Journal
BRITISH JOURNAL OF CANCER
Volume 101, Issue 10, Pages 1683-1691Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.bjc.6605403
Keywords
targeted cancer therapy; spatiotemporal controlled delivery; attenuated Salmonella typhimurium; TRAIL; RecA
Categories
Funding
- National Institutes of Health [1R01CA120825-01A1]
- University of Massachusetts, Amherst
- Department of Surgery at Baystate Medical Center
- [BCTR0601001]
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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 2Gy 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. British Journal of Cancer (2009) 101, 1683-1691. doi: 10.1038/sj.bjc.6605403 www.bjcancer.com Published online 27 October 2009 (C) 2009 Cancer Research UK
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