Bisphosphonates induce apoptosis of stromal tumor cells in giant cell tumor of bone
Bisphosphonates induce apoptosis of stromal tumor cells in giant cell tumor of bone
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DOI：
10.1007/s00223-004-0120-2
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发表时间：
2004-07-01
影响因子：
4.2
通讯作者：
Kumta, SM
中科院分区：
文献类型：
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作者：
Cheng, YY;Huang, L;Kumta, SM
骨巨细胞瘤（GCT）是一种侵袭性原发性肿瘤，会导致溶骨性病变的产生。基质细胞构成该肿瘤的主要肿瘤成分，调节破骨细胞样巨细胞的形成，最终导致骨质破坏。双膦酸盐通过抑制破骨细胞活性和促进破骨细胞凋亡来防止骨吸收，并且已知它们可诱导原发性肿瘤细胞（例如乳腺癌和前列腺癌中的细胞）凋亡。我们假设双磷酸盐不仅可以在体外和体内诱导破骨细胞样巨细胞凋亡，而且还可以诱导 GCT 肿瘤基质细胞凋亡。 12 名 GCT 患者在手术前 6 周内每周注射帕米膦酸盐。 GCT 标本是在活检时和最终手术期间收集的。 TUNEL 测定用于评估细胞中的凋亡 DNA 片段化。此外，来自这些患者的 12 份 GCT 原代培养物用不同剂量（3、30 或 150 [M）的唑来膦酸、帕米膦酸或阿仑膦酸处理 48 小时，并在荧光膜联蛋白-V 标记后通过流式细胞术进行细胞凋亡测定。结果表明，帕米膦酸钠在体内显着诱导破骨细胞样巨细胞和间质瘤细胞凋亡。所有三种二磷酸盐均引起培养物中基质肿瘤细胞的大量凋亡。唑来膦酸是最有效的试剂，150 μM 时平均细胞死亡率为 27.41%，其次是帕米膦酸 (22.23%) 和阿仑膦酸 (15.3%)。我们的观察表明，这些药物可被视为治疗 GCT 的潜在佐剂。
Giant cell tumour of bone (GCT) is an aggressive primary neoplasm that results in the production of osteolytic lesions. Stromal cells, which form the main neoplastic component of this tumor, regulate the formation of osleoclast-like giant cells that are ultimately responsible for bone destruction. Bisphosphonates prevent bone resorption by inhibiting osteoclast activity and promoting osteoclast apoptosis, and they have been known to induce apoptosis of primary neoplastic cells such as those in breast and prostate cancers. We hypothesized that in bisphosphonates may induce apoptosis not only in osteoclast-like giant cells but also in neoplastic stromal cells of GCT both in vitro and in vivo. Twelve patients with GCT were treated with weekly injections of pamidronate for a period of 6 weeks prior to surgery. GCT specimens were collected at the time of biopsy and during definitive surgery. TUNEL assay was used to evaluate apoptotic DNA fragmentation in cells. In addition, twelve GCT primary cultures from these patients were treated with zoledronate, pamidronate, or alendronate for 48 hours at different doses (3, 30, or 150 [M) and subjected to apoptosis assay by flow cytometry following fluorescent Annexin-V labeling. The results showed that pamidronate significantly induced apoptosis in both osteoclast-like giant cells and stromal tumor cells, in vivo. All three bisphosphonates caused substantial apoptosis of stromal tumor cells in cultures. Zoledronate was the most potent reagent, resulting in an average cell death of 27.41% at 150 muM, followed by pamidronate (22.23%) and alendronate (15.3%). Our observations suggest that these drugs may be considered as potential adjuvants in the treatment of GCT.