Analogues of luteinizing hormone-releasing hormone containing cytotoxic groups

T. Janaky, A. Juhasz, S. Bajusz, V. Csernus, G. Srkalovic, L. Bokser, S. Milovanovic, T. W. Redding, Z. Rekasi, A. Nagy, A. V. Schally

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In an attempt to produce better cytotoxic analogues, chemotherapeutic antineoplastic radicals including an alkylating nitrogen mustard derivative of D-phenylalanine (D-melphalan), reactive cyclopropane, anthraquinone derivatives [2-(hydroxymethyl)anthraquinone and the anticancer antibiotic doxorubicin], and an antimetabolite (methotrexate) were coupled to suitably modified agonists and antagonists of luteinizing hormone-releasing hormone (LH-RH). Analogues with D-lysine6 and D-ornithine6 or Nε-(2,3-diaminopropionyl)-0-lysine and A'*-(2,3-diaminopropionyl)-D-ornithine were used as carriers for one or two cytotoxic moieties. The enhanced biological activities produced by the incorporation of D amino acids into position 6 of the agonistic analogues were further increased by the attachment of hydrophobic cytotoxic groups, resulting in compounds with 10-50 times higher activity than LH-RH. Most of the monosubstituted agonistic analogues showed high affinities for the membrane receptors of human breast cancer cells, while the receptor binding affinities of peptides containing two cytotoxic side chains were lower. Antagonistic carriers [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Trp3,Arg 5,D-Lys6,D-Ala10]LH-RH [where Nal(2) is 3-(2-naphthyl)alanine], [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Trp3,Arg 5,Nε-(2,3-diaminopropionyl)-D-Lys 6,D-Ala10]LH-RH, and their D-Pal(3)3 homologs [Pal(3) is 3-(3-pyridyl)alanine] as well as [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Pal(3)3,Tyr 5,Nε-(2,3-diaminopropionyl)-D-Lys 6,D-Ala10]LH-RH were linked to cytotoxic compounds. The hybrid molecules inhibited ovulation in rats at doses of 10 μg and suppressed LH release in vitro. The receptor binding of cytotoxic analogues was decreased compared to the precursor peptides, although analogues with 2-(hydroxymethyl)anthraquinone hemiglutarate had high affinities. All of the cytotoxic analogues tested inhibited [3H]thymidine incorporation into DNA in cultures of human breast and prostate cancer cell lines. Some cytotoxic analogues also significantly suppressed the growth of mammary and prostate cancers in vivo in animal models.

Original languageEnglish (US)
Pages (from-to)972-976
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number3
StatePublished - 1992
Externally publishedYes


  • Alkylating agents
  • Doxorubicin
  • Methotrexate
  • Receptor binding
  • Targeted chemotherapeutic agents

ASJC Scopus subject areas

  • Genetics
  • General


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