title: Efficiency of conditionally attenuated Salmonella enterica serovar Typhimurium in bacterium-mediated tumor therapy.
abstract: Increasing numbers of cancer cases generate a great urge for new treatment options. Applying bacteria like Salmonella enterica serovar Typhimurium for cancer therapy represents an intensively explored option. These bacteria have been shown not only to colonize solid tumors but also to exhibit an intrinsic antitumor effect. In addition, they could serve as tumor-targeting vectors for therapeutic molecules. However, the pathogenic S. Typhimurium strains used for tumor therapy need to be attenuated for safe application. Here, lipopolysaccharide (LPS) deletion mutants (ΔrfaL, ΔrfaG, ΔrfaH, ΔrfaD, ΔrfaP, and ΔmsbB mutants) of Salmonella were investigated for efficiency in tumor therapy. Of such variants, the ΔrfaD and ΔrfaG deep rough mutants exhibited the best tumor specificity and lowest pathogenicity. However, the intrinsic antitumor effect was found to be weak. To overcome this limitation, conditional attenuation was tested by complementing the mutants with an inducible arabinose promoter. The chromosomal integration of the respective LPS biosynthesis genes into the araBAD locus exhibited the best balance of attenuation and therapeutic benefit. Thus, the present study establishes a basis for the development of an applicably cancer therapeutic bacterium.
  
  
  OBJECTIVE
  Cancer has become the second most frequent cause of death in industrialized countries. This and the drawbacks of routine therapies generate an urgent need for novel treatment options. Applying appropriately modified S. Typhimurium for therapy represents the major challenge of bacterium-mediated tumor therapy. In the present study, we demonstrated that Salmonella bacteria conditionally modified in their LPS phenotype exhibit a safe tumor-targeting phenotype. Moreover, they could represent a suitable vehicle to shuttle therapeutic compounds directly into cancerous tissue without harming the host.
authors: Department of Molecular Immunology, Helmholtz Center for Infection Research, Braunschweig, Germany.
authors: Michael
authors: M
authors: Frahm
authors: Department of Molecular Immunology, Helmholtz Center for Infection Research, Braunschweig, Germany sebastian.felgner@helmholtz-hzi.de.
authors: Sebastian
authors: S
authors: Felgner
authors: Department of Molecular Immunology, Helmholtz Center for Infection Research, Braunschweig, Germany.
authors: Dino
authors: D
authors: Kocijancic
authors: Central Facility for Microscopy, Helmholtz Center for Infection Research, Braunschweig, Germany.
authors: Manfred
authors: M
authors: Rohde
authors: Division of Microbiology, University of Osnabrück, Osnabrück, Germany.
authors: Michael
authors: M
authors: Hensel
authors: Biodesign Institute, Center for Infectious Diseases and Vaccinology, Tempe, Arizona, USA.
authors: Roy
authors: R
authors: Curtiss
authors: Junior Research Group Infection Biology of Salmonella, Helmholtz Center for Infection Research, Braunschweig, Germany.
authors: Marc
authors: M
authors: Erhardt
authors: Department of Molecular Immunology, Helmholtz Center for Infection Research, Braunschweig, Germany.
authors: Siegfried
authors: S
authors: Weiss
mesh_terms: D000818:Animals; D001691:Biological Therapy / Q000379:methods*; D004195:Disease Models, Animal; D017353:Gene Deletion; D015964:Gene Expression Regulation, Bacterial; D008070:Lipopolysaccharides / Q000172:deficiency; D060847:Metabolic Engineering / Q000379:methods; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000628:therapy*; D030781:Organisms, Genetically Modified; D012486:Salmonella typhimurium / Q000235:genetics / Q000254:growth & development*; D014774:Virulence
chemical_list: D008070:Lipopolysaccharides