Introduction Rationale of Transcriptional Targeting

Gene therapy is an innovative approach aimed at introducing genetic material into an organism for therapeutic intent. Still in its infancy, this novel concept has witnessed fundamental preclinical success with numerous ongoing clinical trials to confirm these findings. Critical to the success of gene therapy trials are issues relating to specific delivery of physiologically active biomolecules at therapeutically significant concentrations. Initially this was achieved by using direct intralesional injections of vectors to localize the delivery to the target tissue and universal promoters to maximize expression at that site. Over the past several years, we and several other investigators have investigated the potential of tumor-specific promoters to transcriptionally regulate gene expression in the laboratory and in clinical trials. The safety demonstrated by these trials using tumor/tissue-specific promoters has led to the recent approval of a trial administering a conditionally replicative adenovirus systemically for the treatment of metastatic prostate cancer.

In order for gene therapy to be widely applicable, there is an urgent need to develop a new generation of viral vectors capable of achieving these goals of targeted delivery and controlled gene expression at the target site. The aim of this chapter is to discuss various potential strategies that have been utilized to achieve tissue/tumor-specific expression using adenoviral vectors. A better understanding of tissue specific gene expression necessitates a basic review of the eukaryotic transcription process at the molecular level. Consequently, we

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Copyright 2002, Elsevier Science (USA). All rights reserved.

begin by examining the molecular architecture of DNA and its relationship with the transcriptional mechanism.

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