Journal of the National Cancer Institute Advance Access originally published online on July 29, 2008
JNCI Journal of the National Cancer Institute 2008 100(15):1113-1116; doi:10.1093/jnci/djn205
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BRIEF COMMUNICATION |
Inhibition of Tumor Growth Using Salmonella Expressing Fas Ligand
Affiliation of authors: Burnham Institute for Medical Research, La Jolla, CA
Correspondence to: John C. Reed, MD, PhD, Burnham Institute for Medical Research, 10901 North Torrey Pines Rd, La Jolla, CA 92037 (e-mail: reedoffice{at}burnham.org).
Intravenous administration of bacteria leads to their accumulation in tumors and to sporadic tumor regression. We therefore explored the hypothesis that Salmonella typhimurium engineered to express the proapoptotic cytokine Fas ligand (FasL) would exhibit enhanced antitumor activity. Immunocompetent mice carrying tumors derived from syngeneic murine D2F2 breast carcinoma or CT-26 colon carcinoma cells were treated intravenously with FasL-expressing S. typhimurium or with phosphate-buffered saline (PBS; control). Treatment with FasL-expressing S. typhimurium inhibited growth of primary tumors by an average of 59% for D2F2 tumors and 82% for CT-26 tumors (eg, at 25 days after initial treatment, mean volume of PBS-treated CT-26 colon carcinomas = 1385 mm3 and of S. typhimurium FasL-treated CT-26 tumors = 243 mm3, difference = 1142 mm3, 95% confidence interval = 800 mm3 to 1484 mm3, P < .001). Pulmonary D2F2 metastases (as measured by lung weight) were reduced by 34% in S. typhimurium FasL-treated mice compared with PBS-treated mice. FasL-expressing S. typhimurium had similar effects on growth of murine B16 melanoma tumors in wild-type mice but not in lpr/lpr mice, which lack Fas, or in mice with disrupted host inflammatory responses. Antitumor activity was achieved without overt toxicity. These preclinical results raise the possibility that using attenuated S. typhimurium to deliver FasL to tumors may be an effective and well-tolerated therapeutic strategy for some cancers.
| CONTEXT AND CAVEATS Prior knowledge Salmonella typhimurium, a facultative anaerobe, has been shown to accumulate at tumor sites when injected intravenously into mouse tumor models. Intravenous injection of attenuated strains has been well tolerated. Study design Attenuated S. typhimurium were engineered to express Fas ligand (FasL) to deliver this toxic, antitumor cytokine to tumor sites and to thereby enhance therapeutic potential. Contribution S. typhimurium expressing FasL dramatically inhibited the growth of D2F2 murine breast carcinoma and CT-26 murine colon carcinoma tumors, as well as the growth of D2F2 pulmonary metastases in mice. Implications S. typhimurium expressing FasL may hold promise for the treatment of some human tumors. Limitations These experiments involved murine tumor models, and the effects of FasL-expressing S. typhimurium on human tumor models are not yet known. From the Editors
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Manuscript received October 2, 2007; revised May 14, 2008; accepted May 21, 2008.
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J Natl Cancer Inst 2008 100: 1045.
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  V. H. Nguyen, H.-S. Kim, J.-M. Ha, Y. Hong, H. E. Choy, and J.-J. Min Genetically Engineered Salmonella typhimurium as an Imageable Therapeutic Probe for Cancer Cancer Res., January 1, 2010; 70(1): 18 - 23. [Abstract] [Full Text] [PDF]
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