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

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

Author information

1
Program in Molecular and Cellular Biology, University of Massachusetts Amherst, Amherst, MA 01003, USA.

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.

PMID:
19861961
PMCID:
PMC2778534
DOI:
10.1038/sj.bjc.6605403
[Indexed for MEDLINE]
Free PMC Article

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