title: Short-chain analogs of luteinizing hormone-releasing hormone containing cytotoxic moieties.
abstract: Five hexapeptide and heptapeptide analogs of luteinizing hormone-releasing hormone (LH-RH) were synthesized for use as carriers for cytotoxic compounds. These short analogs were expected to enhance 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 amidated with ethylamine and acylated on the N terminus. The receptor-binding affinity of one hexapeptide carrier AJ-41 (Ac-Ser-Tyr-D-Lys-Leu-Arg-Pro-NH-Et) to human breast cancer cell membranes was similar to that of [D-Trp6]LH-RH. Alkylating nitrogen mustards (melphalan, Ac-melphalan), anthraquinone derivatives including anticancer antibiotic doxorubicin, antimetabolite (methotrexate), and cisplatin-like platinum complex were linked to these peptides through their omega-amino group at position 6. The hybrid molecules showed no LH-RH agonistic activity in vitro and in vivo but had nontypical antagonistic effects on pituitary cells in vitro at the doses tested. These analogs showed a wide range of receptor-binding affinities to rat pituitaries and cell membranes of human breast cancer and rat Dunning prostate cancer. Several of these conjugates exerted some cytotoxic effects on MCF-7 breast cancer cell line.
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Tulane University School of Medicine, New Orleans, LA 70146.
authors.forename: T
authors.initials: T
authors.lastname: Janáky
authors.forename: A
authors.initials: A
authors.lastname: Juhász
authors.forename: Z
authors.initials: Z
authors.lastname: Rékási
authors.forename: P
authors.initials: P
authors.lastname: Serfözö
authors.forename: J
authors.initials: J
authors.lastname: Pinski
authors.forename: L
authors.initials: L
authors.lastname: Bokser
authors.forename: G
authors.initials: G
authors.lastname: Srkalovic
authors.forename: S
authors.initials: S
authors.lastname: Milovanovic
authors.forename: T W
authors.initials: TW
authors.lastname: Redding
authors.forename: G
authors.initials: G
authors.lastname: Halmos
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008558:Melphalan / Q000494:pharmacology; D008727:Methotrexate / Q000494:pharmacology; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D009919:Orchiectomy; D010902:Pituitary Gland / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism; D051381:Rats; D011966:Receptors, LHRH / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000880:Anthraquinones; D000970:Antineoplastic Agents; D009842:Oligopeptides; D011966:Receptors, LHRH; C077912:2-(hydroxymethyl)anthraquinone; D007987:Gonadotropin-Releasing Hormone; D004317:Doxorubicin; D007986:Luteinizing Hormone; D002945:Cisplatin; D008558:Melphalan; D008727:Methotrexate