Journal of the National Cancer Institute Advance Access originally published online on September 23, 2008
JNCI Journal of the National Cancer Institute 2008 100(19):1389-1400; doi:10.1093/jnci/djn308
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© The Author 2008. Published by Oxford University Press.
ARTICLES |
A Genetically Enhanced Anaerobic Bacterium for Oncopathic Therapy of Pancreatic Cancer
Affiliations of authors: Departments of Gene and Cell Medicine (ZL, SLCW), Pathology (JF), Community and Preventive Medicine (JM), and Microbiology (JW), Mount Sinai School of Medicine, New York, NY
Correspondence to: Savio L. C. Woo, PhD, Department of Gene and Cell Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1496, New York, NY 10029-6574 (e-mail: savio.woo{at}mssm.edu).
Background: A major obstacle in treatment of solid tumors is the inefficient delivery of therapeutic agents to the hypoxic cores. Hypoxia offers the potential for anaerobic bacteria colonization and tumor destruction by the bacteria, and dormant spores of wild-type Clostridium perfringens (Cp) germinate and proliferate within the hypoxic cores of pancreatic tumors in mice. However, the oncopathic effects of Cp were limited by host inflammatory responses and by Cp’s residual tolerance to oxygen, which caused toxic effects in animals.
Methods: Recombinant Cp strains in which superoxide dismutase, a major oxygen tolerance gene, was deleted (Cp/sod–) were constructed to enhance its selective growth in tumors. In addition, Panton-Valentine Leukocidin (PVL), an inflammation-suppressing gene from Staphylococcus aureus, was inserted into the Cp/sod– genome to enhance its oncopathic potency. The ability of the recombinant Cp strains to kill tumors was investigated in C57/BL6 mice bearing murine PANC02 tumors. Systemic and organ toxic effects were assessed by monitoring serum chemistries and histopathological examination. Statistical tests were two-sided.
Results: Cp/sod– showed reduced toxic effects compared with wild-type Cp when spores were administered intravenously into PANC02 tumor–bearing mice. Mice treated with Cp/sod–/PVL spores demonstrated a reduction in neutrophils and macrophages in tumors, logarithmically elevated growth of intratumoral bacteria, enhanced tumor necrosis, and substantially prolonged survival without apparent systemic and organ toxic effects, compared with mice treated with both wild-type Cp and Cp/sod– spores. Accordingly, 47% of Cp/sod–/PVL–treated mice (n = 15) achieved tumor-free survival for over 120 days, whereas all mice treated with Cp/sod– or phosphate-buffered saline (n = 10 per group) died within 50 days. The median survival for Cp/sod–/PVL–treated mice was 77 days (95% confidence interval [CI] = 45 to 120 days) and for Cp/sod––treated mice was 30 days (95% CI = 23 to 36 days; P < .001).
Conclusions: Cp/sod–/PVL provides a prototype for a novel class of oncopathic microbes that may have potential for the safe and effective treatment of pancreatic cancer and other poorly vascularized tumors.
| CONTEXT AND CAVEATS Prior knowledge Live anaerobic bacteria can selectively grow in the hypoxic cores of tumors, but use of Clostridium perfringens (Cp) as a cancer therapy has been limited by toxic effects due to host inflammatory responses and to this bacterium’s residual tolerance to oxygen. Study design Mutant strains of Cp were constructed in which the superoxide dismutase (sod) gene was deleted to further enhance growth in tumors and in which the Panton-Valentine Leukocidin (PVL) gene from Staphylococcus aureus was inserted to limit severe inflammation by killing tumor-infiltrating macrophages and neutrophils. Spores of the double mutant were then compared with sod– and wild-type Cp in terms of their growth properties and abilities to kill pancreatic tumors in mice. Contribution Cp/sod–/PVL bacteria grew more rapidly and killed macrophages and neutrophils more effectively than previous strains in pancreatic tumors in treated mice. Tumor necrosis and overall survival of Cp/sod–/PVL–treated mice were substantially increased compared with mice treated with earlier strains of these bacteria. Implications Deletion of sod and insertion of PVL are improvements in the development of oncopathic Cp. Limitations Cp/sod–/PVL bacteria did not eliminate all tumor cells. They were tested on only one tumor type in mice and must be made less pathogenic before tests on humans can be considered. From the Editors
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Manuscript received November 30, 2007; revised July 10, 2008; accepted July 30, 2008.
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J Natl Cancer Inst 2008 100: 1337.