Oncotarget

Research Papers:

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

Yong Zhang, Wenluo Cao, Makoto Toneri, Nan Zhang, Tasuku Kiyuna, Takashi Murakami, Scott D. Nelson, Sarah M. Dry, Yunfeng Li, Shukuan Li, Xiaoen Wang, Huaiyu Ma, Arun S. Singh, Fritz C. Eilber, Robert M. Hoffman and Ming Zhao _

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Oncotarget. 2017; 8:54616-54628. https://doi.org/10.18632/oncotarget.17605

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Abstract

Yong Zhang1, Wenluo Cao1,2, Makoto Toneri1,2, Nan Zhang1, Tasuku Kiyuna1,2, Takashi Murakami1,2, Scott D. Nelson3, Sarah M. Dry3, Yunfeng Li3, Shukuan Li1, Xiaoen Wang1, Huaiyu Ma1, Arun S. Singh4, Fritz C. Eilber5, Robert M. Hoffman1,2 and Ming Zhao1

1AntiCancer, Inc., San Diego, California, USA

2Department of Surgery, University of California, San Diego, California, USA

3Department of Pathology, University of California, Los Angeles, California, USA

4Department of Hematology/Oncology, University of California, Los Angeles, California, USA

5Division of Surgical Oncology, University of California, Los Angeles, California, USA

Correspondence to:

Ming Zhao, email: [email protected]

Fritz C. Eilber, email: [email protected]

Keywords: Salmonella typhimurium A1-R, VNP20009, toxicity, tumor targeting, biodistribution

Received: March 01, 2017     Accepted: March 21, 2017     Published: May 03, 2017

ABSTRACT

Salmonella typhimurium A1-R (S. typhimurium 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 S. typhimurium A1-R and S. typhimurium VNP20009 (VNP 20009) were performed in a syngeneic tumor model growing in immunocompetent BALB/c mice. Single or multiple doses of S. typhimurium A1-R of 2.5 × 105 and 5 × 105 were tolerated. A single dose of 1 × 106 resulted in mouse death. S. typhimurium A1-R (5 × 105 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. S. typhimurium A1-R was cleared from other organs much more rapidly. S. typhimurium A1-R and VNP 20009 toxicity to the spleen and liver was minimal. S. typhimurium A1-R showed higher selective targeting to the necrotic areas of the tumors than VNP20009. S. typhimurium 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 S. typhimurium A1-R administration in BALB/c mice, which is also efficacious against tumor growth. The results of the present report indicate similar toxicity of S. typhimurium A1-R and VNP20009, but greater antitumor efficacy of S. typhimurium 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 S. typhimurium A1-R.


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