Abstract
Naturally occurring isoforms of the decapeptide gonadotropin-releasing hormone (GnRH) share residues 1-4 and 9-10. lGnRH-III, the third isoform isolated in the sea lamprey has no endocrine effect in mammals but shows a direct antiproliferative effect on human breast, prostate and endometrial cancer cell lines. To investigate these features, residues 5-8 of lGnRH-III were systematically replaced with Ala. The ability of the synthetic analogs to interact with receptors on MDA-MB 231 human breast cancer cells and their effect on the growth of the same cell line were investigated. [Ala6]lGnRH-III and [Ala7]lGnRH-III have neither receptor binding nor antiproliferative activity. Replacement of His5 with Ala resulted in an analog that binds to the receptor but does not have antiproliferative activity. The results are in agreement with previous reports that modifications of Lys at position 8 are well tolerated.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alanine / chemistry
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Animals
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Breast Neoplasms / drug therapy*
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Cell Line, Tumor
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Cell Membrane / metabolism
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Gonadotropin-Releasing Hormone / chemistry*
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Gonadotropin-Releasing Hormone / metabolism*
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Histidine / chemistry
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Humans
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Inhibitory Concentration 50
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Lampreys
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Lysine / chemistry
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Oligopeptides / chemistry*
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Oligopeptides / metabolism*
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Peptides / therapeutic use
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Protein Binding
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Protein Isoforms
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Protein Structure, Tertiary
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Pyrrolidonecarboxylic Acid / analogs & derivatives*
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Pyrrolidonecarboxylic Acid / chemistry*
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Pyrrolidonecarboxylic Acid / metabolism*
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Radioligand Assay
Substances
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Oligopeptides
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Peptides
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Protein Isoforms
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gonadotropin-releasing hormone-III
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Gonadotropin-Releasing Hormone
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Histidine
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Lysine
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Alanine
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Pyrrolidonecarboxylic Acid