Inhibition of oncogenic K-ras signaling by aerosolized gene delivery in a mouse model of human lung cancer

Clin Cancer Res. 2002 Sep;8(9):2970-5.

Abstract

Purpose: Transfer of growth-suppressive genes to lung tumors has therapeutic potential, but effective delivery techniques have not been developed. Here, we investigated gene delivery to lung tumors by aerosolization of adenoviral vectors incorporated into calcium phosphate precipitates.

Experimental design: To investigate the efficacy of this delivery method in normal and neoplastic lung, an adenoviral vector expressing beta-galactosidase was administered by jet nebulization to K-ras(LA1) mice, which develop lung adenocarcinomas through activation of a latent allele carrying mutant K-ras(G12D). Furthermore, we investigated whether aerosolized delivery of Ad-MKK4 (KR), an adenoviral vector expressing dominant-negative mutant mitogen-activated protein kinase kinase 4(MKK4), can block Ras-dependent signaling in K-ras(LA1) mice.

Results: After a single administration, beta-galactosidase was detected in lung tissue for up to 21 days, and expression was much greater in tumors than in normal lung tissue. MKK4 was activated in the lungs of K-ras(LA1) mice, and aerosolized treatment with Ad-MKK4 (KR) decreased c-Jun-NH(2)-terminal kinase but not extracellular signal- regulated kinase activity, providing evidence that MKK4 was selectively inhibited.

Conclusions: These findings demonstrate a novel approach to targeting oncogenic pathways in lung tumors by aerosolized gene delivery.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / therapy*
  • Adenoviridae / genetics
  • Aerosols
  • Alleles
  • Amino Acid Substitution
  • Animals
  • Exons / genetics
  • Genes, Dominant
  • Genes, Reporter
  • Genes, ras*
  • Genetic Therapy*
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / therapeutic use
  • Humans
  • Lac Operon
  • Lung Neoplasms / genetics
  • Lung Neoplasms / therapy*
  • MAP Kinase Kinase 4*
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Mitogen-Activated Protein Kinase Kinases / physiology
  • Point Mutation
  • Signal Transduction / genetics*
  • Xenograft Model Antitumor Assays

Substances

  • Aerosols
  • MAP Kinase Kinase 4
  • MAP2K4 protein, human
  • Map2k4 protein, mouse
  • Mitogen-Activated Protein Kinase Kinases