Enhanced tumor therapy using vaccinia virus strain GLV-1h68 in combination with a β-galactosidase-activatable prodrug seco-analog of duocarmycin SA.
Enhanced tumor therapy using vaccinia virus strain GLV-1h68 in combination with a β-galactosidase-activatable prodrug seco-analog of duocarmycin SA.
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DOI：
10.1038/cgt.2010.49
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发表时间：
2011-01
影响因子：
6.4
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中科院分区：
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乳腺癌是全世界癌症相关死亡的最常见原因，因此，尽管传统治疗取得了进展，但乳腺癌仍然是妇女的一个重要健康问题。因此，需要新的替代策略来进行有效的诊断和治疗。一种方法是使用溶瘤病毒进行基因导向的酶前药治疗。在此，将携带lacZ的牛痘病毒（VACV）株GLV-1h 68与衍生自天然抗生素倍癌霉素SA的开环类似物的β-半乳糖苷酶可活化的前药组合使用。用VACV菌株GLV-1h 68感染肿瘤细胞导致β-半乳糖苷酶的产生，这是前药转化为毒性化合物所必需的。此外，在使用前药和GLV-1h 68菌株的联合治疗中也观察到药物依赖性细胞杀伤和肿瘤细胞内在凋亡途径的诱导，尽管VACV菌株编码抗凋亡蛋白。此外，GI-101 A乳腺癌异种移植物通过组合疗法有效治疗。总之，β-半乳糖苷酶可激活的前药与编码该酶的肿瘤特异性牛痘病毒株的组合诱导了人GI-101 A乳腺癌细胞培养物中的细胞凋亡，其中观察到协同溶瘤作用。此外，在体内，额外的前药治疗对GLV-1h 68治疗的GI-101 A异种移植小鼠的肿瘤消退具有有益作用。
Breast cancer is the most common cause of cancer-related death worldwide, thus remaining a crucial health problem among women despite advances in conventional therapy. Therefore, new alternative strategies are needed for effective diagnosis and treatment. One approach is the use of oncolytic viruses for gene-directed enzyme prodrug therapy. Here, the lacZ-carrying vaccinia virus (VACV) strain GLV-1h68 was used in combination with a β-galactosidase-activatable prodrug derived from a seco-analog of the natural antibiotic duocarmycin SA. Tumor cell infection with the VACV strain GLV-1h68 led to production of β-galactosidase, essential for the conversion of the prodrug to the toxic compound. Furthermore, drug-dependent cell kill and induction of the intrinsic apoptosis pathway in tumor cells was also observed on combination therapy using the prodrug and the GLV-1h68 strain, despite the fact that VACV strains encode antiapoptotic proteins. Moreover, GI-101A breast cancer xenografts were effectively treated by the combination therapy. In conclusion, the combination of a β-galactosidase-activatable prodrug with a tumor-specific vaccinica virus strain encoding this enzyme, induced apoptosis in cultures of the human GI-101A breast cancer cells, in which a synergistic oncolytic effect was observed. Moreover, in vivo, additional prodrug treatment had beneficial effects on tumor regression in GLV-1h68-treated GI-101A-xenografted mice.