Optimization of a synthetic beta-catenin-dependent promoter for tumor-specific cancer gene therapy

Molecular Therapy : the Journal of the American Society of Gene Therapy
K S LipinskiC J Wrighton

Abstract

We recently published the construction and evaluation of a beta-catenin-dependent, highly active promoter, CTP1, and its possible application for the treatment of colorectal cancer using gene-directed enzyme prodrug therapy with adenoviral (Ad) vectors. Alternative Ad-based approaches such as tumor-specific, replication-competent vectors and/or exploiting therapeutic gene products with intrinsic toxic activity, such as gibbon ape leukemia virus fusogenic membrane glycoprotein, diphtheria toxin A (DTA), and ricin, would demand a very tightly regulated promoter to avoid breakthrough replication and toxicity in nontumor tissue and Ad producer cell lines. In this study we optimized the activity/specificity profile of the synthetic beta-catenin-dependent promoter by varying its basal promoter, the number of Tcf binding sites, and the distance between these and the basal promoter. The optimal promoter, CTP4, showed virtually undetectable expression in cells with normal beta-catenin regulation but high level expression in cells deregulated for beta-catenin. Using CTP4 we were able to generate, for the first time to our knowledge, an Ad vector expressing fully active wild-type DTA without the need for time-consuming and cumbersome prod...Continue Reading

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Citations

Sep 30, 2006·Cancer Gene Therapy·N ZarovniM S Fabbrini
Mar 2, 2010·Cancer Biotherapy & Radiopharmaceuticals·Ladan Teimoori-ToolabiSirous Zeinali
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