1. Effect of [D-Trp6]LHRH infusion on prolactin secretion by perifused rat pituitary cells
I Torres-Aleman, M Fernández, L Debeljuk, A L Charro Regul Pept. 1987 Jul;18(1):19-28. doi: 10.1016/0167-0115(87)90046-2.
The effect of a superactive agonistic analog of luteinizing hormone-releasing hormone (LHRH), [D-Trp6]LHRH on prolactin (PRL) secretion by perifused rat pituitary cells was investigated. Constant infusion of [D-Trp6]LHRH (0.5 ng/min) for 2-3 h elicited a significant decrease in PRL secretion by these cells. This decrease in PRL release started ca. 30 min after the beginning of the infusion with the LHRH analog and lasted up to 1.5-2 h. [D-Trp6]LHRH significantly stimulated luteinizing hormone (LH) secretion during the first 30 min of peptide infusion; thereafter, LH levels began to return to control values. In animals pretreated in vivo with 50 micrograms of [D-Trp6]LHRH (s.c.) 1 h before sacrifice, PRL secretion by the rat pituitary cell perifusion system was significantly lower than vehicle-injected controls throughout the entire [D-Trp6]LHRH infusion period. On the other hand, thyrotropin-releasing hormone (TRH)-stimulated PRL secretion was slightly, but significantly imparied by [D-Trp6]LHRH infusion, while dopamine (DA) inhibition of PRL release was unaffected by this same treatment. These results reinforce previous observations of a modulatory effect of [D-Trp6]LHRH, probably mediated by pituitary gonadotrophs, on PRL secretion by the anterior pituitary. In addition, our findings suggest that basal PRL secretion by the lactotroph may be dependent on a normal function of the gonadotroph. The collected data from this and previous reports support the existence of a functional link between gonadotrophs and lactotrophs in the rat pituitary gland.
2. LHRH receptor targeted therapy for breast cancer
S S Kakar, H Jin, B Hong, J W Eaton, Kyung A Kang Adv Exp Med Biol. 2008;614:285-96. doi: 10.1007/978-0-387-74911-2_32.
Breast cancer remains the most common cancer among women, with an estimated 212,920 new cases and 40,970 deaths in the United States in 2006. The present work extends the studies of nanoparticles targeted to the luteinizing hormone-releasing hormone (LHRH) receptor which is overexpressed in breast, ovarian, endometrial and prostate cancer cells. In contrast, LHRH receptors are not expressed, or expressed at a low level in most visceral organs. In our studies, we conjugated Fe3O4 nanoparticles (20-30 nm) with [D-Trp6]LHRH (Triptorelin), a decapeptide analog of LHRH currently used for treatment of sex-hormone-dependent tumors. Conjugation of [D-Trp6]LHRH to Fe3O4 particles retained its binding affinity and biological activity for the LHRH receptor. Treatment of two separate breast tumor cell lines (MCF-7 and MDA-MB231) with these conjugated nanoparticles resulted in 95-98% cell death and loss of viability within 24 h whereas no change in cell proliferation or cell apoptosis was observed in cells treated with equal amounts of either [D-Trp6]LHRH or unconjugated Fe3O4 nanoparticles. These studies provide critical and important information regarding use of LHRH receptor targeted therapy for breast cancer.
3. Metabolism of [Des-Gly10,D-Trp6]LHRH ethylamide in rabbit nasal tissue
U B Kompella, B A Dani Life Sci. 1996;58(24):2201-7. doi: 10.1016/0024-3205(96)00214-7.
The objective of this study was to determine whether [Des-Gly10, D-Trp6] LHRH ethylamide, a nonapeptide LHRH agonist known as deslorelin, is degraded by the rabbit nasal tissue. Deslorelin was incubated with nasal tissue either alone or in the presence of 0.1 mM ouabain, 0.1% 2,4-dinitrophenol, 0.1 mM phosphoramidon, 0.1 mM N-tosyl-L-phenylalanine chloromethylketone (TPCK) or 2% EDTA at 37 degrees C. Furthermore, deslorelin alone was incubated with nasal tissue at 4 degrees C. All incubation solutions were adjusted to isotonicity and pH 5.0. At the end of 90 min, the supernatants were analyzed using a reversed-phase HPLC. Metabolite peaks could be detected in all the above experiments except the low temperature study, suggesting inhibition of metabolism at low temperature. Intact drug remaining in the supernatant was elevated by about 32% by ouabain and dinitrophenol, suggesting that energy-dependent cellular uptake is likely for deslorelin. Phosphoramidon and TPCK failed to alter deslorelin levels, suggesting that phosphoramidon and TPCK sensitive endopeptidases did not contribute to the observed deslorelin metabolism. However, EDTA significantly elevated the intact deslorelin levels in a dose-dependent manner, with an elevation of 113% with 2% EDTA. With 2% EDTA, the metabolite peaks almost completely disappeared, indicating a possible role for either metal-activated peptidases or metallo-endopeptidases in the nasal metabolism of deslorelin.
