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Intratumoral Delivery and Suppression of Prostate Tumor Growth by Attenuated Salmonella enterica serovar typhimurium Carrying Plasmid-Based Small Interfering RNAs

¹ Prostate Diseases Prevention and Treatment Research Centre and Department of Pathophysiology, School of Basic Medicine, Jilin University, Changchun, P.R. China; ² Greenebaum Cancer Center, Department of Microbiology and Immunology, Molecular Biology Program, University of Maryland School Medicine; ³ Department of Diagnostic Sciences and Pathology, University of Maryland, Baltimore, Maryland; and ⁴ Laboratory of Enteric and Sexually Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland

Requests for reprints: Xuejian Zhao, Prostate Diseases Prevention and Treatment Research Centre and Department of Pathophysiology, School of Basic Medicine, Jilin University, Xinmin Street, Changchun, 130021, P.R. China. Phone: 86-431-563-2348; Fax: 86-431-563-2348; E-mail: pro_2{at}jlu.edu and De-Qi Xu, Laboratory of Enteric and Sexually Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892. Phone: 301-496-1894; Fax: 301-402-8701; E-mail: xud{at}cber.fda.gov.

The facultative anaerobic, invasive Salmonella enterica serovar typhimurium (S. typhimurium) has been shown to retard the growth of established tumors. We wondered if a more effective antitumor response could be achieved in vivo if these bacteria were used as tools for delivering specific molecular antitumor therapeutics. Constitutively activated transcription factor signal transducer and activator of transcription 3 (STAT3) promotes the survival of a number of human tumors. In this study, we investigated the relative efficacies of attenuated S. typhimurium alone or combined with Stat3-specific small interfering RNA (siRNA) in terms of tumor growth and metastasis. The bacteria preferentially homed into tumors over normal liver and spleen tissues in vivo. S. typhimurium expressing plasmid-based Stat3-specific siRNAs significantly inhibited tumor growth, reduced the number of metastastic organs, and extended the life time for C57BL6 mice bearing an implanted prostate tumor, versus bacterial treatment alone. These results suggest that attenuated S. typhimurium combined with an RNA interference approach might be more effective for the treatment of primary as well as metastatic cancer. [Cancer Res 2007;67(12):5859–64]

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