Dass Crispin R, Choong Peter F M
Department of Orthopaedics, St. Vincent's Hospital Melbourne, P.O. Box 2900, Fitzroy 3065, Melbourne, Australia.
Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3263-70. doi: 10.1158/1535-7163.MCT-07-0546.
Zoledronic acid (ZOL) has been shown to reduce osteolysis in bone metastasis. Its efficacy in osteosarcoma has not been convincingly proved in a clinically relevant model for the disease. In vitro, ZOL decreased osteosarcoma cell proliferation, mainly due to an increase in apoptosis in a dose-dependent fashion. There was a decrease in cell migration at >or=10 micromol/L concentrations, but invasion was inhibited at a much lower dose of 0.1 micromol/L. Reverse transcription-PCR showed that ZOL overall caused an increased expression of osteocalcin and decreased expression of alkaline phosphatase, osteopontin, osteonectin, and vascular endothelial growth factor, with no change in expression of osteoprotegerin. ZOL administration s.c. twice weekly at 0.12 mg/kg to SaOS-2 tumor-bearing mice resulted in primary tumor growth inhibition, reduction in lung metastases, and dramatic decrease in osteolysis. Furthermore, in the ZOL cohort, there was a clear reduction in the number of osteoclasts in bone exposed to tumor and a lower tumor vessel density. These data point to the adjuvant potential of ZOL in the management of osteosarcoma not only for its antiosteolytic properties but also for its ability to directly halt tumor cell growth and metastasis via its effects on viability, invasion, differentiation, and angiogenesis.
唑来膦酸（ZOL）已被证明可减少骨转移中的骨溶解。其在骨肉瘤中的疗效尚未在该疾病的临床相关模型中得到令人信服的证明。在体外，ZOL以剂量依赖性方式降低骨肉瘤细胞增殖，主要是由于凋亡增加。在浓度≥10 μmol/L时细胞迁移减少，但在低得多的0.1 μmol/L剂量下侵袭受到抑制。逆转录聚合酶链反应显示，ZOL总体上导致骨钙素表达增加，碱性磷酸酶、骨桥蛋白、骨连接蛋白和血管内皮生长因子表达降低，骨保护素表达无变化。每周两次以0.12 mg/kg的剂量皮下注射ZOL给荷SaOS-2肿瘤的小鼠，导致原发性肿瘤生长受到抑制、肺转移减少以及骨溶解显著降低。此外，在ZOL组中，暴露于肿瘤的骨中破骨细胞数量明显减少，肿瘤血管密度降低。这些数据表明ZOL在骨肉瘤治疗中具有辅助潜力，这不仅是因为其抗骨溶解特性，还因为其通过对细胞活力、侵袭、分化和血管生成的影响直接阻止肿瘤细胞生长和转移的能力。
