Biotechnologically Relevant Enzymes and Proteins

Applied Microbiology and Biotechnology

, Volume 97, Issue 10, pp 4393-4401

Tumor-targeting Salmonella typhimurium, a natural tool for activation of prodrug 6MePdR and their combination therapy in murine melanoma model

  • Guo ChenAffiliated withThe State Key Laboratory of Pharmaceutical Biotechnology, Nanjing UniversityDepartment of Biochemistry, College of Life Sciences, Nanjing University
  • , Bo TangAffiliated withThe State Key Laboratory of Pharmaceutical Biotechnology, Nanjing UniversityChangzhou High-Tech Research Institute of Nanjing UniversityDepartment of Biochemistry, College of Life Sciences, Nanjing UniversityJiangsu TargetPharma Laboratories Inc.
  • , Bing-Ya YangAffiliated withThe State Key Laboratory of Pharmaceutical Biotechnology, Nanjing UniversityDepartment of Biochemistry, College of Life Sciences, Nanjing University
  • , Jian-Xiang ChenAffiliated withThe State Key Laboratory of Pharmaceutical Biotechnology, Nanjing UniversityDepartment of Biochemistry, College of Life Sciences, Nanjing University
  • , Jia-Hua ZhouAffiliated withDepartment of Biliary–Pancreatic Surgery, Zhongda Hospital of Southeast University
  • , Jia-Huang LiAffiliated withThe State Key Laboratory of Pharmaceutical Biotechnology, Nanjing UniversityDepartment of Biochemistry, College of Life Sciences, Nanjing University Email author 
  • , Zi-Chun HuaAffiliated withThe State Key Laboratory of Pharmaceutical Biotechnology, Nanjing UniversityChangzhou High-Tech Research Institute of Nanjing UniversityDepartment of Biochemistry, College of Life Sciences, Nanjing UniversityJiangsu TargetPharma Laboratories Inc. Email author 

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Abstract

The PNP/6-methylpurine 2′-deoxyriboside (6MePdR) system is an efficient gene-directed enzyme prodrug therapy system with significant antitumor activities. In this system, Escherichia coli purine nucleoside phosphorylase (ePNP) activates nontoxic 6MePdR into potent antitumor drug 6-methylpurine (6MeP). The Salmonella typhimurium PNP (sPNP) gene has a 96-% sequence homology in comparison with ePNP and also has the ability to convert 6MePdR to 6MeP. In this study, we used tumor-targeting S. typhimurium VNP20009 expressing endogenous PNP gene constitutively to activate 6MePdR and a combination treatment of bacteria and prodrug in B16F10 melanoma model. The conversion of 6MePdR to 6MeP by S. typhimurium was analyzed by HPLC and the enzyme activity of sPNP was confirmed by in vitro (tetrazolium-based colorimetric assay) MTT cytotoxicity assay. After systemic administration of VNP20009 to mice, the bacteria largely accumulated and specifically delivered endogenous sPNP in the tumor. In comparison with VNP20009 or 6MePdR treatment alone, combined administration of VNP20009 followed by 6MePdR treatment significantly delayed the growth of B16F10 tumor and increased the CD8+ T-cell infiltration. In summary, our results demonstrated that the combination therapy of S. typhimurium and prodrug 6MePdR is a promising strategy for cancer therapy.

Keywords

Salmonella typhimurium Tumor therapy Purine nucleoside phosphorylase Bacteria/prodrug therapy system