Toxicology and efficacy of tumor-targeting A1-R compared to VNP 20009 in a syngeneic mouse tumor model in immunocompetent mice.

A1-R ( A1-R) attenuated by leu and arg auxotrophy has been shown to target multiple types of cancer in mouse models. In the present study, toxicologic and biodistribution studies of tumor-targeting A1-R and VNP20009 (VNP 20009) were performed in a syngeneic tumor model growing in immunocompetent BALB/c mice. Single or multiple doses of A1-R of 2.5 × 10 and 5 × 10 were tolerated. A single dose of 1 × 10 resulted in mouse death. A1-R (5 × 10 CFU) was eliminated from the circulation, liver and spleen approximately 3-5 days after bacterial administration via the tail vein, but remained in the tumor in high amounts. A1-R was cleared from other organs much more rapidly. A1-R and VNP 20009 toxicity to the spleen and liver was minimal. A1-R showed higher selective targeting to the necrotic areas of the tumors than VNP20009. A1-R inhibited the growth of CT26 colon carcinoma to a greater extent at the same dose of VNP20009. In conclusion, we have determined a safe dose and schedule of A1-R administration in BALB/c mice, which is also efficacious against tumor growth. The results of the present report indicate similar toxicity of A1-R and VNP20009, but greater antitumor efficacy of A1-R in an immunocompetent animal. Since VNP2009 has already proven safe in a Phase I clinical trial, the present results indicate the high clinical potential of A1-R.