In vivo adenovirus-mediated gene transfer of the Escherichia coli cytosine deaminase gene to human colon carcinoma-derived tumors induces chemosensitivity to 5-fluorocytosine. Academic Article uri icon

Overview

MeSH

  • Adenoviridae
  • Animals
  • Cell Division
  • Cell Line
  • Cytosine Deaminase
  • Escherichia coli
  • Gene Expression
  • Genetic Vectors
  • HT29 Cells
  • Humans
  • Mice
  • Mice, Nude
  • Prodrugs
  • beta-Galactosidase

MeSH Major

  • Antineoplastic Agents
  • Colonic Neoplasms
  • Flucytosine
  • Fluorouracil
  • Gene Transfer Techniques
  • Nucleoside Deaminases

abstract

  • To evaluate the concept that in vivo transfer of the Escherichia coli cytosine deaminase gene will confer sensitivity of a solid tumor to the prodrug 5-fluorocytosine (5FC), we constructed an adenovirus vector (AdCMV.CD) carrying the cytosine deaminase gene driven by the cytomegalovirus (CMV) promoter, infected HT29 colon carcinoma cells in vitro and in vivo, and evaluated cell growth over time. AdCMV.CD produced a functional cytosine deaminase protein in HT29 cells in vitro as evidenced by the ability of lysates from the infected cells to convert [3H]5FC to its active metabolite 5-fluorouracil (5FU). The AdCMV.CD vector effectively suppressed HT29 cell growth in vitro in the presence of 5FC in a dose-dependent manner. Infection with AdCMV.CD, when as few as 10% of cells expressed the cytosine deaminase gene, was associated with a bystander effect when combined with 5FC in cell mixing studies. Further, this bystander effect was not dependent on cell-to-cell contact as demonstrated by suppression of [3H]thymidine incorporation in HT29 cells when supernatant from AdCMV.CD-infected cells treated with 5FC was transferred cells. Consistent with these in vitro observations, when AdCMV.CD was directly injected into established subcutaneous HT29 tumors in nude mice receiving 5FC, there was a four-fold reduction in tumor size at day 15 compared to controls, and a five-fold reduction at day 28. These observations suggest that adenovirus-mediated gene transfer of the E. coli cytosine deaminase gene and concomitant administration of 5FC may have potential as a strategy for local control of the growth of tumor cells susceptible to 5FU.

publication date

  • August 1995

has subject area

  • Adenoviridae
  • Animals
  • Antineoplastic Agents
  • Cell Division
  • Cell Line
  • Colonic Neoplasms
  • Cytosine Deaminase
  • Escherichia coli
  • Flucytosine
  • Fluorouracil
  • Gene Expression
  • Gene Transfer Techniques
  • Genetic Vectors
  • HT29 Cells
  • Humans
  • Mice
  • Mice, Nude
  • Nucleoside Deaminases
  • Prodrugs
  • beta-Galactosidase

Research

keywords

  • Journal Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1089/hum.1995.6.8-1055

PubMed ID

  • 7578418

Additional Document Info

start page

  • 1055

end page

  • 1063

volume

  • 6

number

  • 8