Inhibition of human epithelial ovarian cancer cell growth in vitro by agonistic and antagonistic analogues of luteinizing hormone-releasing hormone.
In this study, we investigated the effects of luteinizing hormone-releasing hormone (LH-RH) agonist [D-Trp6]LH-RH, LH-RH antagonist [Ac-D-Nal(2)1,D-Phe(pCl)2,D-Pal(3)3,D-Cit6,D-Ala10]LH-RH (SB-75), and estradiol on the growth of human epithelial ovarian cancer cell line OV-1063. Cells were cultured under estrogen-deprived conditions. Estradiol inhibited cell proliferation, as measured by cell number at 10(-9)-10(-7) M and [3H]thymidine incorporation into DNA at 10(-13)-10(-8) M. Both LH-RH analogs inhibited cell growth dose dependently in the range 10(-8)-10(-5) M, but SB-75 induced a greater growth inhibition than [D-Trp6]LH-RH. In OV-1063 cells, 125I-labeled [D-Trp6]LH-RH was bound to one class of specific, saturable binding sites with high affinity (Kd = 1.4 +/- 0.3 nM) and low capacity (4000 binding sites per cell). 125I-labeled [D-Trp6]LH-RH could be displaced by unlabeled [D-Trp6]LH-RH and SB-75, suggesting that both analogs are bound to the same receptor on OV-1063 cells. Ligand binding was dependent on time and temperature. Receptor internalization assay showed that the ligand-receptor complex was internalized at 37 degrees C, which indicates the presence of biologically active LH-RH receptors on OV-1063 cells. These results suggest that estradiol and LH-RH analogs can suppress the growth of OV-1063 human epithelial ovarian cancer cells by a direct action and that the inhibitory effect of LH-RH analogs is mediated through the high-affinity LH-RH receptors.
Yano
T
T
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, LA 70146.
Pinski
J
J
Radulovic
S
S
Schally
A V
AV
D002455:Cell Division / Q000187:drug effects; D018283:Cystadenocarcinoma, Papillary / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011966:Receptors, LHRH / Q000187:drug effects / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D017329:Triptorelin Pamoate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D011966:Receptors, LHRH; D017329:Triptorelin Pamoate; D007987:Gonadotropin-Releasing Hormone; D004958:Estradiol; C062876:cetrorelix; D013936:Thymidine