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

Glioma invasion into the surrounding brain tissue is still a major obstacle for any therapeutical approach. As in other solid tumors, matrix-metallopr oteases (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-m ediated invasion process could be a feasible approach. Two human cell lines (U25I and GaMG) and surgical specimens of 6 patients with malignant glioma s were grown as monolayers and spheroid cultures respectively. MMP- and u-P A-mRNA expression was investigated by semi-quantitative RT-PCR. Invasion wa s studied in Matrigel-coated Boyden chamber transwell assays for monolayers and in confrontation cultures of tumor spheroids with fetal rat brain aggr egates in the presence of the synthetic MMP inhibitors batimastat (BB-94) a nd marimastat: (BB-2516). Cytotoxicity/cytostatic effects of high concentra tions 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 mu M) without cytotoxici ty. Both MMP inhibitors effectively reduced glioma invasion in Boyden-chamb er assays at low concentrations of 0.3 mu M. In confrontation cultures, con centrations of 10 mu M and above were necessary to reduce invasion. This ef fect was observable with inter-individual heterogeneity in the patient's tu mor material, MMP inhibitors effectively reduce glioma invasion, although h igh concentrations were required in 3-dimensional culture systems. At these concentrations, both compounds revealed a cytostatic, but no cytotoxic eff ect. Thus, high local concentrations of MMP inhibitors could offer a new th erapeutic strategy for the treatment of gliomas. Int. J, Cancer 80:764-772, 1999. (C) 1999 Wiley-Liss, Inc.