cetrorelix and Adenocarcinoma--Papillary

The inhibition of growth of various hormone-dependent cancers by analogs of luteinizing hormone-releasing hormone (LH-RH) may be exerted in part through receptors for LH-RH present on tumor cells, but the direct mode of action of LH-RH agonists and antagonists is still not completely understood. The aim of this study was to investigate the effects of agonist [D-Trp6]LH-RH and antagonist Cetrorelix, administered s.c. at a dose of 100 microg/day for 3 weeks on the binding characteristics and subcellular localization of receptors for LH-RH in OV-1063 human epithelial ovarian cancers xenografted into nude mice. Using radioligand binding studies, following in vitro desaturation, we demonstrated the presence of specific, high affinity binding sites for LH-RH in both cell membrane and nuclear fraction of OV-1063 tumors. Treatment with Cetrorelix, but not [D-Trp6]LH-RH, caused about 60% reduction (p<0. 01) in tumor volume and weight. [D-Trp6]LH-RH decreased the number of LH-RH receptors on OV-1063 tumor membranes by 44% after 14 days (p<0.01), and the concentration of receptors remained at that level on day 21. The maximal binding capacity of receptors for LH-RH in the nuclei was significantly higher (p<0.05) after 3 weeks of treatment with [D-Trp6]LH-RH. Cetrorelix decreased the concentration of membrane receptors for LH-RH by 53% (p<0.01) after 14 days and the levels on day 21 were even lower, showing a 70% reduction (p<0. 01). In contrast, the number of LH-RH binding sites in the nuclear pellet was significantly increased (p<0.01) by Cetrorelix at that time. Our results demonstrate for the first time that the down-regulation of LH-RH receptors on the cell membranes of OV-1063 human ovarian cancers after therapy with antagonist Cetrorelix or agonist [D-Trp6]LH-RH is associated with an increase in receptor concentration in the nuclei. These phenomena could be related to the internalization and subcellular translocation of receptors in these tumor cells.

Topics: Adenocarcinoma, Papillary; Animals; Antineoplastic Agents, Hormonal; Down-Regulation; Drug Screening Assays, Antitumor; Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Mice; Mice, Nude; Middle Aged; Ovarian Neoplasms; Receptors, LHRH; Triptorelin Pamoate; Tumor Cells, Cultured

Our objective was to study the direct action of the gonadotropin-releasing hormone antagonist SB-75 and the agonist buserelin on the proliferation of endometrial cancer cells.. Two human endometrial cell lines that differ in histologic subtype and estrogen receptor content were treated with gonadotropin-releasing hormone analog. We measured the number of viable cells, cell cycle parameters, and apoptotic processes.. Growth of the Ishikawa cells was inhibited by SB-75 in a dose-dependent manner. 17 beta-Estradiol partially abolished the inhibitory effect of SB-75. The growth of the HEC-1A cells was not affected by the antagonist. Neither endometrial cancer cell line showed significant sensitivity to the agonist buserelin. Tenfold concentration of the gonadotropin-releasing hormone agonist did not abolish the inhibitory effect of the antagonist on cell growth. The growth inhibition was not associated with any change in cell cycle parameters but was associated with an induction of apoptosis.. The gonadotropin-releasing hormone antagonist SB-75 directly inhibits the growth of some human endometrial cancer cells and thus may be suitable for the treatment of endometrial tumors.

Topics: Adenocarcinoma, Papillary; Aged; Apoptosis; Buserelin; Cell Cycle; Cell Division; DNA, Neoplasm; Dose-Response Relationship, Drug; Electrophoresis, Agar Gel; Endometrial Neoplasms; Estradiol; Female; Flow Cytometry; Gonadotropin-Releasing Hormone; Humans; Receptors, Estrogen; Time Factors; Tumor Cells, Cultured