Transcriptional targeting

Gene therapy strategies hold great promise for complementing or even replac ing our current methods of treating cancer. A critical component for succes sful cancer gene therapy is cancer-specific transgene expression in order t o spare normal cells. This goal should be approachable by cell-targeted gen e delivery and/or by imposing stringent transcriptional regulation. In theo ry, tightly restricted transgene expression is feasible because the express ion of most genes is naturally under strict control. To this end, many inve stigators have begun to exploit knowledge about gene regulation to achieve cancer-specific gene expression. For example, a cancer-specific chimeric tr anscription factor resulting from a chromosomal translocation has been harn essed to selectively activate a toxin gene. More generally, targeted expres sion of therapeutic genes has been demonstrated using regulatory sequences from (i) genes that are ectopically expressed in cancers, (ii) viral genes expressed in virus-associated cancers, and (iii) tissue-specific genes expr essed in cancers and their tissues of origin. The latter approach has been applied to models of melanoma, B- and T-lymphoid malignancies, osteosarcoma , prostate cancer, glioma, lung cancer, and various other carcinomas. Regul atory sequences from genes expressed in tumor vasculature and from cell cyc le-regulated genes are also candidates for therapeutic transcriptional targ eting. In addition, much progress has been made in developing systems for r egulating transgene transcription using low molecular weight drugs, especia lly tetracyclines, facilitating precise temporal control of expression. Fin ally, pharmacologic principles must be considered in controlling the expres sion of therapeutic genes. This review summarizes progress in the above are as and discusses prospects for transcriptional targeting of transgene expre ssion in relation to cancer therapy.