Lung metastasis targeting by a tumor-killing Salmonella typhimurium mutant.

Abstract

e13631 Background: We have previously developed a tumor-targeting double auxotroph of Salmonella typhimurium termed A1-R (Cancer Research 66, 7647-7652, 2006; Proc. Natl. Acad. Sci. USA 104, 10170-10174, 2007). A1-R requires arginine and leucine, which disable these bacteria from growing in normal tissue but allow the bacteria to have high antitumor virulence in nude mouse models. In the present study, we have observed the efficacy of A1-R bacteria on Lewis lung cancer-bearing C57 immunocompetent mice. Methods: Lung tumors were obtained after injection of 2×106 Lewis lung cancer cells, expressing red fluorescent protein (RFP), into the tail vein of C57 B16 immunocompetent mice. Three days after tumor cell transplantation, the animals were treated with A1-R bacteria via tail-vein injection. Results: Lung tumor growth was inhibited in the treated group, and the mice had much fewer lung metastases tumors compared to the untreated group. A1-R was also injected into the thoracic cavity of the Lewis lung cancer-bearing C57 mice weekly for three weeks. All animals were sacrificed at the end of the experiment. The excised lungs were weighed and imaged by RFP fluorescence. The lung tumors in the treated group were significantly smaller than in the untreated group. Intrathoracic injection of bacteria allowed 108 bacteria to be administered weekly to the host with no obvious toxicity. Various i.v. doses of A1-R were tested, including bolus treatment with a single i.v. injection, medium dose using weekly i.v. administration, and metronomic treatment using a small dose twice a week, i.v. In contrast to intrathoracic administration of A1-R, bolus treatment was toxic to the host. However, the medium i.v. dose and the i.v. metronomic dosing of A1-R were well tolerated. Conclusions: These results suggest that S. typhimurium A1-R is effective against metastatic tumors in immunocompetent mice which is important for future clinical development of bacterial cancer therapy. No significant financial relationships to disclose.