Intratumoral Delivery and Suppression of Prostate Tumor Growth by AttenuatedSalmonella entericaserovartyphimuriumCarrying Plasmid-Based Small Interfering RNAs

Abstract

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]

Plasmid-based Survivin shRNA and GRIM-19 carried by attenuated Salmonella suppresses tumor cell growth

“…In fact, attenuated Salmonella vectors have already been applied in vivo for the treatment of some malignancies, such as PCa. 24 Further efforts are clearly necessary for exploring the therapeutic value of parenteral administration of attenuated Salmonella carrying various anti-tumor therapies. In addition, the use of additional cell lines would be informative.…”

“…Attenuated S. typhimurium as a gene delivery vector provides more advantages when compared to viral vectors, such as good targeting. [24][25][26] For example, Salmonella can: (i) specifically colonize in hypoxic tumor tissues if administered through the intravenous or intraperitoneal routes; (ii) be used across a wide range of tissues; (iii) express foreign genes in any hypoxic region, unlike a retroviral vector which can only infect dividing cells; (iv) proliferate in vivo and efficiently express exogenous gene products; and by itself exerts antitumor effects; (v) be an ideal and safe vehicle for gene transfer since that it is sensitive to antibiotics and small doses of currently available antibiotics can kill it; and (vi) not be rejected by the host upon longterm use. Taken together, these characteristics make S. typhimurium an ideal vector for gene therapy.…”

Plasmid-based Stat3 siRNA delivered by hydroxyapatite nanoparticles suppresses mouse prostate tumour growth in vivo

“…Primary tumour blocks (1.5 mm 3 ) were implanted into the right abdomens of C57BL/6 mice as previously described. 16 On day 5, tumours were visible at the sites of implantation (mean volume: 52.7612.1 mm 3 , n58). Cancer bearing mice were independently injected intratumourally with PBS, HAP-si-scramble or HAP-si-Stat3, which was repeated on day 20.…”

Gene therapy for cancer: bacteria-mediated anti-angiogenesis therapy

“…66 Combined oncolytic and siRNA therapy using systematically administered attenuated S. typhimurium expressing siRNA against tumor transcription factor STAT3 has also been evaluated. 67 Both of these studies demonstrated higher efficiency for combined therapy compared with treatment with nonRNAi-inducing bacteria. In addition to being used to produce and deliver silencing short-hairpin RNA, bacteria can also been exploited to deliver eukaryotic short-hairpin RNA-expression plasmids to mammalian tumor cells.…”