Lipopeptide antagonists of growth hormone-releasing hormone with improved antitumor activities.
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 at the dose of 10 mug/day. GHRH antagonists including MZ-J-7-46 and MZ-J-7-114 acylated with octanoic acid and MZ-J-7-30 and MZ-J-7-110 acylated with 1,12-dodecanedicarboxylic acid represent relevant improvements over earlier antagonists. These and previous results suggest that this class of GHRH antagonists might be effective in the treatment of various cancers.
Zarandi
Marta
M
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, and Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112-2699, USA.
Varga
Jozsef L
JL
Schally
Andrew V
AV
Horvath
Judit E
JE
Toller
Gabor L
GL
Kovacs
Magdolna
M
Letsch
Markus
M
Groot
Kate
K
Armatis
Patricia
P
Halmos
Gabor
G
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D003998:Dicarboxylic Acids / Q000737:chemistry; D006801:Humans; D008074:Lipoproteins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D018013:Receptors, Neuropeptide / Q000187:drug effects; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000187:drug effects; D017337:Sermorelin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D003998:Dicarboxylic Acids; D008074:Lipoproteins; D010455:Peptides; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D017337:Sermorelin; C048250:somatotropin releasing hormone receptor