Inhibition of gelatinase A (MMP-2) by batimastat and captopril reduces tumor growth and lung metastases in mice bearing Lewis lung carcinoma
Inhibition of gelatinase A (MMP-2) by batimastat and captopril reduces tumor growth and lung metastases in mice bearing Lewis lung carcinoma
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DOI：
10.1002/(sici)1097-0215(19990531)81:5
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发表时间：
1999-05-31
影响因子：
6.4
通讯作者：
Rotilio, D
中科院分区：
文献类型：
--
作者：
Prontera, C;Mariani, B;Rotilio, D
我们观察了人工合成的基质金属蛋白酶抑制剂batimastat(BB-94)和血管紧张素转换酶抑制剂卡托普利对小鼠Lewis肺癌细胞(3LL)体外金属蛋白酶活性的影响，以及对同基因C57BL/6小鼠肌肉移植瘤局部生长和肺转移的影响。同时观察了BB-94和卡托普利对3LL荷瘤小鼠存活的影响。在这里，我们报告了卡托普利处理导致3LL细胞明胶酶A的转录和蛋白水平降低。BB-94和卡托普利也能阻止培养细胞在条件培养液中释放的明胶酶A和B对底物的降解。BB-94对荷瘤动物的治疗作用或卡托普利(饮用水中)对平均肿瘤体积(分别为25%和33%)和平均肺转移数(分别为26%和29%)有显著抑制作用。当给予这两种药物时，它们起协同作用，导致51%和80%的肿瘤生长和转移被抑制。BB-94和卡托普利联合治疗的小鼠的存活时间也明显长于单独使用两种药物或使用赋形剂的小鼠。我们的数据支持金属蛋白酶(S)在肿瘤转移过程中起重要作用的假说。此外，阻断侵袭、血管生成等过程可能是BB-94和卡托普利及其联合应用的抗肿瘤和抗转移作用的基础。可以想象，这种组合可以在选定的临床条件下作为细胞毒治疗的辅助方式进行测试。(C)1999年Wiley-Liss，Inc.
We have examined the effects of the synthetic matrix metalloproteinase inhibitor, batimastat (BB-94) and the angiotensin-converting enzyme inhibitor, captopril, on metalloproteinase activity of murine Lewis-lung-carcinoma cells (3LL) in vitro, and on local growth and lung metastasis of the same tumor implanted intramuscularly in syngeneic C57BL/6 mice. The effect of BB-94 and captopril on the survival of the 3LL-tumor-bearing mice was also examined. Here we report that captopril treatment resulted in decreased transcription and protein levels of gelatinase A by 3LL cells. Both BB-94 and captopril also prevented substrate degradation by gelatinase A and B released in conditioned medium by cultured cells. Treatment of tumor-bearing animals with BB-94 (i.p.) or captopril (in drinking water) resulted in significant inhibition of the mean tumor volume (25 and 33% respectively) and of the mean lung metastasis number (26 and 29% respectively). When both agents were given, they acted in synergy, resulting in 51 and 80% inhibition of tumor growth and metastasis. The survival time of the mice treated with both BB-94 and captopril was also significantly longer compared with the groups treated with each agent alone or with the vehicle. Our data support the hypothesis of an essential role of metalloproteinase(s) in the metastatic process. Moreover, blockade of invasion, angiogenesis and other processes mediated by metalloproteinases may underlie the anti-tumor and antimetastatic effect of BB-94 and captopril and their combination. It is conceivable that this combination could be tested in selected clinical conditions as an adjuvant modality to cytotoxic therapy. (C) 1999 Wiley-Liss, Inc.