title: Clostridium sporogenes delivers interleukin-12 to hypoxic tumours, producing antitumour activity without significant toxicity.
abstract: Clostridium sporogenes ATCC 3584 is an obligate anaerobe that has been reported to possess excellent tumour-targeting capacity. Here, we use Cl. sporogenes as a vector to deliver IL-12, a potent antitumour cytokine that bears numerous antitumour properties but that has limited clinical applications due to its strong toxicity when delivered systemically. In this study, Cl. sporogenes was genetically engineered to secrete murine IL-12, and its antitumour efficacy and toxicity were investigated in a murine EMT6 mammary carcinoma model. After intravenous injection, Cl. sporogenes was able to selectively settle and reproduce in the tumours without encroaching on normal tissues, resulting in a clear delay of tumour growth and a 14·3% cure rate. Importantly, the mice showed no obvious toxicity-associated side effects, such as diarrhoea and weight loss, during the treatment process. The significant antitumour efficacy and low toxicity of this treatment may be explained by the selective tumour-targeting properties of Cl. sporogenes and by the sustained release of IL-12 accompanying bacterial proliferation. This moderate local IL-12 concentration would not induce the severe response in the entire body, that is inevitable when IL-12 is administered directly.
  
  
  CONCLUSIONS
  Interleukin-12 (IL-12) is a potent antitumour cytokine, but it is toxic when administrated systemically. This study demonstrates that murine IL-12 can be systemically delivered to hypoxic sites in solid tumours by Clostridium sporogenes, producing a clear delay in tumour growth and a 14·3% cure rate in a mouse tumour model. Importantly, there is no obvious toxicity associated with IL-12 during the treatment process. This result may be accounted for by the excellent tumour-targeting capacity of Cl. sporogenes, targeting IL-12 directly to the tumour site instead of to the entire body.
authors.affiliation: Laboratory of Pathogenic Biology, Medical College, Qingdao University, Qingdao, 266071, China.
authors.forename: Y-L
authors.initials: YL
authors.lastname: Zhang
authors.forename: R
authors.initials: R
authors.lastname: Lü
authors.forename: Z-S
authors.initials: ZS
authors.lastname: Chang
authors.forename: W-Q
authors.initials: WQ
authors.lastname: Zhang
authors.forename: Q-B
authors.initials: QB
authors.lastname: Wang
authors.forename: S-Y
authors.initials: SY
authors.lastname: Ding
authors.forename: W
authors.initials: W
authors.lastname: Zhao
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D003013:Clostridium / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000382:microbiology* / Q000628:therapy*; D008807:Mice, Inbred BALB C; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma
keywords: Clostridium sporogenes; EMT6; IL-12; antitumour efficacy; deliver; mammary carcinoma; toxicity