Zoledronic acid inhibits visceral metastases in the 4T1/luc mouse breast cancer model
Zoledronic acid inhibits visceral metastases in the 4T1/luc mouse breast cancer model
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DOI：
10.1158/1078-0432.ccr-03-0325
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发表时间：
2004-07-01
影响因子：
11.5
通讯作者：
Yoneda, T
中科院分区：
文献类型：
--
作者：
Hiraga, T;Williams, PJ;Yoneda, T
目的：双膦酸盐（BPs）是破骨细胞的特异性抑制剂，对乳腺癌的骨转移具有有益的作用。此外，最近的研究报道，BPs具有抗癌作用并抑制内脏转移。然而，临床研究的结果仍然相互矛盾。在本研究中，我们使用动物模型研究了BP唑来膦酸（ZOL）（目前最有效的BP之一）对乳腺癌内脏转移的影响，在该动物模型中，小鼠乳腺癌细胞4 T1/luc植入原位乳腺脂肪垫，自发转移到雌性BALB/c小鼠的多个器官，包括骨、肺和肝脏。实验设计和结果：在整个实验期间，携带4 T1/lac的小鼠接受单次或四次ZOL静脉内注射（0.5或5 μ g/小鼠）。ZOL治疗减少了骨转移。更重要的是，ZOL显著抑制肺和肝转移。此外，ZOL延长了荷瘤小鼠的总体生存期。有趣的是，ZOL增加了骨中定殖的4 T1/luc细胞的凋亡;然而，肺中的凋亡没有改变。体外研究表明，ZOL抑制细胞的迁移和侵袭，并促进4 T1/luc cells.Conclusions凋亡：这些结果是一致的概念，ZOL影响乳腺癌转移到内脏器官以及骨。ZOL的这些作用可能归因于抑制乳腺癌细胞的迁移和侵袭。我们的实验结果的临床相关性需要在乳腺癌内脏转移患者中确定。
Purpose: It is established that bisphosphonates (BPs), specific inhibitors of osteoclasts, have beneficial effects on bone metastases of breast cancer. In addition, recent studies have reported that BPs; have anticancer effects and suppress visceral metastases, too. However, the results of clinical studies are still conflicting. In the present study, we examined the effects of the BP zoledronic acid (ZOL), one of the most potent BPs currently available, on visceral metastases of breast cancer using an animal model in which mouse breast cancer cells 4T1/luc implanted at the orthotopic mammary fat pad spontaneously metastasize to multiple organs including bone, lung, and liver in female BALB/c mice.Experimental Design and Results: The 4T1/luc-bearing mice received single or four i.v. injections of ZOL (0.5 or 5 mug/mouse) during the whole experimental period. Bone metastases were reduced by the ZOL treatment. More importantly, ZOL significantly suppressed lung and liver metastases. Furthermore, ZOL prolonged overall survival of the tumor-bearing mice. Of interest, apoptosis in 4T1/luc cells colonized in bone was increased by ZOL; however, those in lung were not changed. In vitro studies demonstrated that ZOL inhibited cell migration and invasion and promoted apoptosis of 4T1/luc cells.Conclusions: These results are consistent with the notion that ZOL affects breast cancer metastasis to visceral organs as well as bone. These effects of ZOL may be attributable to inhibition of migration and invasion of breast cancer cells. Clinical relevance of our experimental results needs to be determined in breast cancer patients with visceral metastases.