Effect of synthetic matrix-metalloproteinase inhibitors on invasive capacity and proliferation of human malignant gliomasIn vitro

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Abstract
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.