Prodrug activation enzymes in cancer gene therapy

Cell surface display of a lysosomal enzyme for extracellular gene-directed enzyme prodrug therapy

“…1 One possibility to circumvent this problem is gene-directed enzyme prodrug therapy (GDEPT), also referred to as molecular chemotherapy. 2,3 Central to this approach is the tumor-directed delivery of a gene encoding an enzyme that cleaves a systemically applied inactive prodrug to a toxic drug. Since prodrugs usually possess little toxicity, relatively large amounts can be administered, which in turn will lead to high drug concentrations at the tumor.…”

In vitro evaluation of cancer-specific NF-κB-CEA enhancer–promoter system for 5-fluorouracil prodrug gene therapy in colon cancer cell lines

“…Lack of selectivity for malignant cells leading to dose-limiting toxicity is one of the major obstacles for the success of cancer chemotherapy. Gene-directed enzyme prodrug therapy (GDEPT) is potentially an elegant way to improve the therapeutic index of active anticancer drugs, but one of the major limitations for the clinical application of this approach is the lack of strong cancerspecific promoters (Aghi et al, 2000;Rooseboom et al, 2004).Carcinoembryonic antigen (CEA) is not expressed in normal and overexpressed in epithelial cancer cells (Shively and Beatty, 1985). Four cis-acting DNA-binding elements mapped on the CEA promoter region within 300 bp upstream of CEA translation starting point, especially, the first three elements are essential for specific CEA transcription (Hauck and Stanners, 1995;Richards et al, 1995a).…”

“…Lack of selectivity for malignant cells leading to dose-limiting toxicity is one of the major obstacles for the success of cancer chemotherapy. Gene-directed enzyme prodrug therapy (GDEPT) is potentially an elegant way to improve the therapeutic index of active anticancer drugs, but one of the major limitations for the clinical application of this approach is the lack of strong cancerspecific promoters (Aghi et al, 2000;Rooseboom et al, 2004).…”

Herpes simplex virus thymidine kinase/ganciclovir system in multicellular tumor spheroids

“…1 It consists of the introduction into cancer cells of a gene, whose product is capable of converting a nontoxic prodrug into a cytotoxic drug. 2 One of such suicide genes, the thymidine kinase gene from the herpes simplex virus (HSVtk), in combination with the prodrug ganciclovir (GCV), has been extensively and successfully used for the treatment of a variety of cancers in some animal models. HSVtk can efficiently phosphorylate the guanosine analogue GCV and allows its further transformation, after subsequent phosphorylation by cellular kinases, into cytotoxic ganciclovir-triphosphate, which inhibits cellular DNA polymerases.…”