Luteinizing hormone-releasing hormone antagonists (original) (raw)
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Journal of Medicinal Chemistry, 1976
<Glu-Leu-Leu-Ser-Tyr-~-Ala-Leu-Arg-Prc-Gly-NH2) and [Valz,Leu3,~-Ala6]-LH-RH completely inhibited the release of LH and FSH induced by 0.3 ng/ml of medium of LH-RH on isolated rat pituitaries, at a dosage of 10 g. [Leuz,Val3,~-Alas]-LH-RH and [Valz,Val3p-Alas]-LH-RH also completely inhibited this response but were one-tenth as active as [ L~u~, L~u~,
Cancer Letters, 2000
We studied the effects of luteinising hormone-releasing hormone (LHRH) agonist leuproreline (1 mM for 96 h) and LHRH antagonist cetrorelix on the cell growth of primary cultures from nine human endometrial cancers using the sulphorhodamine colorimetric test. Histological examinations and reverse transcription and polymerase chain reaction ampli®cation (RT±PCR) for LHRH receptors were also performed. The endometrial cancers examined had a medium to high degree of proliferative activity and a low degree of apoptotic power; furthermore, they expressed the LHRH receptor RNA variably, detectable in 71% of cases. The addition of leuproreline or cetrorelix to cell cultures inhibited growth in a statistically signi®cant way compared to untreated control cells; nevertheless, the percentage of cell growth inhibition obtained was very variable. These data suggest that LHRH analogues can exert differential inhibitory effects on the growth of endometrial cancer, which seems to be independent of the expression of speci®c LHRH receptors.
Biology of Reproduction, 2005
Targeted chemotherapy is a modern approach aimed at increasing the efficacy of systemic chemotherapy and reducing its side effects. The peptide receptors expressed primarily on cancerous cells can serve as targets for a selective destruction of malignant tumors. Binding sites for LHRH (now known in genome and microarray databases as GNRH1), were found on 52% of human breast cancers, about 80% of human ovarian and endometrial cancers, and 86% of human prostatic carcinoma specimens. Because LHRH receptors are not expressed on most normal tissues, they represent a specific target for cancer chemotherapy with antineoplastic agents linked to an LHRH vector molecule. To test the efficacy of targeted chemotherapy based on LHRH analogs, we recently developed a cytotoxic analog of LHRH, designated AN-152, which consists of [D-Lys 6 ]LHRH covalently linked to one of the most widely used chemotherapeutic agents, doxorubicin (DOX). In addition, we designed and synthesized a highly active derivative of DOX, 2pyrrolino-DOX (AN-201), which is 500-1000 times more potent than DOX in vitro. AN-201 is active against tumors resistant to DOX, and noncardiotoxic. As in the case of DOX, AN-201 was coupled to carrier peptide [D-Lys 6 ]LHRH to form a superactive targeted cytotoxic LHRH analog, AN-207. Both AN-152 and AN-207 can effectively inhibit the growth of LHRH receptor-positive human breast, ovarian, endometrial, and prostate cancers xenografted into nude mice. DOX-containing cytotoxic LHRH analog AN-152 is scheduled for clinical phase I/IIa trials in patients with advanced ovarian and breast cancers in 2005.
Gynecologic Oncology, 1998
In addition to its function as a key hormone in the regulation of the pituitary-gonadal axis, luteinizing hormone-releasing hormone (LHRH) probably also affects various extrapituitary tissues. LHRH binding sites and in vitro antiproliferative effects of LHRH analogues have been reported in human endometrial cancer. The effects of the LHRH agonist leuproreline and LHRH antagonist antide were studied on the cell growth, DNA synthesis, and cell cycle distribution of the human endometrial cancer cell lines HEC-1A and HEC-1B by the sulforhodamine B (SRB) method, [ 3 H]thymidine assay incorporation, and propidium iodide DNA staining, respectively. In the presence of 1.0 -100 M leuproreline the proliferation of HEC-1A cells was significantly reduced as early as 3 days after drug exposure, with a minimum growth value of 69.9 ؎ 3.6% (mean ؎ SE) at the highest concentration tested (100 M). Similar antiproliferative effects were obtained following a 6-day treatment with the LHRH antagonist antide. Also, inhibitory effects on [ 3 H]thymidine incorporation into the DNA of the HEC-1A cell line were noted after a 6-day exposure to both LHRH analogues, in the above-mentioned concentration range. Cell cycle analysis of HEC-1A cells cultured in the presence of 10 M leuproreline and antide showed a slight accumulation of cells in the G 0 /G 1 phase, while the proportions of cells in the S and G 2 /M phases concomitantly decreased. No significant effects on proliferation, DNA synthesis, and cell cycle distribution were observed in HEC-1B cells with either leuproreline or antide (up to 100 and 10 M, respectively) after a 6-day exposure. Both Northern blot analysis and reverse transcription polymerase chain reaction failed to detect expression of mRNA for the LHRH receptor in both HEC-1A and HEC-1B cell lines. In addition, the LHRH analogues did not affect the intracellular free calcium concentration, indicating that the classic signal transduction for LHRH is absent or impaired in HEC-1A cells. The observed direct inhibitory actions on HEC-1A cells support the concept that the two LHRH analogues may exert biological effects via cellular effectors distinct from the "classic" LHRH receptor. Although the mechanism by which these direct actions are produced is still obscure, these results might help to establish the basis for new approaches to the therapy of endometrial cancer.
The AAPS Journal, 2015
The enzymatic stability, antitumor activity, and gonadotropin stimulatory effects of glycosylated luteinizing hormone-releasing hormone (LHRH) analogs were investigated in this study. Conjugation of carbohydrate units, including lactose (Lac), glucose (GS), and galactose (Gal) to LHRH peptide protected the peptide from proteolytic degradation and increased the peptides' half-lives in human plasma, rat kidney membrane enzymes, and liver homogenate markedly. Among all seven modified analogs, compound 1 (Lac-[Q 1 ][w 6 ]LHRH) and compound 6 (GS 4 -[w 6 ]LHRH) were stable in human plasma during 4 h of experiment. The half-lives of compounds 1 and 6 improved significantly in kidney membrane enzymes (from 3 min for LHRH to 68 and 103 min, respectively). The major cleavage sites for most of the glycosylated compounds were found to be at Trp 3 -Ser 4 and Ser 4 -Tyr 5 in compounds 1-5. Compound 6 was hydrolyzed at Ser 4 -Tyr 5 and the sugar conjugation site. The antiproliferative activity of the glycopeptides was evaluated on LHRH receptor-positive prostate cancer cells. The glycosylated LHRH derivatives had a significant growth inhibitory effect on the LNCaP cells after a 48-h treatment. It was demonstrated that compound 1 significantly increased the release of luteinizing hormone (LH) at 5 and 10 nM concentrations and compound 5 (GS-[Q 1 ]LHRH) stimulated the release of follicle-stimulating hormone (FSH) at 5 nM concentration in dispersed rat pituitary cells (p<0.05). In our studies, compound 1-bearing lactose and D-Trp was the most stable and active and is a promising candidate for future preclinical investigations in terms of in vitro biological activity and metabolic stability.
2013
Luteinizing hormone-releasing hormone (LHRH) agonists and antagonists are commonly used androgen deprivation therapies prescribed for patients with advanced prostate cancer (PCa). Both types of agent target the receptor for LHRH but differ in their mode of action: agonists, via pituitary LRHR receptors (LHRH-Rs), cause an initial surge in luteinizing hormone (LH), follicle-stimulating hormone (FSH) and, subsequently, testosterone. Continued overstimulation of LHRH-R down-regulates the production of LH and leads to castrate levels of testosterone. LHRH antagonists, however, block LHRH-R signalling causing a rapid and sustained inhibition of testosterone, LH and FSH. The discovery and validation of the presence of functional LHRH-R in the prostate has led to much work investigating the role of LHRH signalling in the normal prostate as well as in the treatment of PCa with LHRH agonists and antagonists. In this review we discuss the expression and function of LHRH-R, as well as LH/human chorionic gonadotropin receptors and FSH receptors and relate this to the differential clinical responses to agonists and antagonists used in the hormonal manipulation of PCa.
Short-chain analogs of luteinizing hormone-releasing hormone containing cytotoxic moieties
Proceedings of the National Academy of Sciences, 1992
Five hexapeptide and heptapeptide analogs of luteiniSng hormone-releasing hormone (LH-RH) were synthesized for use as carriers for cytotoxic compounds. These short analogs were expected to enhanc target selectivity of the antineoplastic agents linked to them. Native LH-RH-(3-9) and LH-RH-(4-9) containing D-lysine and D-ornithine at position 6 were anidated with ethylamine and acylated on the N termi-Abbreviations: LH, luteinizing hormone; LH-RH, LH-releasing hormone; Mel, 4-[bis(2-chloroethyl)amino]phenylalanine; A2pr, 2,3diaminopropionic acid; IA, indole-3-acetic acid (or -acetyl); Boc, tert-butoxycarbonyl; MTX, methotrexate; HMAQ, 2-(hydroxymethyl)anthraquinone; DOX, doxorubicin. tPresent address:
COMPARISON OF LONG-ACTING ANALOGUES O F LUTEINIZING HORMONE RELEASING HORMONE IN MAN
SUMMARY Currently, LHRH, when used therapeutically, is given b y parenteral injection every 8 h. We have looked at the release of LH and FSH induced by five analogues of LHRH and compared this with gonadotrophin release after synthetic LHRH. The analogues were substituted in position 6 or in positions 6 and 10 and were given intravenously, intranasally or subcutaneously in three separate studies. After intravenous administration of lOOpg,all analogues caused greater release of LH and FSH than did synthetic LHRH. Given intranasally in a dose of 500 pg, three of the four analogues tested caused greater LH and FSH release than did LHRH. With trypto-phan substitution in position 6 (D-TRP6-LHRH), mean LH levels in five subjects were still above the normal range 24 h after a single intranasal dose. The intra-nasal administration of selected analogues of LHRH has great potential in the treatment of conditions associated with deficient gonadotrophin secretion, provided that pituitary overstimulation, which may eventually lead to a decrease in LH and FSH output by the anterior pituitary, is avoided.
Cancer Letters, 1999
Doxorubicin (DOX) and its daunosaminemodified derivative, 2-pyrrolino-DOX, which is 500-1000 times more active than DOX, were incorporated into agonistic and antagonistic analogs of luteinizing hormone-releasing hormone (LH-RH). The conjugation of DOX with LH-RH analogs was performed by using N-(9-fluorenylmethoxycarbonyl)-DOX-14-0-hemiglutarate, a dicarboxylic acid ester derivative of DOX. Coupling this derivative covalently to the E-amino group of the D-Lys side chain of agonist [D-Lys6]LH-RH or antagonistic analog Ac-D-Nal(2)-D-Phe(4C1)-D-Pal(3)-Ser-Tyr-D-Lys-Leu-Arg-Pro-D-Ala-NH2 [where Nal(2) = 3-(2naphthyl)alanine, Pal(3) = 3-(3-pyridyl)alanine, and