Regional 'pro-drug' gene therapy: intravenous administration of an adenoviral vector expressing the E. coli cytosine deaminase gene and systemic administration of 5-fluorocytosine suppresses growth of hepatic metastasis of colon carcinoma. Academic Article uri icon

Overview

MeSH

  • Adenoviridae
  • Animals
  • Colonic Neoplasms
  • Cytosine Deaminase
  • Fluorouracil
  • Gene Expression
  • Gene Transfer Techniques
  • Genetic Vectors
  • Liver
  • Mice
  • Mice, Inbred BALB C

MeSH Major

  • Antimetabolites
  • Escherichia coli
  • Flucytosine
  • Genetic Therapy
  • Liver Neoplasms
  • Nucleoside Deaminases
  • Prodrugs

abstract

  • Direct administration of an adenoviral vector expressing the cytosine deaminase gene (AdCMV.CD) to tumors of colon carcinoma cells, with concomitant systemic administration of 5-fluorocytosine (5FC), results in local production of 5-fluorouracil (5FU) and suppression of tumor growth. Based on the demonstration that in vivo adenovirus-mediated gene transfer to intrahepatic tumors is relatively inefficient compared with in vivo gene transfer to hepatocytes, we developed a 'regional' prodrug strategy using in vivo Ad-mediated CD gene transfer to normal liver, permitting hepatocytes to convert 5FC into 5FU to treat local metastasis effectively in a 'trans' fashion. To show that hepatocytes can generate and export sufficient 5FU to achieve this goal, primary rat hepatocytes were exposed to AdCMV.CD and 5FC. Evaluation of the supernatants by spectrophotometry and by HPLC demonstrated significant conversion of 5FC into 5FU. When supernatants of hepatocytes exposed to AdCMV.CD and 5FC were transferred to cultures of CT26 mouse colon carcinoma cells, the CT26 viability was reduced by 80%. To show that this regional AdCMV.CD/5FC prodrug strategy can suppress tumor growth in vivo, a model of metastatic colon carcinoma was established by injecting CT26 cells into the left lobe of the liver of syngeneic Balb/c mice. The next day, AdCMV.CD was transferred to hepatocytes by intravenous administration, and 5FC treatment was started the following day. Evaluation of tumor growth after 15 days showed marked suppression of tumor growth in AdCMV.CD- and 5FC- treated animals compared to control groups (P < 0.007). We conclude that primary hepatocytes are capable of converting 5FC into 5FU and exporting sufficient amounts of 5FU to the local milieu to suppress the growth of liver metastases of colon carcinoma cells.

publication date

  • April 1998

has subject area

  • Adenoviridae
  • Animals
  • Antimetabolites
  • Colonic Neoplasms
  • Cytosine Deaminase
  • Escherichia coli
  • Flucytosine
  • Fluorouracil
  • Gene Expression
  • Gene Transfer Techniques
  • Genetic Therapy
  • Genetic Vectors
  • Liver
  • Liver Neoplasms
  • Mice
  • Mice, Inbred BALB C
  • Nucleoside Deaminases
  • Prodrugs

Research

keywords

  • Journal Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1038/sj.gt.3300611

PubMed ID

  • 9614575

Additional Document Info

start page

  • 507

end page

  • 513

volume

  • 5

number

  • 4