title: Synthesis and biological evaluation of antagonists of growth hormone-releasing hormone with high and protracted in vivo activities.
abstract: Some antagonists of human growth hormone-releasing hormone (hGH-RH) synthesized previously were shown to inhibit in vivo proliferation of various human cancers in nude mice. However, the activity of these analogs requires an increase to assure clinical efficacy. In an attempt to prepare hGH-RH antagonists with a high and protracted activity, we synthesized and biologically tested 22 antagonistic analogs of hGH-RH(1-29)NH2. The ability of the antagonists to inhibit hGH-RH-induced GH release was evaluated in vitro in a superfused rat pituitary system, as well as in vivo after i.v. injection into rats. The binding affinity of the peptides to GH-RH receptors also was determined. All antagonistic analogs had the common core sequence [PhAc-Tyr1,D-Arg2, Phe(4-Cl)6 (para-chlorophenylalanine), Abu15 (alpha-aminobutyric acid), Nle27]hGH-RH(1-29)NH2 and contained Arg, D-Arg, homoarginine (Har), norleucine (Nle), and other substitutions. The following analogs were determined to have a high and/or protracted antagonistic activity: [PhAc-Tyr1,D-Arg2,Phe(4-Cl)6,Arg9,Abu15,Nle27, D-Arg29]hGH-RH(1-29)NH2 (JV-1-10), [PhAc-Tyr1,D-Arg2,Phe(4-Cl)6, Abu15,Nle27,D-Arg28,Har29]hGH-RH(1-29)NH2 (MZ-6-55), [PhAc-Tyr1, D-Arg2,Phe(4-Cl)6,Arg9,Abu15,Nle27,D-Arg28,Har29 ]hGH-RH(1-29)NH2 (JV-1-36), and [PhAc-Tyr1,D-Arg2,Phe(4-Cl)6,Har9,Tyr(Me)10,Abu15, Nle27,D-Arg28,Har29]hGH-RH(1-29)NH2 (JV-1-38). Among the peptides tested, analog JV-1-36 showed the highest GH-RH antagonistic activity in vitro and also induced a strong and prolonged inhibition of GH release in vivo for at least 30 min. The antagonist JV-1-38 was slightly less potent than JV-1-36 both in vitro and in vivo but proved to be very long-acting in vivo, suppressing the GH-RH-induced GH release even after 60 min. High and protracted in vivo activities of these antagonists indicate an improvement over earlier GH-RH analogs. Some of these hGH-RH antagonists could find clinical applications in the treatment of cancers dependent on insulin-like growth factors I and II.
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Varga
authors.forename: A V
authors.initials: AV
authors.lastname: Schally
authors.forename: V J
authors.initials: VJ
authors.lastname: Csernus
authors.forename: M
authors.initials: M
authors.lastname: Zarándi
authors.forename: G
authors.initials: G
authors.lastname: Halmos
authors.forename: K
authors.initials: K
authors.lastname: Groot
authors.forename: Z
authors.initials: Z
authors.lastname: Rékási
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002478:Cells, Cultured; D013006:Growth Hormone / Q000037:antagonists & inhibitors; D013007:Growth Hormone-Releasing Hormone / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology; D010902:Pituitary Gland / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018013:Receptors, Neuropeptide / Q000378:metabolism; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; C048250:somatotropin releasing hormone receptor