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Title: Highly potent metallopeptide analogues of luteinizing hormone-releasing hormone

Abstract

Metal complexes related to the cytotoxic complexes cisplatin (cis-diamminedichloroplatinum(II)) and transbis(salicylaldoximato)copper(II) were incorporated into suitably modified luteinizing hormone-releasing hormone (LH-RH) analogues containing D-lysine at position 6. Some of the metallopeptides thus obtained proved to be highly active LH-RH agonists or antagonists. Most metallopeptide analogues of LH-RH showed high affinities for the membrane receptors of rat pituitary and human breast cancer cells. Some of these metallopeptides had cytotoxic activity against human breast cancer and prostate cancer and prostate cancer cell lines in vitro. Such cytostatic metallopeptides could be envisioned as targeted chemotherapeutic agents in cancers that contain receptors for LH-RH-like peptides.

Authors:
; ; ; ; ; ; ;  [1]
  1. (Tulane Univ. School of Medicine, New Orleans, LA (USA))
Publication Date:
OSTI Identifier:
7191552
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proceedings of the National Academy of Sciences of the United States of America; (USA); Journal Volume: 86:16
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; AMINO ACIDS; METALLOPROTEINS; CROSS-LINKING; RECEPTORS; IODINE 125; LH; LIBERINS; LIQUID COLUMN CHROMATOGRAPHY; LYSINE; MAMMARY GLANDS; MOLECULAR STRUCTURE; PLATINUM COMPOUNDS; TUMOR CELLS; ANIMAL CELLS; BETA DECAY RADIOISOTOPES; BODY; CARBOXYLIC ACIDS; CHEMICAL REACTIONS; CHROMATOGRAPHY; DAYS LIVING RADIOISOTOPES; ELECTRON CAPTURE RADIOISOTOPES; GLANDS; GONADOTROPINS; HORMONES; INTERMEDIATE MASS NUCLEI; IODINE ISOTOPES; ISOTOPES; MEMBRANE PROTEINS; NUCLEI; ODD-EVEN NUCLEI; ORGANIC ACIDS; ORGANIC COMPOUNDS; ORGANS; PEPTIDE HORMONES; PITUITARY HORMONES; POLYMERIZATION; PROTEINS; RADIOISOTOPES; SEPARATION PROCESSES; TRANSITION ELEMENT COMPOUNDS; 550201* - Biochemistry- Tracer Techniques

Citation Formats

Bajusz, S., Janaky, T., Csernus, V.J., Bokser, L., Fekete, M., Srkalovic, G., Redding, T.W., and Schally, A.V. Highly potent metallopeptide analogues of luteinizing hormone-releasing hormone. United States: N. p., 1989. Web. doi:10.1073/pnas.86.16.6313.
Bajusz, S., Janaky, T., Csernus, V.J., Bokser, L., Fekete, M., Srkalovic, G., Redding, T.W., & Schally, A.V. Highly potent metallopeptide analogues of luteinizing hormone-releasing hormone. United States. doi:10.1073/pnas.86.16.6313.
Bajusz, S., Janaky, T., Csernus, V.J., Bokser, L., Fekete, M., Srkalovic, G., Redding, T.W., and Schally, A.V. 1989. "Highly potent metallopeptide analogues of luteinizing hormone-releasing hormone". United States. doi:10.1073/pnas.86.16.6313.
@article{osti_7191552,
title = {Highly potent metallopeptide analogues of luteinizing hormone-releasing hormone},
author = {Bajusz, S. and Janaky, T. and Csernus, V.J. and Bokser, L. and Fekete, M. and Srkalovic, G. and Redding, T.W. and Schally, A.V.},
abstractNote = {Metal complexes related to the cytotoxic complexes cisplatin (cis-diamminedichloroplatinum(II)) and transbis(salicylaldoximato)copper(II) were incorporated into suitably modified luteinizing hormone-releasing hormone (LH-RH) analogues containing D-lysine at position 6. Some of the metallopeptides thus obtained proved to be highly active LH-RH agonists or antagonists. Most metallopeptide analogues of LH-RH showed high affinities for the membrane receptors of rat pituitary and human breast cancer cells. Some of these metallopeptides had cytotoxic activity against human breast cancer and prostate cancer and prostate cancer cell lines in vitro. Such cytostatic metallopeptides could be envisioned as targeted chemotherapeutic agents in cancers that contain receptors for LH-RH-like peptides.},
doi = {10.1073/pnas.86.16.6313},
journal = {Proceedings of the National Academy of Sciences of the United States of America; (USA)},
number = ,
volume = 86:16,
place = {United States},
year = 1989,
month = 8
}
  • The nitrogen mustard derivatives of 4-phenylbutyric acid and L-phenylalanine, called chlorambucil (Chl) and melphalan (Mel), respectively, have been incorporated into several peptide hormones, including luteinizing hormone-releasing hormone (LH-RH). The alkylating analogues of LH-RH were prepared by linking Chl, as an N-acyl moiety, to the complete amino acid sequence of agonistic and antagonistic analogues. These compounds, in particular the antagonistic analogues, showed much lower potency than their congeners carrying other acyl groups. To obtain highly potent alkylating analogues of LH-RH, the D enantiomer of Mel was incorporated into position 6 of the native hormone and some of its antagonistic analogues. Ofmore » the peptides prepared, (D-Mel{sup 6})LH-RH (SB-05) and (Ac-D-Nal(2){sup 1},D-Phe(pCl){sup 2},D-Pal(3){sup 3},Arg{sup 5},D-Mel{sup 6},D-Ala{sup 10})LH-RH (SB-86, where Nal(2) is 3-(2-naphthyl)alanine and Pal(3) is 3-(3-pyridyl)alanine) possessed the expected high agonistic and antagonistic activities, respectively, and also showed high affinities for the membrane receptors of rat pituitary cells, human breast cancer cells, human prostate cancer cells, and rat Dunning R-3327 prostate tumor cells. These two analogues exerted cytotoxic effects on human and rat mammary cancer cells in vitro. Thus these two D-Mel{sup 6} analogues seem to be particularly suitable for the study of how alkylating analogues of LH-RH could interfere with intracellular events in certain cancer cells.« less
  • Nafarelin acetate, (6-(3-(2-naphthyl)-D-Ala))-luteinizing hormone-releasing hormone (LHRH), is a synthetic LHRH agonist. In the suppression of estrus in female rats, nafarelin acetate was about 200 times as potent as LHRH. The authors have studied the distribution and excretion of radiolabeled nafarelin acetate administered iv to rats and rhesus monkeys and have also compared the pharmacokinetics of nafarelin acetate to LHRH in these two species. Distribution of a single 100-micrograms dose ( UC)nafarelin acetate into tissues in male rats was rapid and of the 13 tissues assayed, highest concentrations of radioactivity were observed in the kidneys, liver, and intestines. The urine tomore » feces ratio of nafarelin-associated UC was 4:1 in rhesus monkeys and 1:3 in rats. Nafarelin acetate and LHRH given iv to female rhesus monkeys in approximately equimolar doses had terminal plasma t1/2 values of 120 min and 33 min, and systemic clearance values of 2.7 ml/min/kg and 31.4 ml/min/kg, respectively. In female rats, the plasma t1/2 was 33.6 min for nafarelin acetate and 6.7 min for LHRH, and the systemic clearance values for nafarelin acetate and LHRH were 12.0 ml/min/kg and 57.6 ml/min/kg, respectively, after approximately equimolar doses.« less
  • Nafarelin acetate (less than Glu-His-Trp-Ser-Tyr-3-(2-naphthyl)-D-Ala-Leu-Arg-Pro-Gly-NH2) is a potent agonistic analogue of luteinizing hormone-releasing hormone. After a single iv administration of nafarelin acetate (with UC label at C-3 of 3-(2-naphthyl)-D-Ala) to female rhesus monkeys, about 80% of the radioactivity was eliminated in urine. Five major radioactive urinary metabolites were isolated and purified by reversed phase HPLC. Four of these metabolites, identified by amino acid analysis, were short peptides: the 5-10-hexapeptide amide, the 6-10-pentapeptide amide, the 5-7-tripeptide, and the 6-7-dipeptide. The fifth metabolite, which accounted for about 15% of the radioactivity administered, was shown by NMR and mass spectrometry to be 2-naphthylaceticmore » acid. A possible pathway of its formation is by oxidative deamination of 3-(2-napthyl)-D-Ala to give the corresponding alpha-keto acid, followed by oxidative decarboxylation of the alpha-keto acid. These five metabolites together accounted for about 70% of the radioactivity recovered in the urine of rhesus monkeys, or more than half of the radioactivity in the administered dose. Nafarelin acetate was also present in small amounts. Several of these metabolites were also present in plasma of the rhesus monkey.« less
  • One hundred sixty-three patients who were given synthetic LH-RH therapeutically underwent monitoring of serum IgG anti-LH-RH antibodies. Five of the patients showed specific binding to antibodies. Development of anti-LH-RH antibodies was not limited to those patients with a congenital deficiency of LH-RH. Urticarial responses occurred in four patients, only one of whom had IgG antibodies. Patients who had IgG antibodies or an urticarial response underwent monitoring of their serum IgE anti-LH-RH antibodies, but none had a positive binding response. The refractory state which has been reported in patients in whom similar antibodies to LH-RH develop was not invariably observed amongmore » these patients.« less
  • In the present study, the authors evaluated the in vitro effects of lead (Pb) on basal and stimulated luteinizing hormone releasing hormone (LHRH) and Prostaglandin E[sub 2] (PGE[sub 2]) secretion. Median eminences (ME) were removed from brains of adult male rats and preincubated for 15 minutes in Krebs-Ringer bicarbonate glucose buffer in an atmosphere of 95% O[sub 2]-5% CO[sub 2]. These media were discarded and all MEs were subjected to one of the following experiments. In Experiment 1, all MEs were incubated for 30 minutes in medium only. These media were collected and replaced with medium only (controls) or withmore » medium containing Pb doses ranging from 5 to 20 [mu]M. After this 60-minute incubation, media were collected, then replaced with new medium containing 60 [mu]M norepinephrine (NE), or NE plus each dose of Pb, then incubated for a final 30-minute period. Experiment 2 was conducted as above, except PGE[sub 2] (2.8 [mu]M) replaced the NE. In both experiments, the amounts of LHRH released was measured by RIA. In experiment 3, NE was again used for the challenge; however, this time, the amount of PGE[sub 2] released was measured by RIA. Results indicate that Pb did not alter basal LHRH release, but compared with controls, significantly blocked NE-induced LHRH release in a dose-related manner. Conversely, Pb had no effect on the PGE[sub 2]-induced release of LHRH. Additionally, Pb did not alter basal PGE[sub 2] release; however, it significantly blocked the NE-induced release of PGE[sub 2]. Since NE-induced LHRH release is mediated by PGE[sub 2], these results support the hypothesis that Pb is capable of altering the hypothalamus and suggest that this effect is due, at least in part, to the diminished PGE[sub 2] synthesis/release within the ME, resulting in diminished LHRH secretion.« less