Adenovirus-Mediated Cytosine Deaminase/5-Fluorocytosine Suicide Gene Therapy of Human Hepatoblastoma In Vitro

被引:11
|
作者
Warmann, Steven W. [1 ]
Armeanu, Sorin [2 ]
Heigoldt, Heike [1 ,3 ]
Ruck, Peter [3 ]
Vonthein, Reinhard [4 ]
Heitmann, Heike [1 ]
Seitz, Guido [1 ]
Lemken, Marie-Luise [2 ]
Bitzer, Michael [2 ]
Fuchs, Joerg [1 ]
Lauer, Ulrich M. [2 ]
机构
[1] Univ Childrens Hosp Tubingen, Dept Pediat Surg, D-72076 Tubingen, Germany
[2] Med Univ Clin Tubingen, Tubingen, Germany
[3] Hosp Leonberg, Inst Pathol, Leonberg, Germany
[4] Univ Clin Tubingen, Dept Med Biometry, Tubingen, Germany
关键词
adenovirus vector; cytosine deaminase; hepatoblastoma; suicide gene therapy; 5-fluorocytosine; COLON-CANCER CELLS; URACIL PHOSPHORIBOSYLTRANSFERASE GENE; DEAMINASE GENE; HEMATOPOIETIC PROGENITORS; BRAIN-TUMORS; TRANSDUCTION; FUSION; VECTOR; DOXORUBICIN; MODULATION;
D O I
10.1002/pbc.21956
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background. Multidrug resistance is a key factor for the sobering outcome of relapsed and metastatic human hepatoblastoma (HB). Gene directed treatment approaches were recently identified as possible treatment options against advanced HB, in which standard chemotherapy regimens are partially insufficient. The aim of this study was to systematically analyze the effects of suicide gene therapy in three HB cell lines using I yeast-derived cytosine deaminase (YCD)-combined yeast uracil phosphoribosyltransferase (YUPRT)-based adenovirus-mediated gene transfer. Procedure. YCD and YUPRT were fused to form the bifunctional Suicide gene SuperCD. Adeonoviral vectors were used for transduction. Tumor cells, transduced at MOI 50 were incubated with 5-fluorocytosine (5-FC) in ascending concentrations. Results. Transduction rates were 87.8% (+6.7) in the mixed HB cell line HUH6, 98.6% (+1.4) in the epithelial HB cell line HepT1 and 93.6% (+0.6) in the multifocal HB embryonal cell line HepT3, respectively. In HepT3 and HepT1 cells, Suicide gene therapy with SuperCD/5-FC was highly effective leading to HB cell damage far above those of application of the prodrug 5-FC only. In HUH6 cells the approach had no effect due to lack in activity of the CMV promoter being employed for transcription of the SuperCD transgene. Conclusion. Assuming employment Of fully active promoters, the SuperCD/5-FC approach may serve as a potentially useful anti-tumor strategy against, advanced HB. Pediatr Blood Cancer 2009;53:145-151. (C) 2009 Wiley-Liss, Inc.
引用
收藏
页码:145 / 151
页数:7
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