Mechanism of synergistic antitumor effect of sorafenib and interferon-α on treatment of renal cell carcinoma

Ario Takeuchi, Masatoshi Eto, Katsunori Tatsugami, Hisakata Yamada, Toshihiro Oki, Keijiro Kiyoshima, Yasunobu Yoshikai, Seiji Naito

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Purpose The multikinase and tyrosine kinase inhibitor sorafenib has antitumor activity in patients with advanced renal cell carcinoma. Recent reports show the ability of sorafenib to synergize with interferon-α, leading to greater antitumor activity. We examined the underlying mechanism of sorafenib and interferon-α synergism for renal cell carcinoma treatment in vitro and in tumor bearing murine models. Materials and Methods We used murine and human renal cell carcinoma cell lines for in vitro cell proliferation assay. ACHN (ATCC®) and RENCA tumors were subcutaneously transplanted into NCr-nu/nu and syngeneic BALB/c mice (Charles River Laboratories, Yokohama, Japan), respectively. Mice were treated with sorafenib and/or interferon-α, and tumor growth was monitored. Immunological assays were done in the RENCA model. Results In the ACHN and RENCA cell lines combination index analysis clearly revealed the synergistic antiproliferative effects of interferon-α and sorafenib in vitro. In the ACHN NCr-nu/nu model we clearly noted the synergistic antitumor effects of interferon-α and sorafenib, indicating the synergistic direct effects of each drug on tumor growth. In the RENCA BALB/c model flow cytometry showed no change in the proportion of lymphocytes. However, while sorafenib alone did not induce natural killer or cytotoxic T-lymphocyte activity against RENCA in that model, interferon-α alone or combined with sorafenib induced natural killer and cytotoxic T-lymphocyte activity. Conclusions Our results show the synergistic activity of interferon-α and sorafenib. These findings provided the rationale for combination therapy with interferon-α and sorafenib in patients with advanced renal cell carcinoma.

Original languageEnglish
Pages (from-to)2549-2556
Number of pages8
JournalJournal of Urology
Volume184
Issue number6
DOIs
Publication statusPublished - Dec 2010

All Science Journal Classification (ASJC) codes

  • Urology

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