Antitumor effects of bisphosphonates
Antitumor effects of bisphosphonates
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DOI：
10.1002/cncr.11128
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发表时间：
2003-02-01
期刊：
影响因子：
6.2
通讯作者：
Green, JR
中科院分区：
文献类型：
--
作者：
Green, JR
背景双膦酸盐广泛用于治疗恶性肿瘤的骨骼并发症。这些药物在骨中蓄积，抑制骨细胞的骨吸收，减少刺激肿瘤生长的因子的局部释放。二膦酸盐的作用机制取决于化学结构：不含氮化合物（例如，etichonate，clodronate）被代谢成ATP的细胞毒性类似物，而更有效的含氮化合物（N-BP;例如，帕米膦酸盐、伊班膦酸盐、唑来膦酸）抑制蛋白质异戊二烯化，从而影响细胞功能和存活。由于蛋白质异戊二烯化是所有细胞所必需的，而不仅仅是破骨细胞，因此N-BPs也可能影响肿瘤细胞的活力。几个研究小组已经研究了双膦酸盐单独或与其他抗癌药物联合使用对许多肿瘤细胞类型的生存力和转移特性的体外作用。类似地，已经在多种动物肿瘤模型中研究了双膦酸盐治疗对骨质溶解和肿瘤负荷的影响。在体外，亚微摩尔浓度的N-BP抑制肿瘤细胞粘附并减少通过细胞外基质的侵袭。在较高浓度下，已报道了抗增殖和促凋亡作用。在骨转移的动物模型中，双膦酸盐治疗显著减少溶骨性病变。也有证据表明，骨肿瘤负荷减少，偶尔在其他器官。生存期可能延长，但双膦酸盐似乎不能抑制原发性软组织肿瘤或原位异种移植物的生长。细胞培养数据清楚地表明，N-BP发挥抗肿瘤特性，并与其他抗肿瘤剂协同作用。由于二膦酸盐在骨中蓄积，它们也可以通过破骨细胞抑制和骨微环境的改变直接或间接地对骨转移中的肿瘤细胞发挥细胞抑制作用。现在需要进一步的体内研究来优化N-BP的给药方案，以充分利用其抗肿瘤潜力。(C)2003年美国癌症协会。
BACKGROUND. Bisphosphonates are widely used to treat skeletal complications of malignancy. These drugs accumulate in bone where they inhibit osteoclastic bone resorption and reduce the local release of factors that stimulate tumor growth. The mechanism of action of bisphosphonates is dependent on chemical structure: Nonnitrogen-containing compounds (e.g., etichonate, clodronate) are metabolized into cytotoxic analogues of ATP, whereas the more potent nitrogen-containing compounds (N-BPs; e.g., pamidronate, ibandronate, zoledronic acid) inhibit protein prenylation, thus affecting cell function and survival. Because protein prenylation is required by all cells, not just osteoclasts, the possibility arises that N-BPs could also affect the viability of tumor cells.METHODS. Several groups have investigated the in vitro effects of bisphosphonates, either alone or in combination with other antineoplastic agents, on the viability and metastatic properties of many tumor cell types. Similarly, the effect of bisphosphonate treatment on osteolysis and tumor burden has been studied in a variety of animal tumor models.RESULTS. in vitro, submicromolar concentrations of N-BPs inhibited tumor cell adhesion and reduced invasion through extracellular matrix. At higher concentrations, antiproliferative and proapoptotic effects have been reported. In animal models of bone metastases, bisphosphonate treatment markedly reduced osteolytic lesions. There is also evidence of a reduction in tumor burden in bone and occasionally in other organs. Survival may be prolonged, but bisphosphonates do not appear to inhibit the growth of primary soft tissue tumors or orthotopic xenografts.CONCLUSIONS. The cell culture data clearly demonstrated that N-BPs exert antitumor properties and interact synergistically with other antineoplastic agents. As bisphosphonates accumulate in bone, they can also exert cytostatic effects on tumor cells in bone metastases, either directly or indirectly via osteoclast inhibition and alterations in the bone microenvironment. Further in vivo research is now required to optimize the dosing regimen of N-BPs to exploit fully their antitumor potential. (C) 2003 American Cancer Society.