14653 Background: We previously published that a genetically-altered Salmonella typhimurium, expressing GFP, could completely destroy subcutaneously-implanted PC-3 tumors in nude mice when injected locally or intravenously (PNAS 102, 755–60, 2005). The bacteria are leu-arg auxotrophs which enable the bacteria to grow in PC-3 tumors but not in normal tissue. Methods: In the current study, we explore the effect of this bacteria, termed S. typhimurium A1, on metastatic PC-3 tumors orthotopically implanted in nude mice. PC-3 is a non-hormone-dependent prostate cancer. 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 controls and followed until death without treatment. Ten mice were given the S. typhimurium A1 weekly intravenously, beginning at 2 weeks when the tumor GFP was first externally visible, and survival time was compared to the untreated mice. Ten additional non-tumor-bearing mice served as controls for the possible toxicity of S. typhimurium A1 and were also injected weekly with the bacteria intravenously. Results: Of the 10 mice with the PC-3 tumors injected weekly with S. typhimurium A1, 7 were alive and well at the time the last untreated mouse died. Currently, 4 treated mice remain alive and well 17 weeks following implantation. 3 of these 4 mice had no external fluorescence for the past 5 weeks despite discontinuing S. typhimurium A1. One mouse shows a progressive decrease in fluorescence, only a tiny spot if left. This mouse continues on S. typhimurium injection weekly. Conclusions: Injection of genetically-altered leu-arg-auxotrophic S. typhimurium into mice with metastatic PC-3 tumors has resulted in more than the tripling of lifespan of 4 of the mice. Three of the mice appear “cured” and have not external fluorescence despite discontinuing S. typhimurium treatment for the past 5 weeks. One mouse continues on weekly injections of S. typhimurium and is well with decreasing fluorescence. 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. No significant financial relationships to disclose.
Intraperitoneal administration of tumor-targeting Salmonella typhimurium A1-R inhibits disseminated human ovarian cancer and extends survival in nude mice
