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Virus-directed enzyme prodrug therapy (VDEPT) utilising cytosine deaminase (CD) converts 5-fluorocytosine (5-FC) into the chemotherapy agent, 5-fluorouracil (5-FU), and has entered into a clinical trial for metastatic colon cancer. To improve this system, a replication-deficient adenovirus, containing a bifunctional fusion gene, CD:uracil phosphoribosyltransferase (UPRT), was constructed (AdCDUPRT). UPRT enhances the conversion of 5-FU into its active metabolites, which inhibit DNA and RNA synthesis. In vitro, AdCDUPRT infection of colon cancer cells resulted in a marked increase in sensitisation to 5-FU, compared with AdCD-infected or uninfected cells. The corollary is a approximately 100-fold and approximately 10 000-fold increase in sensitisation to 5-FC in AdCDUPRT-infected cells, compared to AdCD-infected and uninfected cells, respectively. There was a strong bystander effect in vitro, 70% of tumour cells were killed by 5-FC when only 10% of cells expressed CDUPRT. In vivo, athymic mice with colon cancer xenografts treated with intratumoral AdCDUPRT and intraperitoneal 5-FC, significantly reduced tumour growth rates compared with untreated controls (P = 0.02), whereas AdCD/5-FC treated mice did not. At higher AdCDUPRT virus doses, 5-FC and 5-FU were equally effective at delaying tumour growth compared with controls. In summary, VDEPT for colon cancer utilising AdCDUPRT is more effective than AdCD and the bifunctional CDUPRT gene enables the use of either 5-FC or 5-FU as prodrugs.

Original publication

DOI

10.1038/sj.gt.3301557

Type

Journal article

Journal

Gene Ther

Publication Date

10/2001

Volume

8

Pages

1547 - 1554

Keywords

Adenoviridae, Analysis of Variance, Animals, Artificial Gene Fusion, Bystander Effect, Colonic Neoplasms, Cytosine Deaminase, Flucytosine, Fluorouracil, Genetic Therapy, Genetic Vectors, Humans, Injections, Intralesional, Mice, Mice, Nude, Neoplasm Transplantation, Nucleoside Deaminases, Pentosyltransferases, Prodrugs, Random Allocation, Transfection, Transplantation, Heterologous, Tumor Cells, Cultured