Lipopeptide antagonists of growth hormone-releasing hormone with improved antitumor activities

Proceedings of the National Academy of Sciences of the United States of America
Marta ZarandiGabor Halmos

Abstract

Antagonists of growth hormone-releasing hormone (GHRH) synthesized previously inhibit proliferation of various human cancers, but derivatisation with fatty acids could enhance their clinical efficacy. We synthesized a series of antagonists of GHRH(1-29)NH(2) acylated at the N terminus with monocarboxylic or alpha,omega-dicarboxylic acids containing six to sixteen carbon atoms. These peptides are analogs of prior potent antagonists JV-1-36, JV-1-38, and JV-1-65 with phenylacetyl group at their N terminus. Several new analogs, including MZ-J-7-46 and MZ-J-7-30, more effectively inhibited GHRH-induced GH release in vitro in a superfused rat pituitary system than their parent compound JV-1-36 and had increased binding affinities to rat pituitary GHRH receptors, but they showed weaker inhibition of GH release in vivo than JV-1-36. All antagonists acylated with fatty acids containing 8-14 carbon atoms inhibited the proliferation of MiaPaCa-2 human pancreatic cancer cells in vitro better than JV-1-36 or JV-1-65. GHRH antagonist MZ-J-7-114 (5 mug/day) significantly suppressed the growth of PC-3 human androgen-independent prostate cancers xenografted into nude mice and reduced serum IGF-I levels, whereas antagonist JV-1-38 had no effect...Continue Reading

References

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Feb 3, 2004·Proceedings of the National Academy of Sciences of the United States of America·Jozsef L VargaMarta Zarandi
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Citations

Dec 18, 2007·Nature Clinical Practice. Endocrinology & Metabolism·Andrew V SchallyJörg B Engel
Mar 6, 2007·Endocrinology and Metabolism Clinics of North America·Indraneel Banerjee, Peter E Clayton
Jul 11, 2012·International Journal of Cancer. Journal International Du Cancer·Laura Muñoz-MorenoAna M Bajo
Nov 13, 2014·PloS One·Jamie R DoyleAlan S Kopin
Oct 26, 2016·Frontiers in Endocrinology·Leonid E FridlyandLouis H Philipson
Feb 13, 2018·International Journal of Cancer. Journal International Du Cancer·Haibo WangAndrew V Schally

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