TY - JOUR
T1 - Efficiency of conditionally attenuated Salmonella enterica serovar typhimurium in bacterium-mediated tumor therapy
AU - Frahm, Michael
AU - Felgner, Sebastian
AU - Kocijancic, Dino
AU - Rohde, Manfred
AU - Hensel, Michael
AU - Curtiss, Iii Roy
AU - Erhardt, Marc
AU - Weiss, Siegfried
N1 - Publisher Copyright:
© 2015 Frahm et al.
PY - 2015
Y1 - 2015
N2 - 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 tumortargeting 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.
AB - 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 tumortargeting 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.
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U2 - 10.1128/mBio.00254-15
DO - 10.1128/mBio.00254-15
M3 - Article
AN - SCOPUS:84928796820
SN - 2161-2129
VL - 6
SP - 1
EP - 11
JO - mBio
JF - mBio
IS - 2
M1 - e00254-15
ER -