In vivo gene therapy for colorectal cancer using adenovirus-mediated transfer of the fusion gene cytosine deaminase and uracil phosphoribosyltransferase

Guy Chung-Faye, Ming-Jen Chen, Nicola Green, Andrea Marshall, David Anderson, Vivien Mautner, Peter Searle, David Kerr

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

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 languageEnglish
Pages (from-to)1547-1554
Number of pages8
JournalGene Therapy
Volume8
Issue number20
DOIs
Publication statusPublished - 1 Oct 2001

Keywords

  • colon cancer
  • uracil phosphoribosyl transferase
  • VDEPT
  • adenovirus
  • 5-fluorocytosine
  • 5-fluorouracil

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