Inhibition of osteolytic bone metastasis of breast cancer by combined treatment with the bisphosphonate ibandronate and tissue inhibitor of the matrix metalloproteinase-2.
Inhibition of osteolytic bone metastasis of breast cancer by combined treatment with the bisphosphonate ibandronate and tissue inhibitor of the matrix metalloproteinase-2.
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双膦酸盐伊班膦酸盐和基质金属蛋白酶-2组织抑制剂联合治疗抑制乳腺癌溶骨性骨转移。
DOI：
10.1172/jci119435
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
Mundy,GR
中科院分区：
文献类型：
--
作者：
Yoneda,T;Sasaki,A;Dunstan,C;Williams,PJ;Bauss,F;DeClerck,YA;Mundy,GR
癌细胞从原发部位向远处器官转移涉及多个步骤。在设计预防或抑制转移过程的药理学方法时应考虑这些步骤。在本研究中，我们比较了单独抑制骨转移过程中涉及的几个步骤与两者一起抑制的效果。我们选择的步骤是基质金属蛋白酶（MMP）的分泌，可能参与肿瘤细胞的侵袭，和骨细胞骨吸收，在这个过程中的最后一步。我们使用了一个实验模型，在该模型中，将人雌激素非依赖性乳腺癌MDA-231细胞接种到雌性裸鼠的左心室中，导致骨溶骨性病变。为了抑制癌症侵袭，MMP-2的组织抑制剂（TIMP-2），其是MMP的天然抑制剂，在MDA-231细胞中过表达。为了抑制骨吸收，每天皮下施用有效的双膦酸盐伊班膦酸盐（4微克/小鼠）。裸小鼠接受任一种;（a）未转染的MDA-231细胞;（B）未转染的MDA-231细胞和伊班膦酸盐;（c）TIMP-2转染的MDA-231细胞;或（d）TIMP-2转染的MDA-231细胞和伊班膦酸盐。在a组的小鼠中，放射照片显示多处溶骨性病变。然而，在B组或C组的小鼠中，溶骨性病变显著减少。特别值得注意的是，在接受伊班膦酸盐和TIMP-2转染的MDA-231细胞的d组动物中，没有放射学可检测到的溶骨性病变。c组和d组小鼠的存活率增加。未转染和TIMP-2转染的MDA-231细胞之间的乳腺脂肪垫局部增大没有差异。这些结果表明，抑制MMPs和破骨细胞骨吸收是预防溶骨性病变的更有效的治疗方法，比单独使用任何一种都更有效，并表明当根据骨微环境的独特性设计治疗方法并结合转移过程中的几个常见步骤时，可以更有效且选择性地抑制溶骨性骨转移。
Multiple steps are involved in the metastasis of cancer cells from primary sites to distant organs. These steps should be considered in the design of pharmacologic approaches to prevent or inhibit the metastatic process. In the present study, we have compared the effects of inhibiting several steps involved in the bone metastatic process individually with inhibition of both together. The steps we chose were matrix metalloproteinase (MMP) secretion, likely involved in tumor cell invasion, and osteoclastic bone resorption, the final step in the process. We used an experimental model in which inoculation of human estrogen-independent breast cancer MDA-231 cells into the left cardiac ventricle of female nude mice causes osteolytic lesions in bone. To inhibit cancer invasiveness, the tissue inhibitor of the MMP-2 (TIMP-2), which is a natural inhibitor of MMPs, was overexpressed in MDA-231 cells. To inhibit bone resorption, a potent bisphosphonate, ibandronate (4 microg/mouse) was daily administered subcutaneously. Nude mice received either; (a) nontransfected MDA-231 cells; (b) nontransfected MDA231 cells and ibandronate; (c) TIMP-2-transfected MDA-231 cells; or (d) TIMP-2-transfected MDA-231 cells and ibandronate. In mice from group a, radiographs revealed multiple osteolytic lesions. However, in mice from group b or group c, osteolytic lesions were markedly decreased. Of particular note, in animals from group d receiving both ibandronate and TIMP-2-transfected MDA-231 cells, there were no radiologically detectable osteolytic lesions. Survival rate was increased in mice of groups c and d. There was no difference in local enlargement in the mammary fat pad between nontransfected and TIMP-2-transfected MDA-231 cells. These results suggest that inhibition of both MMPs and osteoclastic bone resorption are more efficacious treatment for prevention of osteolytic lesions than either alone, and suggest that when therapies are designed based on the uniqueness of the bone microenvironment and combined with several common steps in the metastatic process, osteolytic bone metastases can be more efficiently and selectively inhibited.
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DOI：
10.1093/jnci/53.3.661
发表时间：
1974-01-01
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
CAILLEAU, R;YOUNG, R;REEVES, WJ
通讯作者：
REEVES, WJ
参与小鼠骨髓瘤细胞与骨髓基质成分结合的粘附分子
影响因子：
6.4
作者：
T. Okada;R. Hawley
通讯作者：
R. Hawley
影响因子：
11.2
作者：
I. Fidler
通讯作者：
I. Fidler
基质金属蛋白酶抑制剂巴马司他对无胸腺小鼠乳腺癌再生和转移的影响。
DOI：
--
发表时间：
1995
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
G. Sledge;M. Qulali;R. Goulet;E. Bone;R. Fife
通讯作者：
R. Fife
乳腺癌优先转移至骨的机制 -（综述）。
影响因子：
5.2
作者：
Toshiyuki Yoneda
通讯作者：
Toshiyuki Yoneda