Endostatin gene therapy delivered by Salmonella choleraesuis in murine tumor models.
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 tumor-targeted 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 tumor-bearing mice, and its antitumor effect was evaluated.


RESULTS
Systemically administered S. choleraesuis preferentially accumulated within tumors for at least 10 days, forming tumor-to-normal tissue ratios exceeding 1000-10,000 : 1. Transgene expression via S. choleraesuis-mediated gene transfer also persisted for at least 10 days. Host immune responses and tumor hypoxia may influence tumor-targeting 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 40-70% 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 tumor-targeted 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.
Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan.
Che-Hsin
CH
Lee
Chao-Liang
CL
Wu
Ai-Li
AL
Shiau
D020533:Angiogenesis Inhibitors / Q000235:genetics*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000662:veterinary; D016923:Cell Death; D015687:Cell Hypoxia; D049109:Cell Proliferation; D004195:Disease Models, Animal; D043169:Endostatins / Q000235:genetics*; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D007150:Immunohistochemistry; D007263:Infusions, Parenteral; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000662:veterinary; D008545:Melanoma / Q000235:genetics / Q000473:pathology / Q000662:veterinary; D051379:Mice; D012475:Salmonella / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology / Q000662:veterinary; D019076:Transgenes; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000473:pathology / Q000662:veterinary
D020533:Angiogenesis Inhibitors; D043169:Endostatins