title: Primer dosing of S. typhimurium A1-R potentiates tumor-targeting and efficacy in immunocompetent mice.
abstract: We developed the tumor-targeting strain Salmonella typhimuium A1-R (A1-R) and have shown it to be active against a number of tumor types in nude mice. However, in immunocompetent mice, dosing of A1-R has to be adjusted to avoid toxicity. In the present study, we developed a strategy to maximize efficacy and minimize toxicity for A1-R tumor-targeting in immunocompetent mice implanted with the Lewis lung carcinoma. A small primer dose of A1-R was first administered (1×10(6) colony forming unit [cfu] i.v.) followed by a high dose (1×10(7) cfu i.v.) four hours later. The primer-dose strategy resulted in smaller tumors and no observable side-effects compared to treatment with high-dose-alone. The serum level of tumor necrosis factor (TNF-α) was elevated in the mice treated with primer dose compared to mice only given the high dose. Tumor vessel destruction was enhanced by primer dosing of A1-R in immuno-competent transgenic mice expressing the nestin-driven green fluorescent protein, which is selectively expressed in nascent blood vessels. The primer-dose may activate TNF-α and other cytokines in the mouse, necessary for invasion of the tumor by the bacteria, as well as enhance tumor vessel destruction, thereby allowing a subsequent therapeutic dose to be effective and safe. The results of the present study suggest effective future clinical strategies of bacterial treatment of cancer.
authors.affiliation: AntiCancer, Inc., 7917 Ostrow Street, SanDiego, CA 92111, USA.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Tome
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Masashi
authors.initials: M
authors.lastname: Momiyama
authors.forename: Hiroki
authors.initials: H
authors.lastname: Maehara
authors.forename: Fuminori
authors.initials: F
authors.lastname: Kanaya
authors.forename: Katsuro
authors.initials: K
authors.lastname: Tomita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuchiya
authors.forename: Michael
authors.initials: M
authors.lastname: Bouvet
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000382:microbiology / Q000628:therapy*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007121:Immunocompetence; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000382:microbiology / Q000628:therapy*; D012486:Salmonella typhimurium / Q000472:pathogenicity*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins