Abstract
Background
Some anaerobic and facultatively anaerobic bacteria have been used experimentally as anticancer agents because of their selective growth in tumors. In this study, we exploited attenuated Salmonella choleraesuis as a tumoricidal agent and a vector to deliver the endostatin gene for tumorโtargeted gene therapy.
Methods
Attenuated S. choleraesuis carrying a eukaryotic expression plasmid encoding reporter gene was used to evaluate its abilities of tumor targeting and gene delivery in three syngeneic murine tumor models. Furthermore, S. choleraesuis carrying the endostatin expression vector was administered intraperitoneally into tumorโbearing mice, and its antitumor effect was evaluated.
Results
Systemically administered S. choleraesuis preferentially accumulated within tumors for at least 10 days, forming tumorโtoโnormal tissue ratios exceeding 1000โ10 000 : 1. Transgene expression via S. choleraesuisโmediated gene transfer also persisted for at least 10 days. Host immune responses and tumor hypoxia may influence tumorโtargeting potential of S. choleraesuis. When systemically administered into mice bearing melanomas or bladder tumors, S. choleraesuis carrying the endostatin expression vector significantly inhibited tumor growth by 40โ70% and prolonged survival of the mice. Furthermore, immunohistochemical studies in the tumors revealed decreased intratumoral microvessel density, reduced expression of vascular endothelial growth factor (VEGF), and increased infiltration of CD8^+^ T cells.
Conclusions
These results suggest that tumorโtargeted gene therapy using S. choleraesuis carrying the endostatin expression vector, which exerts tumoricidal and antiangiogenic activities, represents a promising strategy for the treatment of solid tumors. Copyright ยฉ 2004 John Wiley & Sons, Ltd.