Wildner O, Morris J C, Vahanian N N, Ford H, Ramsey W J, Blaese R M
Clinical Gene Therapy Branch/National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1851, USA.
Gene Ther. 1999 Jan;6(1):57-62. doi: 10.1038/sj.gt.3300810.
A major obstacle to the success of gene therapy strategies that directly target cancer cells is the poor vector distribution within solid tumors. To address this problem, we developed an E1b 55 kDa attenuated, replication-competent adenovirus (Ad.TKRC) which expresses the herpes simplex-1 thymidine kinase (HSVtk) gene to sensitize tumors to ganciclovir (GCV). Efficacy of this combined strategy was tested in nude mice with subcutaneous human A375 melanoma and ME180 cervical carcinomas. Intratumoral injection of a replication-defective adenoviral vector expressing HSVtk (Ad.TK) followed by GCV treatment resulted in doubling of the survival time of mice bearing A375 tumors and 20% long-term survival of mice with ME180 tumors. Treatment of tumors with Ad.TKRC without GCV resulted in a similar antitumor effect, confirming that the replicating vector has an oncolytic effect. When GCV was initiated 3 days after Ad.TKRC injection, survival of mice with each tumor type was greatly prolonged, with 60% of animals with ME180 tumors surviving for over 160 days. These results confirm that both the oncolysis caused by a replicating virus and suicide/prodrug gene therapy with HSVtk/GCV have potent antitumor effects. When combined, these two approaches are complementary resulting in a significantly improved treatment outcome.
直接靶向癌细胞的基因治疗策略成功的一个主要障碍是实体瘤内载体分布不佳。为了解决这个问题，我们开发了一种E1b 55 kDa减毒、具有复制能力的腺病毒（Ad.TKRC），它表达单纯疱疹病毒1型胸苷激酶（HSVtk）基因，使肿瘤对更昔洛韦（GCV）敏感。在携带人A375黑色素瘤皮下瘤和ME180宫颈癌的裸鼠中测试了这种联合策略的疗效。瘤内注射表达HSVtk的复制缺陷型腺病毒载体（Ad.TK），随后进行GCV治疗，使携带A375肿瘤的小鼠存活时间加倍，使患有ME180肿瘤的小鼠长期存活率达到20%。用Ad.TKRC治疗肿瘤而不使用GCV产生了类似的抗肿瘤效果，证实了复制型载体具有溶瘤作用。当在Ad.TKRC注射后3天开始使用GCV时，每种肿瘤类型的小鼠存活率都大大延长，60%患有ME180肿瘤的动物存活超过160天。这些结果证实，复制型病毒引起的溶瘤作用和HSVtk/GCV的自杀/前药基因治疗都具有强大的抗肿瘤作用。当这两种方法联合使用时，它们是互补的，从而显著改善治疗效果。
