Zhu Z B, Makhija S K, Lu B, Wang M, Kaliberova L, Liu B, Rivera A A, Nettelbeck D M, Mahasreshti P J, Leath C A, Yamamoto M, Alvarez R D, Curiel D T
Division of Human Gene Therapy, Department of Medicine, The Gene Therapy Center, University of Alabama at Birmingham, AL 35291, USA.
Gene Ther. 2004 Apr;11(7):645-8. doi: 10.1038/sj.gt.3302089.
Adenoviral vectors are considered to be good gene delivery vectors for cancer gene therapy due to their wide host tissue range and cell cycle-independent infectivity. However, the disadvantages include the lack of specificity for cancer cells and the high liver accumulation in vivo. The human CXCR4 gene is expressed at high levels in many types of cancers, but is repressed in the liver. We explored the CXCR4 promoter as a candidate to restrict adenoviral transgene expression to tumor cells with a low expression in host tissues. The luciferase activities in multiple cancer cell lines infected with recombinant adenovirus reAdGL3BCXCR4 or the control vector reAdGL3BCMV revealed that the CXCR4 promoter exhibited relatively high transcriptional activity in a breast cancer cell line, MDA-MB-361, and two ovarian cancer cell lines, OVCAR-3 and SKOV3. ip1, 65% (P=0.0087), 16.7% (P=0.1) and 20% (P=0.0079) compared to that of the CMV promoter, respectively, and low expression, 4.9 and 0.1%, respectively, in both normal cell lines HFBC and HMEC. In addition, CXCR4 had a low expression of luciferase (0.32%) compared to that of the CMV promoter in mouse liver in vivo. The data also revealed that the CXCR4 promoter was a stronger tumor-specific promoter (TSP) than the Cox-2M promoter in primary melanomas obtained from two patients. The CXCR4 promoter is shown to have a 'tumor-on' and 'liver-off' status in vitro and in vivo, and CXCR4 may prove to be a good candidate TSP for cancer gene therapy approaches for melanoma and breast cancers.
腺病毒载体因其广泛的宿主组织范围和不依赖细胞周期的感染性，被认为是癌症基因治疗的良好基因递送载体。然而，其缺点包括对癌细胞缺乏特异性以及在体内肝脏中大量蓄积。人CXCR4基因在多种癌症类型中高水平表达，但在肝脏中受到抑制。我们探索将CXCR4启动子作为一种候选元件，以使腺病毒转基因表达局限于在宿主组织中低表达的肿瘤细胞。用重组腺病毒reAdGL3BCXCR4或对照载体reAdGL3BCMV感染多种癌细胞系后的荧光素酶活性显示，CXCR4启动子在乳腺癌细胞系MDA-MB-361以及两种卵巢癌细胞系OVCAR-3和SKOV3中表现出相对较高的转录活性。与CMV启动子相比，在这三种细胞系中荧光素酶活性分别为65%（P = 0.0087）、16.7%（P = 0.1）和20%（P = 0.0079），而在两种正常细胞系HFBC和HMEC中表达较低，分别为4.9%和0.1%。此外，在体内小鼠肝脏中，与CMV启动子相比，CXCR4的荧光素酶表达较低（0.32%）。数据还显示，在从两名患者获得的原发性黑色素瘤中，CXCR4启动子比Cox-2M启动子是更强的肿瘤特异性启动子（TSP）。CXCR4启动子在体外和体内均表现出“肿瘤开启”和“肝脏关闭”状态，CXCR4可能被证明是黑色素瘤和乳腺癌基因治疗方法中一个良好的候选TSP。
