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ToxSci Advance Access published online on September 14, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi316
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received June 28, 2005
Accepted September 6, 2005

Safety Evaluation

Pharmacologic and Toxicologic Evaluation of C. novyi-NT Spores

Luis A. Diaz Jr.1, Ian Cheong 1, Catherine A. Foss 2, Xiaosong Zhang 1, Brock A. Peters 1, Nishant Agrawal 3, Chetan Bettegowda 1, Baktiar Karim 4, Guosheng Liu 4, Khalid Khan 4, Xin Huang 1, Manu Kohli 1, Long H. Dang 5, Paul Hwang 6, Ahava Vogelstein 1, Elizabeth Garrett-Mayer 7, Barry Kobrin 7, Martin Pomper 2, Shibin Zhou 1*, Kenneth W. Kinzler 1, Bert Vogelstein 1, and David L. Huso 4

1 Howard Hughes Medical Institute, The Johns Hopkins School of Medicine, Baltimore, Maryland 21231, USA; Sidney Kimmel Cancer Center, The Johns Hopkins School of Medicine, Baltimore, Maryland 21231, USA
2 Department of Radiology and Radiological Sciences, The Johns Hopkins School of Medicine, Baltimore, Maryland 21231, USA
3 Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins School of Medicine, Baltimore, Maryland 21231, USA
4 Department of Comparative Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland 21231, USA
5 Department of Oncology, University of Michigan, Ann Arbor, Michigan, 48104, USA
6 Cardiovascular Branch, NHLBI, NIH, Bethesda, MD 20892, USA
7 Sidney Kimmel Cancer Center, The Johns Hopkins School of Medicine, Baltimore, Maryland 21231, USA

* To whom correspondence should be addressed.
Shibin Zhou, E-mail: sbzhou{at}jhmi.edu


  Abstract

Clostridium novyi-NT (C. novyi-NT) spores have been shown to be potent therapeutic agents in experimental tumors of mice and rabbits. In the current study, pharmacologic and toxicologic studies were performed to better understand the factors influencing the efficacy and toxicity of this form of therapy. We found that spores were rapidly cleared from the circulation by the reticuloendothelial system (RES). Even after large doses were administered, no clinical toxicity was observed in healthy mice or rabbits. The spores were also not toxic in mice harboring poorly vascularized non-neoplastic lesions, including myocardial infarcts. In tumor-bearing mice, toxicity appeared related to tumor size and spore dose, as expected with any bacterial infection. However, there was no laboratory or histopathologic evidence of sepsis and the toxicity could be effectively controlled by simple hydration.


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