title: Targeted therapy with a Salmonella typhimurium leucine-arginine auxotroph cures orthotopic human breast tumors in nude mice.
abstract: We report here a modified auxotrophic strain of Salmonella typhimurium that can target and cure breast tumors in orthotopic mouse models. We have previously reported development of a genetically modified strain of S. typhimurium, selected for prostate tumor targeting and therapy in vivo. The strain, termed S. typhimurium A1, selectively grew in prostate tumors in xenograft models causing tumor regression. In contrast, normal tissue was cleared of these bacteria even in immunodeficient athymic mice with no apparent side effects. A1 is auxotrophic (leucine-arginine dependent) but apparently receives sufficient nutritional support only from tumor tissue. The ability to grow in viable tumor tissue may account, in part, for the unique antitumor efficacy of the strain. In the present report, to increase tumor-targeting capability of A1, the strain was reisolated after infection of a human colon tumor growing in nude mice. The tumor-isolated strain, termed A1-R, had increased targeting for tumor cells in vivo as well as in vitro compared with A1. Treatment with A1-R resulted in highly effective tumor targeting, including viable tumor tissue and significant tumor shrinkage in mice with s.c. or orthotopic human breast cancer xerographs. Survival of the treated animals was significantly prolonged. Forty percent of treated mice were cured completely and survived as long as non-tumor-bearing mice. These results suggest that amino acid auxotrophic virulent bacteria, which selectively infect and attack viable tumor tissue, are a promising approach to cancer therapy.
authors.affiliation: AntiCancer, Inc., 7917 Ostrow Street, San Diego, CA 92111, USA. all@anticancer.com
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Meng
authors.initials: M
authors.lastname: Yang
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Ma
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Li
authors.forename: Xiuying
authors.initials: X
authors.lastname: Tan
authors.forename: Shukuan
authors.initials: S
authors.lastname: Li
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Yang
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism; D001943:Breast Neoplasms / Q000382:microbiology* / Q000473:pathology / Q000628:therapy*; D002448:Cell Adhesion / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D019073:HT29 Cells; D006801:Humans; D007930:Leucine / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D012486:Salmonella typhimurium / Q000235:genetics / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D049452:Green Fluorescent Proteins; D001120:Arginine; D007930:Leucine