CCR1 blockade reduces tumor burden and osteolysis in vivo in a mouse model of myeloma bone disease
CCR1 blockade reduces tumor burden and osteolysis in vivo in a mouse model of myeloma bone disease
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DOI：
10.1182/blood-2011-10-384784
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发表时间：
2012-08-16
期刊：
影响因子：
20.3
通讯作者：
Jaen, Juan C.
中科院分区：
文献类型：
--
作者：
Dairaghi, Daniel J.;Oyajobi, Babatunde O.;Jaen, Juan C.
趋化因子CCL 3/MIP-1 α是多发性骨髓瘤（MM）结局的危险因素，特别是在溶骨性骨病的发展中。这种由MM细胞高度过表达的趋化因子主要通过2种受体CCR 1和CCR 5发出信号，其中只有1种（CCR 1）对人类和小鼠破骨细胞前体中的CCL 3有反应。CCR 1激活导致溶骨性病变的形成并促进肿瘤生长。在这里，我们表明，成熟破骨细胞的形成是由高度有效的和选择性的CCR 1拮抗剂CCX 721，临床化合物CCX 354的类似物阻断。我们还表明，选择完全抑制CCR 1的CCX 721剂量在MM骨病小鼠5 TGM 1模型中产生肿瘤负荷和溶骨性损伤的显著降低。当拮抗剂用于药物或治疗时，观察到类似的效果，其疗效与唑来膦酸相当。5 TGM 1细胞显示表达最低水平的CCR 1，同时分泌高水平的CCL 3，这表明CCX 721的治疗作用是由于对非MM细胞（最可能是破骨细胞和破骨细胞前体）的CCR 1抑制。这些结果为进一步开发用于治疗MM和相关溶骨性骨病的CCR 1拮抗剂提供了强有力的依据。（血。2012; 120（7）：1449-1457）
The chemokine CCL3/MIP-1 alpha is a risk factor in the outcome of multiple myeloma (MM), particularly in the development of osteolytic bone disease. This chemokine, highly overexpressed by MM cells, can signal mainly through 2 receptors, CCR1 and CCR5, only 1 of which (CCR1) is responsive to CCL3 in human and mouse osteoclast precursors. CCR1 activation leads to the formation of osteolytic lesions and facilitates tumor growth. Here we show that formation of mature osteoclasts is blocked by the highly potent and selective CCR1 antagonist CCX721, an analog of the clinical compound CCX354. We also show that doses of CCX721 selected to completely inhibit CCR1 produce a profound decrease in tumor burden and osteolytic damage in the murine 5TGM1 model of MM bone disease. Similar effects were observed when the antagonist was used prophylactically or therapeutically, with comparable efficacy to that of zoledronic acid. 5TGM1 cells were shown to express minimal levels of CCR1 while secreting high levels of CCL3, suggesting that the therapeutic effects of CCX721 result from CCR1 inhibition on non-MM cells, most likely osteoclasts and osteoclast precursors. These results provide a strong rationale for further development of CCR1 antagonists for the treatment of MM and associated osteolytic bone disease. (Blood. 2012; 120(7): 1449-1457)