Evaluation of tissue-specific promoters in carcinomas of the cervix uteri

被引:22
作者
Rein, DT
Breidenbach, M
Nettelbeck, DM
Kawakami, Y
Siegal, GP
Huh, WK
Wang, MH
Hemminki, A
Bauerschmitz, GJ
Yamamoto, M
Adachi, Y
Takayama, K
Dall, P
Curiel, DT
机构
[1] Univ Alabama Birmingham, Div Human Gene Therapy, Gene Therapy Ctr, Birmingham, AL 35294 USA
[2] Univ Alabama Birmingham, Div Human Gene Therapy, Dept Med, Birmingham, AL 35294 USA
[3] Univ Alabama Birmingham, Div Human Gene Therapy, Dept Surg, Birmingham, AL 35294 USA
[4] Univ Alabama Birmingham, Div Human Gene Therapy, Dept Pathol, Birmingham, AL 35294 USA
[5] Univ Alabama Birmingham, Dept Cell Biol & Surg, Birmingham, AL 35294 USA
[6] Univ Alabama Birmingham, Div Gynecol & Oncol, Birmingham, AL 35294 USA
[7] Univ Erlangen Nurnberg, Dept Dermatol, D-8520 Erlangen, Germany
[8] Univ Helsinki, Rat Drug Design Program, Helsinki, Finland
[9] Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki, Finland
[10] Univ Dusseldorf, Ctr Med, Dept Obstet & Gynecol, D-4000 Dusseldorf, Germany
关键词
cervical cancer; VEGF; midkine; CXCR4; adenovirus; promoter;
D O I
10.1002/jgm.606
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Background Gene therapy is a novel approach for treatment of patients with advanced, recurrent, or metastatic cervical cancer. One effective way to direct transgene expression to specific tissues or tumors is the use of tissue-specific-promoters (TSPs). In the context of adenovirus (Ad)-mediated cancer gene therapy it is rational to choose a TSP which is highly expressed in the tumor but has potentially low activity in non-tumor cells, especially the liver. In this study, we have investigated several promoters which fulfill these criteria. Candidate cervical cancer specific TSPs include promoters of the genes for secretory leukoprotease inhibitor (SLPI), cyclooxygenase-2 (COX-2), Midkine (MK), vascular endothelial growth factor receptor type 1 (flt-1), vascular endothelial growth factor (VEGF), Survivin and the receptor for chemokine SDS-1 (CXCR4). Methods To evaluate the specific gene expression of the different promoters in the context of cervical cancer, we constructed a panel of EI-deleted Ads that express luciferase under the control of the promoters of interest. We investigated various established cervical cancer cell lines, as well as purified primary cancer cells and normal control cells from the cervix uteri. Results In all cell lines tested, promoters for MK, VEGF and CXCR4 showed the highest activity. Both MK and VEGF promoters also resulted in a high activity in primary cervical cancer cells. interestingly, gene expression profiles correlate with luciferase activity in both cell lines and primary cancer samples. Conclusions Our study demonstrates that the promoters for MK and VEGF are active in cervical cancer. We believe that both promoters can be successfully employed as TSPs for gene therapy targeted to cervical cancer. Copyright (C) 2004 John Wiley Sons, Ltd.
引用
收藏
页码:1281 / 1289
页数:9
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