Aerosolised 5-azacytidine suppresses tumour growth and reprogrammes the epigenome in an orthotopic lung cancer model

Br J Cancer. 2013 Oct 1;109(7):1775-81. doi: 10.1038/bjc.2013.575. Epub 2013 Sep 17.


Background: Epigenetic silencing by promoter methylation and chromatin remodelling affects hundreds of genes and is a causal event for lung cancer. Treatment of patients with low doses of the demethylating agent 5-azacytidine in combination with the histone deacetylase inhibitor entinostat has yielded clinical responses. The subcutaneous dosing route for consecutive days and reduced bioavailability of 5-azacytidine because of inactivation by cytidine deaminase may limit the expansion of epigenetic therapy into Phase III trials. To mitigate these barriers, an aerosol of 5-azacytidine was generated and characterised.

Methods: The effect of aerosol vs systemic delivery of 5-azacytidine on tumour burden and molecular response of engrafted lung tumours in the nude rat was compared.

Results: Pharmacokinetics revealed major improvement in the half-life of 5-azacytidine in lung tissue with aerosol delivery. Aerosolised 5-azacytidine significantly reduced lung tumour burden and induced global demethylation of the epigenome at one-third of the comparable effective systemic dose. High commonality for demethylation of genes was seen in tumours sampled throughout lung lobes and across treated animals receiving the aerosolised drug.

Conclusion: Collectively, these findings show that aerosolised 5-azacytidine targets the lung, effectively reprogrammes the epigenome of tumours, and is a promising approach to combine with other drugs for treating lung cancer.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Aerosols
  • Animals
  • Antimetabolites, Antineoplastic / administration & dosage*
  • Antimetabolites, Antineoplastic / pharmacokinetics
  • Antimetabolites, Antineoplastic / therapeutic use
  • Azacitidine / administration & dosage*
  • Azacitidine / pharmacokinetics
  • Azacitidine / therapeutic use*
  • Benzamides / therapeutic use*
  • Cytidine Deaminase / metabolism
  • DNA Methylation / drug effects
  • Epigenesis, Genetic / drug effects
  • Histone Deacetylase Inhibitors / administration & dosage
  • Histone Deacetylase Inhibitors / therapeutic use
  • Lung Neoplasms / drug therapy*
  • Male
  • Neoplasm Transplantation
  • Pyridines / therapeutic use*
  • Rats
  • Tumor Burden / drug effects


  • Aerosols
  • Antimetabolites, Antineoplastic
  • Benzamides
  • Histone Deacetylase Inhibitors
  • Pyridines
  • entinostat
  • Cytidine Deaminase
  • Azacitidine