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Adjuvant Therapy with Small Hairpin RNA Interference Prevents Non–Small Cell Lung Cancer Metastasis Development in Mice

Departments of ¹ Medicine, Hematology and Oncology, ² Pediatric Hematology and Oncology, and ³ Medical Biochemistry, University of Münster, Münster, Germany; ⁴ Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts; and ⁵ Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom

Requests for reprints: Carsten Müller-Tidow, Department of Medicine A, Hematology and Oncology, University of Münster, Domagkstr. 3, 48129 Münster, Germany. Phone: 49-251-835-2995; Fax: 49-251-835-2673; E-mail: muellerc{at}uni-muenster.de.

Key Words: adjuvant • hairpin • metastasis • mice • NSCLC • RNAi

Development of distant metastasis is the major reason for cancer-related deaths worldwide. Adjuvant therapy approaches after local therapies are most effective when specific targets are inhibited. Recently, we identified S100P overexpression as a strong predictor for metastasis development in early-stage non–small cell lung cancer (NSCLC) patients. Here, we show that S100P overexpression increased angiogenesis in and metastasis formation from s.c. xenotransplants of NSCLC cells. Plasmid-derived short hairpin RNAs (shRNA) were developed as specific adjuvant therapy. I.v. injected shRNA against S100P significantly decreased S100P protein expression in xenograft tumors and inhibited tumor angiogenesis in vivo. Metastasis formation 8 weeks after primary tumor resection was significantly reduced. Lung metastases developed in 31% of mice treated with S100P-targeting shRNAs compared with 64% in control shRNA–treated mice (P < 0.05). These findings suggest that RNA interference–based therapy approaches can be highly effective in the adjuvant setting. [Cancer Res 2008;68(6):1896–904]

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