LOCALIZATION AND CHARACTERIZATION OF ENDOTHELIN RECEPTORS IN HUMAN GLIOMAS - A GROWTH-FACTOR

Localization and characterization of endothelin receptors in surgical specimens of human gliomas (6 benign astrocytomas and 7 lastomas multiforme) and in normal human cortices were studied using quantitative receptor autoradiographic methods. Low numbers of [125I]endothelin-1 ([125I]ET-1) binding sites were detected in the gray matter of the human frontal cortex, with little binding in the white matter. Conversely, relatively high numbers of [125I]ET-1 binding sites were homogeneously present in tissue sections derived from astrocytomas, whereas higher numbers of [125I]ET-1 binding sites were heterogeneously located on groups of cells with a pseudopalisading appearance and pleomorphic astrocytes in glioblastoma multiforme. Necrotic areas within the tissue sections derived from glioblastoma were devoid of binding. Binding of [125I]Et-1 to gliomas and normal gray matter was specific. Unlabeled ET-1 and natural analogs (ET-2 and ET-3) inhibited the binding of [125I]ET-1 to these lesions in a concentration-dependent manner and with similar high potencies. Possibly related substances, such as ion channel regulators (ω-conotoxin, apamin, and tetrodotoxin), a Ca2+ channel blocker (nicardipine), and growth factors (epidermal growth factor and insulin-like growth factor I), did not affect the binding to tissue sections derived from gliomas or from normal frontal cortices. Scatchard analysis revealed the presence of a single class and high-affinity binding sites for endothelin in normal cortex and in gliomas. There was no significant difference in the binding affinities: dissociation constants (K(d)) were 2.1 ± 0.5 nM in 6 astrocytomas, 2.5 ± 0.4 nM in 7 glioblastomas, and 1.4 and 1.5 nM in two normal cortices. The concentrations of [125I]ET-1 binding sites were significantly higher in glioblastomas than in astrocytomas; the maximum number of binding sites (B(max)) was 30 ± 6 fmol/mg astrocytomas and 60 ± 11 fmol/mg in 7 glioblastomas (P < 0.05, F = 5.61), and 14 and 16 fmol/mg in two normal cortices. These observations suggest the presence of a specific receptor for endothelin in human gliomas. Endothelin may be involved in the modulation of growth in gliomas.