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Gonadotropin releasing hormone binding sites in human epithelial ovarian carcinomata
1Department of Obstetrics and Gynecology, Medical University of Lübeck, F.R.G.
Abstract:
As a first step to investigate whether gonadotropin releasing hormone (GnRH) analogs might be able to modulate directly the proliferation of human epithelial ovarian carcinomata, we checked if binding sites for GnRH are present in these malignancies. Specific binding of [125I][D-Ala6-des Gly10]-GnRH-ethylamide (GnRH agonist = GnRH-A) could be demonstrated in plasma membranes from 32 out of 40 ovarian carcinomata tested. This binding was dependent on temperature, time and plasma membrane concentration. Mathematical analysis of the binding data showed that the interaction of GnRH-A with the binding sites was consistent with a single class of low affinity, high capacity binding sites (Ka = 1.42 +/- 0.14 X 10(5) M-1; range: 0.3-3.8 X 10(5) M-1; R = 209 +/- 69 X 10(-12) M/mg membrane protein; range 16-400 X 10(-12) M/mg MP; means +/- S.E., n = 32). Native GnRH and the GnRH antagonist [D-p-Glu1, D-Phe2, D-Trp3,6]-GnRH had Ka values comparable to those of the GnRH-A used. [125I]GnRH-A binding could not be displaced by oxytocin, thyrotropin releasing hormone and corticotropin releasing factor in concentrations up to 10(-4) M. Somatostatin cross-reacted with binding sites from some carcinomata, while it did not displace GnRH-A binding in membranes from others. Though the functional role of this specific binding site for GnRH in human epithelial ovarian carcinomata is still obscure, it might be part of an autocrine regulatory system and provide a possible point of attack for therapeutic approaches using GnRH analogs in this malignancy.
Insights
Gonadotropin releasing hormone (GnRH) binding sites are present in human ovarian carcinomata. This discovery suggests GnRH analogs may offer new therapeutic strategies for ovarian cancer.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Human epithelial ovarian carcinomata are a significant cause of cancer-related mortality.
- Gonadotropin releasing hormone (GnRH) analogs are used in treating hormone-dependent cancers.
- The presence and function of GnRH receptors in ovarian cancer require investigation.
Purpose of the Study:
- To determine if binding sites for GnRH exist in human epithelial ovarian carcinomata.
- To characterize the binding properties of GnRH in these tumors.
- To explore the potential of GnRH analogs as a therapeutic approach for ovarian cancer.
Main Methods:
- Radioligand binding assays using a labeled GnRH agonist ([125I][D-Ala6-des Gly10]-GnRH-ethylamide).
- Incubation of plasma membranes from ovarian carcinomata with the radioligand under varying conditions (temperature, time, concentration).
- Displacement studies using native GnRH, GnRH antagonist, oxytocin, thyrotropin releasing hormone, corticotropin releasing factor, and somatostatin.
Main Results:
- Specific binding of the GnRH agonist was detected in 32 out of 40 (80%) ovarian carcinomata samples.
- Binding was dependent on temperature, time, and membrane concentration.
- Mathematical analysis indicated a single class of low-affinity, high-capacity binding sites for GnRH.
- Native GnRH and a GnRH antagonist showed comparable binding affinities.
- Other tested peptides (oxytocin, TRH, CRF) did not displace binding, while somatostatin showed variable cross-reactivity.
Conclusions:
- Specific binding sites for GnRH are present in a majority of human epithelial ovarian carcinomata.
- These findings suggest that GnRH receptors may play a role in ovarian cancer.
- GnRH analogs represent a potential therapeutic avenue for treating ovarian cancer, possibly through an autocrine regulatory mechanism.