Effect of Interleukin-8 Gene Silencing With Liposome-Encapsulated Small Interfering RNA on Ovarian Cancer Cell Growth

作者：William M. Merritt, Yvonne Gail Lin, Whitney A. Spannuth, Mavis S. Fletcher, Aparna A. Kamat, Liz Y. Han, Charles N. Landen, Nicholas Jennings, Koen De Geest, Robert R. Langley, Gabriel J. Villares, Angela M. Sanguino, Susan K. Lutgendorf, Gabriel Lopez‐Berestein, Menashe Bar‐Eli, Anil K. Sood · 发表于：JNCI Journal of the National Cancer Institute · 年份：2008 · DOI：10.1093/jnci/djn024 · 被引用次数：257 · 研究领域：Chemokine receptors and signaling、Immunotherapy and Immune Responses、Toxin Mechanisms and Immunotoxins

BACKGROUND: Interleukin-8 (IL-8) is a proangiogenic cytokine that is overexpressed in many human cancers. We investigated the clinical and biologic significance of IL-8 in ovarian carcinoma using human samples and orthotopic mouse models. METHODS: Tumor expression of IL-8 was assessed by immunohistochemistry among ovarian cancer patients (n = 102) with available clinical and survival data. We examined the effect of IL-8 gene silencing with small interfering RNAs incorporated into neutral liposomes (siRNA-DOPCs), alone and in combination with docetaxel, on in vivo tumor growth, angiogenesis (microvessel density), and tumor cell proliferation in mice (n = 10 per treatment group) bearing orthotopic taxane-sensitive (HeyA8 and SKOV3ip1) and taxane-resistant (SKOV3ip2.TR) ovarian tumors. All statistical tests were two-sided. RESULTS: Of the 102 cancer specimens, 43 (42%) had high IL-8 expression and 59 (58%) had low or no IL-8 expression; high IL-8 expression was associated with advanced tumor stage (P = .019), high tumor grade (P = .031), and worse survival (median survival for patients with high vs low IL-8 expression: 1.62 vs 3.79 years; P < .001). Compared with empty liposomes, IL-8 siRNA-DOPC reduced the mean tumor weight by 32% (95% confidence interval [CI] = 14% to 50%; P = .03) and 52% (95% CI = 27% to 78%; P = .03) in the HeyA8 and SKOV3ip1 mouse models, respectively. In all three mouse models, treatment with IL-8 siRNA-DOPC plus the taxane docetaxel reduced tumor growth ...