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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Lipopeptide antagonists of growth hormone-releasing hormone with improved antitumor activities
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Lipopeptide antagonists of growth hormone-releasing hormone with improved antitumor activities

机译：具有改善的抗肿瘤活性的生长激素释放激素的脂肽拮抗剂

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摘要

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 α,ω-dicarboxy-lic 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 μg/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 μg/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.
机译：先前合成的生长激素释放激素（GHRH）拮抗剂可抑制各种人类癌症的增殖，但脂肪酸衍生化可增强其临床疗效。我们合成了一系列在N末端与含有6至16个碳原子的单羧酸或α，ω-二羧酸-酸酰化的GHRH（1-29）NH_2拮抗剂。这些肽是先前有效的拮抗剂JV-1-36，JV-1-38和JV-1-65的类似物，在其N端带有苯乙酰基。几个新的类似物，包括MZ-J-7-46和MZ-J-7-30，在超融合大鼠垂体系统中比其母体化合物JV-1-36更有效地抑制了GHRH诱导的GH的体外释放，并增加了结合与大鼠垂体GHRH受体有亲和力，但它们对体内GH释放的抑制作用比JV-1-36弱。所有被含8-14个碳原子的脂肪酸酰化的拮抗剂在体外对MiaPaCa-2人胰腺癌细胞的抑制作用均优于JV-1-36或JV-1-65。 GHRH拮抗剂MZ-J-7-114（5μg/天）显着抑制异种移植到裸鼠中的PC-3非雄激素依赖性前列腺癌的生长并降低血清IGF-1水平，而拮抗剂JV-1-38没有剂量为10μg/天。 GHRH拮抗剂包括用辛酸酰化的MZ-J-7-46和MZ-J-7-114以及用1，12-十二烷二羧酸酰化的MZ-J-7-30和MZ-J-7-110相对于早期的对手。这些和先前的结果表明，这类GHRH拮抗剂可能有效地治疗各种癌症。

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