A selective endothelin ETA antagonist, BQ-123, inhibits 125I-endothelin-1 (125I-ET-1) binding to human meningiomas and antagonizes ET-1-induced proliferation of meningioma cells.
1. We studied the effects of BQ-123, a selective ETA receptor antagonist, on 125I-endothelin-1 (125I-ET-1) binding to cell surface receptors in surgically exercised human meningiomas and on ET-1-induced DNA synthesis in cultured human meningioma cells in vitro, using a quantitative receptor autoradiographic technique with radioluminography and 3H-thymidine incorporation, respectively. 2. All of the human meningiomas expressed high-affinity binding sites for 125I-ET-1, regardless of differences in histological subtypes (Kd = 2.6 +/- 0.2 nM, Bmax = 374 +/- 93 fmol/mg; mean +/- SE; n = 9). 3. BQ-123 competed for 125I-ET-1 binding to sections of meningiomas with IC50S of 3.2 +/- 0.9 x 10(-7) M, and 10(-4) M 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(-9) M ET-1. BQ-123 inhibited ET-1 (10(-9) M)-induced DNA synthesis in meningioma cells, in a dose-dependent manner, and 10(-5) M 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(-7) M). The growth rate of meningioma cells, incubated with 10(-9) M ET-1, was reduced by 50% in the presence of 10(-7) M BQ-123.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Neurosurgery, Nagasaki University School of Medicine, Japan.
N
N
Kitagawa
K
K
Tsutsumi
M
M
Niwa
S
S
Yamaga
T
T
Anda
H
H
Khalid
A
A
Himeno
K
K
Taniyama
S
S
Shibata
D000595:Amino Acid Sequence; D002455:Cell Division / Q000187:drug effects*; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007457:Iodine Radioisotopes; D008577:Meningeal Neoplasms / Q000378:metabolism*; D008579:Meningioma / Q000378:metabolism*; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011485:Protein Binding; D013936:Thymidine / Q000378:metabolism; D014316:Tritium; D014407:Tumor Cells, Cultured
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007457:Iodine Radioisotopes; D010456:Peptides, Cyclic; D014316:Tritium; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D013936:Thymidine