Abstract
One of the major limitations of conventional cancer chemotherapy is its lack of selectivity; there is cytotoxicity to both tumor cells and normal cells. Genetic prodrug activation therapy (GPAT) uses transcriptional differences between normal and neoplastic cells to drive the selective expression of a metabolic suicide gene able to convert a nontoxic prodrug into its toxic metabolite. Genetically modified cells that express the nonmammalian enzyme cytosine deaminase (CD) gene are able to convert the nontoxic prodrug 5-fluorocytosine (5-FC) to the toxic metabolite 5-fluorouracil (5-FU), which inhibits RNA and DNA synthesis during S-phase of the cell cycle (1,2). We have devised a transcriptionally targeted GPAT strategy in which expression of CD is restricted to ERBB2-expressing tumor cells. Exposure of CD-expressing cells to 5-FC should result in tumor-selective cell kill thereby sparing normal breast cells.
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