Combination with third-generation bisphosphonate (YM529) and interferon-alpha can inhibit the progression of established bone renal cell carcinoma.
Combination with third-generation bisphosphonate (YM529) and interferon-alpha can inhibit the progression of established bone renal cell carcinoma.
复制标题
DOI：
10.1111/cas.12711
复制
发表时间：
2015-08
期刊：
影响因子：
5.7
通讯作者：
Furihata M
中科院分区：
文献类型：
--
作者：
Kurabayashi A;Inoue K;Fukuhara H;Karashima T;Fukata S;Kawada C;Shuin T;Furihata M
本研究旨在探讨第三代含氮双膦酸盐(YM529)能否抑制骨肾细胞癌(RCC)的进展，并探讨其作用机制。采用细胞计数、体内软X射线、TUNEL法和抗酒石酸酸性磷酸酶染色等方法评价YM529和/或干扰素-α对肾癌细胞和小鼠破骨细胞的抗增殖和诱导凋亡作用。在体内实验中，用YM529和/或干扰素-α对荷人肾癌细胞株RBM1IT4的裸鼠进行了体内实验。用小凹形成法检测破骨细胞的生物学活性。用微血管密度和原位基因杂交分析YM529和/或干扰素-α的抗血管生成作用。YM529治疗组小鼠骨肿瘤破骨细胞数量减少。YM529在体外也能抑制破骨细胞的活性和增殖，而干扰素-α则抑制肿瘤内碱性成纤维细胞生长因子的表达和微血管密度。YM529和干扰素-α单独应用均不能明显抑制已建立的骨转移瘤的生长。YM529联合干扰素-α治疗人肾细胞癌骨转移可能是有益的。它们的作用是通过YM529抑制破骨细胞募集和失活以及通过干扰素-α抑制血管生成来实现的。
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.