Short-chain analogs of luteinizing hormone-releasing hormone containing cytotoxic moieties

T. Janaky, A. Juhasz, Z. Rekasi, P. Serfozo, J. Pinski, L. Bokser, G. Srkalovic, S. Milovanovic, T. W. Redding, G. Halmos, A. Nagy, A. V. Schally

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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 ω-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.

Original languageEnglish (US)
Pages (from-to)10203-10207
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume89
Issue number21
DOIs
StatePublished - 1992
Externally publishedYes

Keywords

  • Cancer
  • Peptides
  • Receptors on tumors
  • Targeted chemotherapeutic agents

ASJC Scopus subject areas

  • Genetics
  • General

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