Amino-acid auxotrophic Salmonella typhimurium profoundly increases survival in nude mice with metastatic PC-3 prostate tumors Free

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We previously published that a genetically-altered Salmonella typhimurium could cure subcutaneously-implanted PC-3 tumors in nude mice when injected locally or intravenously (Zhao, M., et al. Tumor-targeting bacterial therapy with amino acid auxotrophs of GFP-expressing Salmonella typhimurium. Proc. Natl. Acad. Sci USA 102, 755-760, 2005). The mechanism for this effect is attributed to the auxotrophic mutations in the bacteria treated with nitrosoguamidine, resulting in Leu/Arg dependence. The auxotrophic mutations allow the bacteria to grow in PC-3 tumors but not in normal tissue. In the current study, we explored the effect of this bacteria, termed S. typhimurium A1 (A1), on metastatic PC-3 tumors orthotopically implanted in nude mice. PC-3 is a non-hormone-dependent prostate cancer and is a prototype of a type of metastatic tumor that results in the killing of 40,000 new prostate cancer patients yearly. In this study, 20 mice were implanted orthotopically with PC-3 tumors expressing GFP. Approximately 2 weeks following implantation, the tumors were externally imageable. Ten of the 20 mice served as untreated controls and were followed until death. Ten mice were given A1 weekly intravenously and survival time was compared to the untreated mice. An additional non-tumor-bearing 10 mice served as controls for the possible toxicity of S. typhimurium A1 and were injected weekly with the bacteria intravenously. Progressive tumor enlargement and metastasis were externally imaged by GFP expression of the tumors. All untreated mice died within 6 weeks of tumor implantation. Of the 10 mice with the PC-3 tumors injected weekly with A1, beginning at 2 weeks when the tumor GFP was first externally visible, 7 were alive and well at the time the last untreated mouse died. Currently, 4 treated mice remain alive and well 12 weeks following implantation and are still being injected weekly with S. typhimurium A1. Since human prostate cancer eventually becomes non-androgen-dependent similar to PC-3 tumors, genetically-altered bacteria represent a novel potential treatment for this disease.