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

J Urol. 2010 Dec;184(6):2549-56. doi: 10.1016/j.juro.2010.07.033. Epub 2010 Oct 28.

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Benzenesulfonates / therapeutic use*
  • Carcinoma, Renal Cell / drug therapy*
  • Cell Line, Tumor
  • Drug Synergism
  • Drug Therapy, Combination
  • Female
  • Humans
  • Immunologic Factors / therapeutic use*
  • Interferon-alpha / therapeutic use*
  • Kidney Neoplasms / drug therapy*
  • Mice
  • Mice, Inbred BALB C
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds
  • Pyridines / therapeutic use*
  • Sorafenib

Substances

  • Antineoplastic Agents
  • Benzenesulfonates
  • Immunologic Factors
  • Interferon-alpha
  • Phenylurea Compounds
  • Pyridines
  • Niacinamide
  • Sorafenib