only in mice so far...
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%.
Br J Cancer. 2009 Oct 27. [Epub ahead of print]
Tumour-targeted delivery of TRAIL using Salmonella typhimurium enhances breast cancer survival in mice.
Ganai S, Arenas RB, Forbes NS.
[1] Program in Molecular and Cellular Biology, University of Massachusetts Amherst, Amherst, MA 01003, USA [2] Department of Surgery, Baystate Medical Center/Tufts University School of Medicine, Springfield, MA 01199, USA.
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.British Journal of Cancer advance online publication, 27 October 2009; doi:10.1038/sj.bjc.6605403
www.bjcancer.com.
PMID: 19861961
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