166 COMBINATION THERAPY WITH HUMANIZED ANTIHUMAN IL-6R ANTIBODY AND INTERFERON-α SUCCESSFULLY PREVENTS THE GROWTH OF 786-O RENAL CELL CARCINOMA CELLS

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research (I)1 Apr 2013166 COMBINATION THERAPY WITH HUMANIZED ANTIHUMAN IL-6R ANTIBODY AND INTERFERON-α SUCCESSFULLY PREVENTS THE GROWTH OF 786-O RENAL CELL CARCINOMA CELLS Kei Ishibashi, Toshiki Oguro, Shin Kumagai, Norio Takahashi, Nobuhiro Haga, Masanori Nomiya, Tomohiko Yanagida, Ken Aikawa, and Yoshiyuki Kojima Kei IshibashiKei Ishibashi Fukushima, Japan More articles by this author , Toshiki OguroToshiki Oguro Fukushima, Japan More articles by this author , Shin KumagaiShin Kumagai Fukushima, Japan More articles by this author , Norio TakahashiNorio Takahashi Fukushima, Japan More articles by this author , Nobuhiro HagaNobuhiro Haga Fukushima, Japan More articles by this author , Masanori NomiyaMasanori Nomiya Fukushima, Japan More articles by this author , Tomohiko YanagidaTomohiko Yanagida Fukushima, Japan More articles by this author , Ken AikawaKen Aikawa Fukushima, Japan More articles by this author , and Yoshiyuki KojimaYoshiyuki Kojima Fukushima, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1546AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Clinical studies have revealed that increased serum IL-6 concentrations in patients are associated with advanced tumor stages of renal cell carcinoma (RCC) and short survival. We evaluated the effect of combination therapy with humanized antihuman IL-6R antibody tocilizumab and interferon-α in vitro and in vivo against RCC 786-O cells which induce autocrine secretion of IL-6 by interferon-α. METHODS MTT assays were performed for determination of cellular proliferation and viability by tocilizumab and/or interferon-α use in 786-O cells. Real-time quantitative RT-PCR and western blotting analysis were performed to detect SOCS3 mRNA expression and phosphorylation of STAT proteins and ERK. Xenograft assays in nude mice were used for analysis in vivo effects of combination therapy with tocilizumab and interferon-α. RESULTS Use of tocilizumab or interferon-α alone could not suppress the growth of 786-O cells. A significant interferon-α-induced growth inhibitory effect was observed when both tocilizumab and interferon-α were added to 786-O cells. Real-time quantitative PCR revealed that the absolute level of SOCS-3 mRNA was significantly increased upon interferon-α treatment. Tocilizumab significantly decreased the SOCS3 expression level after IFN stimulation in 786-O cells (p=0.023). Western blot analysis revealed that the addition of tocilizumab enhanced the interferon-induced phosphorylation of STAT1 and inhibited SOCS3 expression and the phosphorylation of both STAT3 and ERK. The growth of tumors in athymic mice receiving combination therapy with tocilizumab and interferon-α was retarded in comparison with those in the tocilizumab, interferon-α and untreated groups. The tumor volume was significantly lower in the combination therapy group than in the other groups at the end of the study (p<0.05). Morphological observation of the tumors revealed apoptosis, invasion of inflammatory cells and fibrosis. A remarkable reduction in interferon-induced SOCS3 protein expression by tocilizumab was confirmed. CONCLUSIONS Inhibition of SOCS3 by tocilizumab enhanced the anti-tumor activity of interferon-α, both in vitro and in vivo. Our findings suggest that combination therapy using an antihuman IL-6R antibody with interferon may represent a novel therapeutic approach for the treatment of RCC. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e68-e69 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kei Ishibashi Fukushima, Japan More articles by this author Toshiki Oguro Fukushima, Japan More articles by this author Shin Kumagai Fukushima, Japan More articles by this author Norio Takahashi Fukushima, Japan More articles by this author Nobuhiro Haga Fukushima, Japan More articles by this author Masanori Nomiya Fukushima, Japan More articles by this author Tomohiko Yanagida Fukushima, Japan More articles by this author Ken Aikawa Fukushima, Japan More articles by this author Yoshiyuki Kojima Fukushima, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...