Targeted delivery of a suicide gene to human colorectal tumors by a conditionally replicating vaccinia virus
Targeted delivery of a suicide gene to human colorectal tumors by a conditionally replicating vaccinia virus
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DOI：
10.1038/gt.2008.82
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发表时间：
2008-10-01
期刊：
影响因子：
5.1
通讯作者：
Erbs, P.
中科院分区：
文献类型：
--
作者：
Foloppe, J.;Kintz, J.;Erbs, P.
我们已经产生了一种胸苷激酶基因缺失的痘苗病毒(VV)(哥本哈根株)，它表达来自酵母胞嘧啶脱氨酶和尿嘧啶磷酸核糖转移酶基因的融合自杀基因FCU1。在系统给药前药5-氟胞嘧啶(5-FC)存在的情况下，瘤内接种编码FCU1的胸苷激酶基因缺失的VV(VV-FCU1)，与胸苷激酶基因缺失的VV治疗或单独使用5-氟尿嘧啶相比，裸鼠皮下人类结肠癌的生长显著减少。前药物治疗的局限性通常是要求将病毒直接注射到相对较大、可接近的肿瘤中。在这里，我们演示了VV-FCU1全身给药后，肿瘤皮下生长的载体靶向。更重要的是，我们还证明，全身注射VV-FCU1在裸鼠体内携带人结肠癌原位肝转移，并同时给予5-FC，会导致显著的肿瘤生长迟缓。总之，融合的FCU1自杀基因的插入增强了胸苷激酶基因缺失的VV的溶瘤效率，并为结肠癌和其他癌症的远处转移的基因治疗提供了一种潜在的有效手段。
We have generated a thymidine kinase gene-deleted vaccinia virus (VV) (Copenhagen strain) that expressed the fusion suicide gene FCU1 derived from the yeast cytosine deaminase and uracil phosphoribosyltransferase genes. Intratumoral inoculation of this thymidine kinase gene-deleted VV encoding FCU1 (VV-FCU1) in the presence of systemically administered prodrug 5-fluorocytosine (5-FC) produced statistically significant reductions in the growth of subcutaneous human colon cancer in nude mice compared with thymidine kinase gene-deleted VV treatments or with control 5-fluorouracil alone. A limitation of prodrug therapies has often been the requirement for the direct injection of the virus into relatively large, accessible tumors. Here we demonstrate vector targeting of tumors growing subcutaneously following systemic administration of VV-FCU1. More importantly we also demonstrate that the systemic injection of VV-FCU1 in nude mice bearing orthotopic liver metastasis of a human colon cancer, with concomitant administration of 5-FC, leads to substantial tumor growth retardation. In conclusion, the insertion of the fusion FCU1 suicide gene potentiates the oncolytic efficiency of the thymidine kinase gene-deleted VV and represents a potentially efficient means for gene therapy of distant metastasis from colon and other cancers.