and an enhanced cellular immune response is associated with tumor regression in immunocompetent animals. Our results demonstrate the feasibility of direct in situ administration of HSV-TK retroviral vectors for the treatment of cancer and suggest that a cellular immune response may be elicited by this therapy.