Abstract 2677: Determination of the optimal route of administration of Salmonella typhimurium A1-R to target breast cancer in nude mice

Abstract

Abstract We have previously developed the genetically-modified strain Salmonella typhimurium A1-R that selectively targets tumors. S. typhimurium A1-R is auxotrophic for leu and arg, which precludes it from growing in normal tissues but allows high tumor virulence. We report here the efficacy and safety of three different routes of S. typhimurium A1-R delivery oral (p.o.), intravenous (i.v.), and intra-tumor (i.t.) in nude mice with orthotopic human breast cancer. Nude mice with MDA-MB-435 human breast cancer expressing red fluorescence protein (RFP) were administered S. typhimurium A1-R by either of 3 routes: (p.o.: 2 × 108 CFU/200 αl; i.v.: 2.5 × 107 CFU/100 αl; i.t.: 2.5 × 107 CFU/50 µl) twice a week. Tumor growth was monitored by florescence imaging and caliper measurement in two dimensions. Treatment with S. typhimurium A1-R via all three routes resulted in effective targeting and tumor growth inhibition. Efficacy was observed earliest in the animals treated by i.v. injection. GFP-expressing S. typhimurium A1-R were imaged to target, colonize, and replicate in the human breast tumor, liver, and spleen as observed by fluorescence imaging. Bacterial colonization of tumor and normal organs at different time points were determined after S. typhimurium delivery by either of the 3 routes. S. typhimurium A1-R targeted tumors at much higher levels than normal organs with all 3 routes of administration. The bacteria replicated and survived longer in the tumor than normal organs with all 3 routes of administration. Two weeks after bacteria administration by all 3 routes, the bacteria disappeared from normal organs, but grew continuously in the tumor. The fewest bacteria were detected in normal organs after oral administration, which suggests oral administration has the highest safety. The i.v. route had the greatest anti-tumor efficacy. There were no obvious toxic effects on the host with any of the routes of administration. Non-tumor-bearing mice tolerated S. typhimurium A1-R, p.o., twice weekly treatment and could survive as long as untreated mice. The results of this study suggest that oral administration was the most safe to the host and the i.v. route was most effective for tumor targeting with S. typhimurium A1-R. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2677. doi:1538-7445.AM2012-2677