Antitumor Effects in Mice of the Intravenous Injection of Attenuated Salmonella Typhimurium

Rosenberg, Steven A.; Spiess, Paul J.; Kleiner, David E.

doi:10.1097/00002371-200205000-00004

Cited by 72 publications

(71 citation statements)

References 7 publications

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“…Salmonella reportedly accumulate in solid tumors in vivo (4,5,20). To explore the tumor targeting of the attenuated purI Ϫ / msbB Ϫ strain, we transformed these bacteria with a plasmid encoding luciferase and injected them i.v.…”

Section: Protein Expression and Intratumoral Accumulation Of Attenuatedmentioning

confidence: 99%

“…injection accumulate in solid tumors. In mouse studies, for example, Salmonella typhimurium (a facultative anaerobe) accumulate within tumors to concentrations as high as 10 9 colony-forming units (cfu) per gram of tumor tissue (4,5). Various explanations have been proposed for the preferential growth of bacteria in tumors, including superior nutrient availability from materials released by necrotic cells in hypoxic regions, impaired bactericidal activity of macrophages and neutrophil granulocytes in low oxygen environments found in solid tumors, suppression of the immune system by tumor-derived factors such as TGF-␤, and reduced exposure to antibodies and complement-factors because of irregular vasculature and positive pressure within tumors.…”

mentioning

confidence: 99%

“…Humans are not a natural host for S. typhimurium, and the elimination of lipid A prevents production of endotoxin (lipopolysaccharide), making these microorganisms nonvirulent. Because they have an acceptable safety profile (5,8) and are able to synthesize recombinant cytokines at high levels (9), we chose these bacteria for our studies, with a goal to explore the preclinical antitumor activity of S. typhimurium engineered to secrete cytokines. With the ability to grow anaerobically, we reasoned that S. typhimurium could grow even in hypoxic areas of tumors, which tend to be resistant to radiation or chemotherapy.…”

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confidence: 99%

See 2 more Smart Citations

AttenuatedSalmonellaengineered to produce human cytokine LIGHT inhibit tumor growth

Loeffler

Le'Negrate

Krajewska

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

160

105

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Intravenously administered bacteria reportedly accumulate in tumors. Furthermore, systemic administration of attenuated Salmonella typhimurium has little or no significant side-effects in humans. Consequently, we engineered such bacteria to improve their oncolytic activity by stably inserting a gene encoding LIGHT, a cytokine known to promote tumor rejection. Unlike control bacteria, attenuated S. typhimurium expressing LIGHT inhibited growth of primary tumors, as well as the dissemination of pulmonary metastases, in various mouse tumor models employing murine carcinoma cell lines in immunocompetent mice. Antitumor activity was achieved without significant toxicity and was associated with infiltration of inflammatory cells and dependent on the LIGHT receptors, herpes virus entry mediator (HVEM), and lymphotoxin-␤ receptor (LT␤R). These findings provide evidence that nonvirulent bacteria can be exploited as targeting vehicles for local generation of therapeutic proteins in tumors.cancer therapy ͉ immunotherapy ͉ tumor homing

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Section: Protein Expression and Intratumoral Accumulation Of Attenuatedmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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AttenuatedSalmonellaengineered to produce human cytokine LIGHT inhibit tumor growth

Loeffler

Le'Negrate

Krajewska

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

160

105

View full text Add to dashboard Cite

show abstract

“…Moreover, recently there has been renewed interest in the clinical applications of live bacteria, particularly to treat human solid tumors. 6,7 This interest is based in part on the observation that various non-pathogenic anaerobic bacteria are given intravenously, they can infiltrate and replicate within solid tumors. Significantly, genetically modified Salmonella typhimurium A1 bacteria were found to accumulate and replicate 1000-10 000 times more efficiently in tumorous mouse tissue than in healthy tissues, 8,9 reaching a concentration of B1Â10 9 CFU per tumor.…”

Section: Introductionmentioning

confidence: 99%

Targeting tumor gene by shRNA-expressing Salmonella-mediated RNAi

2010

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RNA interference (RNAi) has been established as an important research tool that carries great potential for gene therapy. However, targeted induction of RNAi in vivo has met with significant challenges. In this study, a novel pSLS plasmid capable of expressing short hairpin RNAs (shRNAs) was transformed into attenuated Salmonella enterica serovar typhimurium strain 7207 (SL). In vitro infection studies with the transformed S. enterica containing pSLS (SL-pSLS-CAT) demonstrated that expression of shRNA targeting the CTNNB1 gene induced potent and specific silencing of CTNNB1 expression in cultured SW480 cells. CTNNB1 knockdown in SW480 cells was associated with markedly reduced proliferation and cell death compared with that of control infected cells. In addition, SL-pSLS-CAT-mediated CTNNB1 knockdown markedly reduced tumor growth in SW480 xenograft mice. These tumors exhibited reduced levels of CTNNB1, as well as c-Myc and cyclin D1. Finally, SL-pSLS-CAT treatment also resulted in reduced expression levels of these genes in polyps, mucosal tissues and in small intestines of APC Min mice. Taken together, these data suggest that attenuated shRNA-expressing Salmonella may be a powerful new tool for in vitro gene silencing, functional genomics, and the development of RNAi-based anticancer or human immunodeficiency virus therapeutics.

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“…1 Currently, Bifidobacterium, 2-4 Clostridium, [5][6][7][8][9][10][11][12] Salmonella [13][14][15][16][17] and Vibrio 18 are under investigation as tumor-selective bacterial vectors in preclinical models. In order to determine the efficiency of targeting in a human clinical trial, detection of the vectors is necessary.…”

mentioning

confidence: 99%

Positron emission tomography (PET) imaging of tumor-localized Salmonella expressing HSV1-TK

et al. 2004

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In order to noninvasively detect Salmonella delivery vectors within tumors, we used a genetically modified Salmonella, VNP20009, that expresses the herpes simplex thymidine kinase (HSV1-tk) reporter gene. VNP20009-TK were able to selectively localize within murine tumor models and to effectively sequester a radiolabeled nucleoside analogue, 2 ]FIAU positron emission tomography (PET) and subsequent tissue radioactivity and bacterial concentration measurements were compared. A log-log relationship was found, and the PET images could identify multiple tumor sites. The ability to noninvasively detect Salmonella vectors by PET imaging has the potential to be conducted in a clinical setting, and could aid in development of these vectors by demonstrating the efficiency and duration of targeting as well as indicating the locations of tumors.

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Antitumor Effects in Mice of the Intravenous Injection of Attenuated Salmonella Typhimurium

Cited by 72 publications

References 7 publications

AttenuatedSalmonellaengineered to produce human cytokine LIGHT inhibit tumor growth

AttenuatedSalmonellaengineered to produce human cytokine LIGHT inhibit tumor growth

Targeting tumor gene by shRNA-expressing Salmonella-mediated RNAi

Positron emission tomography (PET) imaging of tumor-localized Salmonella expressing HSV1-TK

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