Tumour-targeted delivery of TRAIL using Salmonella typhimurium enhances breast cancer survival in mice

Br J Cancer. 2009 Nov 17;101(10):1683-91. doi: 10.1038/sj.bjc.6605403. Epub 2009 Oct 27.

Abstract

Background: An effective cancer therapeutic must selectively target tumours with minimal systemic toxicity. Expression of a cytotoxic protein using Salmonella typhimurium would enable spatial and temporal control of delivery because these bacteria preferentially target tumours over normal tissue.

Methods: We engineered non-pathogenic S. typhimurium to secrete murine TNF-related apoptosis-inducing ligand (TRAIL) under the control of the prokaryotic radiation-inducible RecA promoter. The response of the RecA promoter to radiation was measured using fluorometry and immunoblotting. TRAIL toxicity was determined using flow cytometry and by measuring caspase-3 activation. A syngeneic murine tumour model was used to determine bacterial accumulation and the response to expressed TRAIL.

Results: After irradiation, engineered S. typhimurium secreted TRAIL, which caused caspase-3-mediated apoptosis and death in 4T1 mammary carcinoma cells in culture. Systemic injection of Salmonella and induction of TRAIL expression using 2 Gy gamma-irradiation caused a significant delay in mammary tumour growth and reduced the risk of death by 76% when compared with irradiated controls. Repeated dosing with TRAIL-bearing Salmonella in conjunction with radiation improved the 30-day survival from 0 to 100%.

Conclusion: These results show the pre-clinical utility of S. typhimurium as a TRAIL expression vector that effectively reduces tumour growth and extends host survival.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic
  • Immunoblotting
  • Immunohistochemistry
  • Mammary Neoplasms, Experimental / drug therapy*
  • Mammary Neoplasms, Experimental / microbiology*
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Inbred BALB C
  • Promoter Regions, Genetic
  • Rec A Recombinases / genetics
  • Salmonella typhimurium / genetics
  • Salmonella typhimurium / metabolism
  • Salmonella typhimurium / physiology*
  • TNF-Related Apoptosis-Inducing Ligand / administration & dosage*
  • TNF-Related Apoptosis-Inducing Ligand / genetics
  • TNF-Related Apoptosis-Inducing Ligand / metabolism

Substances

  • TNF-Related Apoptosis-Inducing Ligand
  • Rec A Recombinases
  • Caspase 3