In vivo human carboxylesterase cDNA gene transfer to activate the prodrug CPT-11 for local treatment of solid tumors. Academic Article uri icon

Overview

MeSH

  • Adenoviridae
  • Animals
  • Carboxylesterase
  • Gene Transfer Techniques
  • Genetic Vectors
  • Humans
  • Mice
  • Mice, Nude
  • Tumor Cells, Cultured

MeSH Major

  • Antineoplastic Agents, Phytogenic
  • Camptothecin
  • Carboxylic Ester Hydrolases
  • Genetic Therapy
  • Neoplasms
  • Prodrugs

abstract

  • To evaluate the concept that in vivo transfer of the human carboxylesterase gene will confer sensitivity of a solid tumor to the prodrug CPT-11 (irinotecan), we constructed an adenovirus vector (AdCMV.CE) carrying the human carboxylesterase gene driven by the cytomegalovirus (CMV) promoter, infected A549 human lung adenocarcinoma cells in vitro and in vivo, and evaluated cell growth over time. AdCMV.CE produced a functional carboxylesterase protein in A549 cells in vitro and in vivo as evidenced by ability of lysates from the infected cells to convert CPT-11 to its active metabolite SN-38. The AdCMV.CE vector effectively suppressed A549 cell growth in vitro in the presence of CPT-11. Cell mixing studies demonstrated that when as few as 10% of cells expressed the human carboxylesterase gene, there was bystander growth suppression in the presence of CPT-11. Consistent with these in vitro observations, when AdCMV.CE was directly injected into established subcutaneous A549 tumors in nude mice receiving CPT-11, there was 35% reduction in tumor size at day 27 compared to controls, and a 41% reduction at day 34 (P < 0.01, both comparisons to controls). Similar observations were made with the cell line H157 and HeLa. These observations suggest that local gene transfer of the human carboxylesterase gene and concomitant local administration of CPT-11 may have potential as a strategy for control of the growth of solid tumors.

publication date

  • April 15, 1998

has subject area

  • Adenoviridae
  • Animals
  • Antineoplastic Agents, Phytogenic
  • Camptothecin
  • Carboxylesterase
  • Carboxylic Ester Hydrolases
  • Gene Transfer Techniques
  • Genetic Therapy
  • Genetic Vectors
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasms
  • Prodrugs
  • Tumor Cells, Cultured

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC508762

Digital Object Identifier (DOI)

  • 10.1172/JCI119888

PubMed ID

  • 9541511

Additional Document Info

start page

  • 1789

end page

  • 1796

volume

  • 101

number

  • 8