Journal of the National Cancer Institute Advance Access published online on February 26, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn024
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© The Author 2008. Published by Oxford University Press.
ARTICLES |
Effect of Interleukin-8 Gene Silencing With Liposome-Encapsulated Small Interfering RNA on Ovarian Cancer Cell Growth
Affiliations of authors: Departments of Gynecologic Oncology (WMM, YGL, WAS, AAK, LYH, CNL, NJ, AKS), Cancer Biology (RRL, GV, MMBE, AKS), and Experimental Therapeutics (AS, GLB), University of Texas M. D. Anderson Cancer Center, Houston, TX; Department of Pathology and Microbiology, Nebraska Medical Center, Omaha, NE (MSF); Department of Obstetrics and Gynecology, University of Iowa Hospitals and Clinics, Iowa City, IA (KDG); Department of Psychology, University of Iowa, Iowa City, IA (SKL)
Correspondence to: Anil K. Sood, MD, Departments of Gynecologic Oncology and Cancer Biology, Unit 1362, PO Box 301439, Houston, TX 77230-1439 (e-mail: asood{at}mdanderson.org).
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 the most compared with empty liposomes (77% to 98% reduction in tumor growth; P < .01 for all). In the HeyA8 and SKOV3ip1 models, tumors from mice treated with IL-8 siRNA-DOPC alone had lower microvessel density than tumors from mice treated with empty liposomes (HeyA8: 34% lower, 95% CI = 32% to 36% lower [P = .002]; SKOV3ip1: 39% lower, 95% CI = 34% to 44% lower [P = .007]). Compared with empty liposomes, IL-8 siRNA-DOPC plus docetaxel reduced tumor cell proliferation by 35% (95% CI = 25% to 44%; P < .001) and 38% (95% CI = 28% to 48%; P < .001) in the HeyA8 and SKOV3ip1 models, respectively.
Conclusions: Increased IL-8 expression is associated with poor clinical outcome in human ovarian carcinoma, and IL-8 gene silencing decreases tumor growth through antiangiogenic mechanisms.
| CONTEXT AND CAVEATS Prior knowledge The proangiogenic cytokine interleukin-8 (IL-8) is overexpressed in most human cancers, including ovarian carcinoma. In murine cancer models, IL-8 expression promotes tumor growth, angiogenesis, and metastasis, whereas monoclonal antibody blockade of IL-8 activity decreases tumor growth. Study design IL-8 expression was examined in tumor specimens from ovarian cancer patients with available clinical and survival data. The therapeutic efficacy of using neutral liposome–encapsulated small interfering RNAs (siRNAs) to silence IL-8 gene expression was examined in orthotopic mouse models of ovarian cancer. Contribution Increased IL-8 expression in human ovarian carcinoma was associated with worse clinical outcome. In the mouse models, siRNA-mediated IL-8 gene silencing decreased tumor growth through antiangiogenic mechanisms. Implications IL-8 may be a potential therapeutic target in ovarian cancer. Limitations The cell lines used to create the mouse models may not accurately reflect the heterogeneity seen in human tumors. Patterns of tumor growth in mice could differ from that in humans because of differences in the host immune response. Because mice do not produce IL-8, it is possible that toxic effects of IL-8 silencing may not be fully realized in this preclinical model.
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Manuscript received May 29, 2007; revised December 21, 2007; accepted January 14, 2008.
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