Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.4.1 (cytosine deaminase)
 747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Current treatments for metastatic malignant disease are often ineffective. One of the most promising of the selective genetic strategies against cancer is VDEPT (virally directed enzyme prodrug therapy). This uses a viral vector to carry a prodrug-activating enzyme gene into both tumour and normal cells. By linking the foreign gene downstream of tumour-specific transcription units, tumour-specific expression of the foreign enzyme gene can be achieved. We have developed a genetic therapy strategy using VDEPT against cancers that overexpress the oncogene ERBB2. This occurs in approximately one-third of breast and pancreatic tumours (and in a smaller proportion of other tumours) and involves transcriptional up-regulation of the ERBB2 gene with or without gene amplification. We have constructed a chimeric minigene consisting of the proximal ERBB2 promoter linked to the gene encoding cytosine deaminase, an enzyme that can deaminate the prodrug 5-fluorocytosine (5-FC) to form cytotoxic 5-fluorouracil (5-FU). We have constructed a double-copy recombinant retrovirus to deliver the enzyme gene under the control of the ERBB2 promoter into a panel of ERBB2 expression-positive (ERBB2+) and -negative (ERBB2-) pancreatic and breast cell lines. Cytosine deaminase activity was high in ERBB2+ transduced cells but was not detected in ERBB2- transduced cells. Significant cell death was observed in ERBB2+ transduced cells treated with 5-FC whereas ERBB2- cells were not affected. Hence we present a novel gene therapy strategy that is potentially tumour-specific and could be used against a range of tumour types that overexpress the ERBB2 oncogene.
 ...
PMID:Gene therapy for cancer using tumour-specific prodrug activation. 758 78

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.
 ...
PMID:Intratumoral gene transfer of the Cytosine deaminase gene for the treatment of breast cancer. 2139 Aug 28