A novel bisphosphonate minodronate (YM529) specifically inhibits osteolytic bone metastasis produced by human small-cell lung cancer cells in NK-cell depleted SCID mice
A novel bisphosphonate minodronate (YM529) specifically inhibits osteolytic bone metastasis produced by human small-cell lung cancer cells in NK-cell depleted SCID mice
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DOI：
10.1023/a:1022621622063
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发表时间：
2004
影响因子：
4
通讯作者：
He-long Zhang;S. Yano;T. Miki;H. Goto;T. Kanematsu;Hiroaki Muguruma;H. Uehara;S. Sone
中科院分区：
文献类型：
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作者：
He-long Zhang;S. Yano;T. Miki;H. Goto;T. Kanematsu;Hiroaki Muguruma;H. Uehara;S. Sone
在本研究中，我们研究了一种新开发的双膦酸盐，米诺膦酸盐（YM 529），对肺癌引起的溶骨性骨转移的影响。将人小细胞肺癌（SBC-5）细胞静脉注射到自然杀伤细胞耗竭的SCID小鼠中，在第18天产生放射学可检测的骨转移，在第35天产生肉眼可见的内脏转移（肺、肝、肾、全身淋巴结）。在第1天用YM 529预防性治疗以剂量依赖性方式显著抑制了X射线照片上评估的溶骨性骨转移的形成。此外，在骨转移建立后（第21天）用YM 529治疗也抑制了骨转移，尽管治疗在较早开始时更有效。单次给药与重复给药一样有效，表明YM 529对骨转移具有持续的抑制作用。YM 529在体内可减少骨转移灶中破骨细胞的数量，但在体外对SBC-5细胞的增殖和细胞因子的产生无影响。这些结果表明，YM 529是一个有效的抑制人肺癌骨转移，可能通过抑制骨细胞骨吸收。相反，用YM 529治疗对内脏转移没有影响，即使在第1天开始，也没有延长小鼠的存活。因此，联合治疗对于延长小细胞肺癌多器官转移患者的生存期是必要的。
In the present study, we examined the effects of a newly developed bisphosphonate, minodronate (YM529), on osteolytic bone metastasis caused by lung cancer. Human small-cell lung cancer (SBC-5) cells, injected intravenously into natural killer cell-depleted SCID mice, produced radiologically detectable bone metastasis by day 18 and macroscopically visible visceral metastases (lung, liver, kidney, systemic lymph node) by day 35. Prophylactic treatment with YM529 on day 1 significantly inhibited the formation of osteolytic bone metastasis evaluated on X-ray photographs in a dose-dependent manner. In addition, treatment with YM529 after establishment of bone metastasis (on day 21) also inhibited bone metastasis, although the treatment was more effective when started earlier. Single administration was as effective as repeated treatment, suggesting a sustained inhibitory effect of YM529 on bone metastasis. YM529 reduced the number of osteoclasts in the bone metastatic lesionsin vivo, but had no effect on the proliferation or cytokine production of SBC-5 cellsin vitro. These results suggest that YM529 is a potent inhibitor of bone metastasis of human lung cancer, probably by suppressing osteoclastic bone resorption. In contrast, treatment with YM529 had no effect on visceral metastasis, even if started on day 1, and did not prolong the survival of the mice. Therefore, development of a combined modality is necessary for prolonging the survival of small-cell lung cancer patients with multiple-organ metastasis.