Use of tumor-targeting salmonella typhimurium to eradicate human glioma in an orthotopic model in nude mice

2044 Background: Prognosis remains poor for glioma and therefore requires new approaches. We have previously developed a genetically-engineered strain of Salmonella typhimurium, A1-R, that targets tumors without overt toxicity in mouse models (Proc. Natl. Acad. Sci. USA 102, 755-760, 2005; Cancer Research 66, 7647-7652, 2006; Proc. Natl. Acad. Sci. USA 104, 10170-10174, 2007; Expert Opinion on Drug Discovery 7, 73-83, 2012). In the present study, we demonstrated that Salmonella typhimurium A1-R can inhibit and eradicate human glioma in an orthotopic nude mouse model. Methods: S. typhimuirum A1-R was administered by injection through a craniotomy open-window or intravenously in nude mice. To establish the model, 2×105 U87 human glioma cells, expressing red fluorescent protein (RFP), were injected stereotactically into the mouse brain through the craniotomy open window. Two weeks after glioma-cell implantation, mice were treated with S. typhimurium A1-R (2×107 CFU / 200 μl intravenous injection [i.v.] or 1×106 CFU / 1 μl intracranial injection [i.c.]) once a week for 3 weeks. Results: Brain tumors were observed by fluorescence imaging through the craniotomy open window over time. S. typhimurium A1-R, administered i.c., inhibited brain tumor growth 7.6-fold compared with untreated mice (p = 0.009) and improved survival 73% (p = 0.001). Two of ten mice had their tumors eradicated. Intravenous administration of S. typhimurium A1-R was not effective. Conclusions: The results of the present study demonstrate that bacterial therapy of glioma is a novel, effective and safe treatment strategy in a highly treatment-resistance cancer in an orthothopic model, a first step toward clinical development.