Abstract
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 tissueβspecificβpromoters (TSPs). In the context of adenovirus (Ad)βmediated cancer gene therapy it is rational to choose a TSP which is highly expressed in the tumor but has potentially low activity in nonβtumor 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), cyclooxygenaseβ2 (COXβ2), Midkine (MK), vascular endothelial growth factor receptor type 1 (fltβ1), vascular endothelial growth factor (VEGF), Survivin and the receptor for chemokine SDSβ1 (CXCR4).
Methods
To evaluate the specific gene expression of the different promoters in the context of cervical cancer, we constructed a panel of E1βdeleted 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 Β© 2004 John Wiley & Sons, Ltd.