A selective endothelin ETA antagonist,BQ-123, inhibits125I-endothelin-1 (125I-ET-1) binding to human meningiomas and antagonizes ET-1-induced proliferation of meningioma cells

Summary 1. We studied the effects of BQ-123, a selective ET_A receptor antagonist, on¹²⁵I-endothelin-1 (¹²⁵I-ET-1) binding to cell surface receptors in surgically excised human meningiomas and on ET-1-induced DNA synthesis in cultured human meningioma cellsin vitro, using a quantitative receptor autoradiographic technique with radioluminography and³H-thymidine incorporation, respectively.2. All of the human meningiomas expressed high-affinity binding sites for¹²⁵I-ET-1, regardless of differences in histological subtypes (K_d=2.6±0.2 nM,B_max=374±93 fmol/mg; mean ± SE;n=9).3. BQ-123 competed for¹²⁵I-ET-1 binding to sections of meningiomas with IC₅₀s of 3.2±0.9×10^–7M, and 10^–4M BQ-123 displaced 80% of the binding.4. ET-1 significantly stimulated DNA synthesis in cultured human meningioma cells, up to 170% of the basal level in the presence of 10^–9M ET-1. BQ-123 inhibited ET-1 (10^–9M)-induced DNA synthesis in meningioma cells, in a dose-dependent manner, and 10^–5M BQ-123 reduced it to 120% of the basal level.5. The number of meningioma cells determined after 4 days in culture was dose dependently increased in the presence of ET-1 (10^–9 and 10^–7M). The growth rate of meningioma cells, incubated with 10^–9M ET-1, was reduced by 50% in the presence of 10^–7M BQ-123.6. Our data suggest that (a) human meningioma cells express a large number of ET_A endothelin receptors, with a small proportion of non-ET_A receptors linked to proliferation of the cells, and (b) ET receptor antagonists, including BQ-123, might prove to be effective treatment for patients with meningioma.