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The aim of this study was to investigate whether the third‐generation nitrogen‐containing bisphosphonate ( YM 529) can inhibit the progression of established bone renal cell carcinoma ( RCC ) and to elucidate its mechanism. Antiproliferative effect and apoptosis induction of  RCC  cells and mouse osteoclasts by  YM 529 and/or interferon‐alpha ( IFN ‐α) were evaluated  in vitro  using cell counting and  in vivo  using soft X‐ray, the  TUNEL  method and tartrate‐resistant acid phosphatase stain. For the in  vivo  study, male athymic  BALB / cA  Jc1‐nu nude mice bearing human  RCC  cell line  RBM 1‐ IT 4 cells were treated with  YM 529 and/or  IFN ‐α. The biological activity of osteoclasts was evaluated using the pit formation assay. The antiangiogenetic effect by  YM 529 and/or  IFN ‐α was analyzed using micro‐vessel density and  in situ   mRNA  hybridization. Osteoclast number in bone tumors was decreased in  YM 529‐treated mouse.  YM 529 also inhibited osteoclast activity and proliferation  in vitro , whereas basic fibroblast growth factor expressions and micro‐vessel density within tumors were inhibited by  IFN ‐α. Neither  YM 529 nor  IFN ‐α alone significantly inhibited the growth of established bone metastatic tumors. Combined treatment with  YM 529 and  IFN ‐α may be beneficial in patients with human  RCC  bone metastasis. Their effects are mediated by osteoclast recruitment inhibition and inactivation by  YM 529 and antiangiogenesis by  IFN ‐α.

Combination with third‐generation bisphosphonate ( YM 529) and interferon‐alpha can inhibit the progression of established bone renal cell carcinoma