Endostatin gene therapy delivered by Salmonella choleraesuis in murine tumor models

Che Hsin Lee, Chao-Liang Wu, Ai-Li Shiau

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish
Pages (from-to)1382-1393
Number of pages12
JournalJournal of Gene Medicine
Volume6
Issue number12
DOIs
Publication statusPublished - 2004 Dec

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Endostatins
Salmonella
Genetic Therapy
Neoplasms
Gene Targeting
Anaerobic Bacteria
Growth
Microvessels
Transgenes
Reporter Genes
Urinary Bladder Neoplasms
Antineoplastic Agents
Vascular Endothelial Growth Factor A
Genes
Melanoma

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

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title = "Endostatin gene therapy delivered by Salmonella choleraesuis in murine tumor models",
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 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.",
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Endostatin gene therapy delivered by Salmonella choleraesuis in murine tumor models. / Lee, Che Hsin; Wu, Chao-Liang; Shiau, Ai-Li.

In: Journal of Gene Medicine, Vol. 6, No. 12, 12.2004, p. 1382-1393.

Research output: Contribution to journalArticle

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