Effect of synthetic matrix‐metalloproteinase inhibitors on invasive capacity and proliferation of human malignant gliomas In vitro
Effect of synthetic matrix‐metalloproteinase inhibitors on invasive capacity and proliferation of human malignant gliomas In vitro
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合成基质金属蛋白酶抑制剂对人恶性胶质瘤体外侵袭能力和增殖的影响
DOI：
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发表时间：
1999
影响因子：
6.4
通讯作者：
K. Roosen
中科院分区：
文献类型：
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作者：
J. Tonn;S. Kerkau;A. Hanke;H. Bouterfa;J. Mueller;S. Wagner;G. Vince;K. Roosen
胶质瘤侵入周围脑组织仍然是任何治疗方法的主要障碍。与其他实体瘤一样，基质金属蛋白酶（MMP）也被认为参与其中。本研究的目的是评估使用MMP抑制剂靶向蛋白酶介导的侵袭过程是否是一种可行的方法。两个人细胞系（U251和GaMG）和6例恶性胶质瘤患者的手术标本分别生长为单层和球形培养物。通过半定量RT-PCR研究MMP-和u-PA-mRNA表达。在存在合成MMP抑制剂巴马司他（BB-94）和马马司他（BB-2516）的情况下，在单层Matrigel包被Boyden小室transwell试验中以及肿瘤球状体与胎鼠脑聚集体的对抗培养物中研究了侵袭。高浓度的两种化合物的细胞毒性/细胞生长抑制作用通过生长曲线、MTT测定和流式细胞术在人脑胶质瘤细胞系中进行评估。巴马司他和马马司他在高浓度（高于1 μM）下显示出细胞抑制作用，无细胞毒性。在Boyden小室试验中，两种MMP抑制剂在0.3 μM的低浓度下均可有效降低胶质瘤侵袭。在对峙培养中，10 μM及以上的浓度是减少入侵所必需的。这种效应在患者肿瘤材料的个体间异质性中观察到。MMP抑制剂有效地减少胶质瘤侵袭，尽管在三维培养系统中需要高浓度。在这些浓度下，两种化合物均显示出细胞抑制作用，但无细胞毒性作用。因此，局部高浓度的MMP抑制剂可以为神经胶质瘤的治疗提供新的治疗策略。Int. J. Cancer 80：764-772，1999.© 1999 Wiley利斯公司
Glioma invasion into the surrounding brain tissue is still a major obstacle for any therapeutical approach. As in other solid tumors, matrix‐metalloproteases (MMPs) have been suggested as being involved. The aim of this study was to evaluate whether the use of MMP inhibitors to target the protease‐mediated invasion process could be a feasible approach. Two human cell lines (U251 and GaMG) and surgical specimens of 6 patients with malignant gliomas were grown as monolayers and spheroid cultures respectively. MMP‐ and u‐PA‐mRNA expression was investigated by semi‐quantitative RT‐PCR. Invasion was studied in Matrigel‐coated Boyden chamber transwell assays for monolayers and in confrontation cultures of tumor spheroids with fetal rat brain aggregates in the presence of the synthetic MMP inhibitors batimastat (BB‐94) and marimastat (BB‐2516). Cytotoxicity/cytostatic effects of high concentrations of both compounds were assessed by growth curves, MTT assays and flow cytometry in human glioma cell lines. Batimastat and marimastat revealed a cytostatic effect at high concentrations (above 1 μM) without cytotoxicity. Both MMP inhibitors effectively reduced glioma invasion in Boyden‐chamber assays at low concentrations of 0.3 μM. In confrontation cultures, concentrations of 10 μM and above were necessary to reduce invasion. This effect was observable with inter‐individual heterogeneity in the patient's tumor material. MMP inhibitors effectively reduce glioma invasion, although high concentrations were required in 3‐dimensional culture systems. At these concentrations, both compounds revealed a cytostatic, but no cytotoxic effect. Thus, high local concentrations of MMP inhibitors could offer a new therapeutic strategy for the treatment of gliomas. Int. J. Cancer 80:764–772, 1999. © 1999 Wiley‐Liss, Inc.