The aim of this study was to investigate whether the third-generation
nitrogen-containing
bisphosphonate (
YM529) 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
YM529 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 RBM1-IT4 cells were treated with
YM529 and/or IFN-α. The
biological activity of osteoclasts was evaluated using the pit formation assay. The antiangiogenetic effect by
YM529 and/or IFN-α was analyzed using micro-vessel density and in situ
mRNA hybridization. Osteoclast number in bone
tumors was decreased in YM529-treated mouse.
YM529 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
YM529 nor IFN-α alone significantly inhibited the growth of established bone metastatic
tumors. Combined treatment with
YM529 and IFN-α may be beneficial in patients with human RCC bone
metastasis. Their effects are mediated by osteoclast recruitment inhibition and inactivation by
YM529 and antiangiogenesis by IFN-α.