New antagonists of LHRH II. Inhibition and potentiation of LHRH by closely related analogues

Abstract

Modifications of the previously described LHRH antagonists, [Ac‐d‐Nal(2)1, d‐Phe(4Cl)2, d‐Trp3, d‐Cit6, d‐Ala10]LHRH and the corresponding d‐Hci6 analogue, have been made to alter the hydrophobicity of the N‐terminal acetyl‐tripeptide portion. Substitution of d‐Trp3 with the less hydrophobic d‐Pal(3) had only marginal effects on the antagonistic activities and receptor binding potencies of the d‐Cit/d‐Hci6 analogues, but it appeared to further improve the toxicity lowering effect of d‐Cit/d‐Hci6 substitution. Antagonists containing d‐Pal(3)3 and d‐Cit/d‐Hci6 residues, i.e. [Ac‐d‐Nal(2)1, d‐Phe(4Cl)2, d‐Pal(3)3d‐Cit6, d‐Ala10]LHRH (SB‐75) and [Ac‐d‐Nal(2)1, d‐Phe(4Cl)2, d‐Pal(3)3, d‐Hci6, d‐Ala10]LHRH (SB‐88), were completely free of the toxic effects, such as cyanosis and respiratory depression leading to death, which have been observed in rats with the d‐Trp3, d‐Arg6 antagonist and related antagonists. Replacement of the N‐acetyl group with the hydrophilic carbamoyl group caused a slight decrease in antagonistic activities, particularly in vitro. Introduction of urethane type acyl group such as methoxycarbonyl (Moc) or t‐butoxycarbonyl (Boc) led to analogues that showed LHRH‐potentiating effect. The increase in potency induced by these analogues, e.g. [Moc‐d‐Nal(2)1, d‐Phe(4Cl)2, d‐Trp3, d‐Cit6, d‐Ala10]LHRH and [Boc‐d‐Phe1, d‐Phe(4Cl)2, d‐Pal(3)3, d‐Cit6, d‐Ala10]LHRH, was 170‐260% and persisted for more than 2 h when studied in a superfused rat pituitary system.

Inhibitory effects of antagonists of growth hormone releasing hormone on experimental prostate cancers are associated with upregulation of wild‐type p53 and decrease in p21 and mutant p53 proteins

“…A depot formulation of the LHRH antagonist Cetrorelix (Ac‐D‐Nal (2) 1 ,D‐Phe(4Cl) 2 ,D‐Pal (3) 3 ,D‐Cit 6 ,D‐Ala‐ 10 )LHRH 35 was supplied by Zentaris (Frankfurt) as Cetrorelix pamoate (D20762) and contained Cetrorelix peptide‐base and pamoic acid in a molar ratio of 2:1 and mannitol. For the injections, Cetrorelix pamoate was suspended in injection vehicle containing 5% mannitol in distilled water at a final concentration of 15 mg/ml.…”

Luteinizing Hormone-Releasing Hormone (LHRH)-I Antagonist Cetrorelix Inhibits Myeloma Cell Growth In vitro and In vivo

“…The LHRH- (2) is 3-(2-naphthyl)alanine, Pal(3) is 3-(3-pyridyl)alanine, and Cit is citrulline], was originally synthesized in our laboratory (25). Cetrorelix was dissolved in distilled water containing 5% mannitol (vehicle solution for injection).…”

Triple-negative breast cancers express receptors for luteinizing hormone-releasing hormone (LHRH) and respond to LHRH antagonist Cetrorelix with growth inhibition

“…Specific receptors for LHRH were detected on human breast, prostatic, ovarian, endometrial and pancreatic cancers (8)(9)(10)(11)(12)(13)(14)(15)(16). In an unselected series of human breast cancer samples (containing steroid receptor positive and negative as well as HER2-positive and -negative samples) our group detected high-affinity binding sites for LHRH in >50% of the cases.…”

“…Specific receptors for luteinizing hormone-releasing hormone (LHRH) have been so far detected on a variety of human cancer cells, such as breast, prostatic, ovarian, endometrial, colorectal and pancreatic cancers as well as melanomas and non-Hodgkin's lymphoma (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). The production of an LHRH-like peptide and/or the expression of mRNA for LHRH was also demonstrated in various human cancer cell lines (8,14,18).…”