Varga J L, Schally A V, Csernus V J, Zarándi M, Halmos G, Groot K, Rékási Z
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):692-7. doi: 10.1073/pnas.96.2.692.
Some antagonists of human growth hormone-releasing hormone (hGH-RH) synthesized previously were shown to inhibit in vivo proliferation of various human cancers in nude mice. However, the activity of these analogs requires an increase to assure clinical efficacy. In an attempt to prepare hGH-RH antagonists with a high and protracted activity, we synthesized and biologically tested 22 antagonistic analogs of hGH-RH(1-29)NH2. The ability of the antagonists to inhibit hGH-RH-induced GH release was evaluated in vitro in a superfused rat pituitary system, as well as in vivo after i.v. injection into rats. The binding affinity of the peptides to GH-RH receptors also was determined. All antagonistic analogs had the common core sequence [PhAc-Tyr1,D-Arg2, Phe(4-Cl)6 (para-chlorophenylalanine), Abu15 (alpha-aminobutyric acid), Nle27]hGH-RH(1-29)NH2 and contained Arg, D-Arg, homoarginine (Har), norleucine (Nle), and other substitutions. The following analogs were determined to have a high and/or protracted antagonistic activity: [PhAc-Tyr1,D-Arg2,Phe(4-Cl)6,Arg9,Abu15,Nle27, D-Arg29]hGH-RH(1-29)NH2 (JV-1-10), [PhAc-Tyr1,D-Arg2,Phe(4-Cl)6, Abu15,Nle27,D-Arg28,Har29]hGH-RH(1-29)NH2 (MZ-6-55), [PhAc-Tyr1, D-Arg2,Phe(4-Cl)6,Arg9,Abu15,Nle27,D-Arg28,Har29 ]hGH-RH(1-29)NH2 (JV-1-36), and [PhAc-Tyr1,D-Arg2,Phe(4-Cl)6,Har9,Tyr(Me)10,Abu15, Nle27,D-Arg28,Har29]hGH-RH(1-29)NH2 (JV-1-38). Among the peptides tested, analog JV-1-36 showed the highest GH-RH antagonistic activity in vitro and also induced a strong and prolonged inhibition of GH release in vivo for at least 30 min. The antagonist JV-1-38 was slightly less potent than JV-1-36 both in vitro and in vivo but proved to be very long-acting in vivo, suppressing the GH-RH-induced GH release even after 60 min. High and protracted in vivo activities of these antagonists indicate an improvement over earlier GH-RH analogs. Some of these hGH-RH antagonists could find clinical applications in the treatment of cancers dependent on insulin-like growth factors I and II.
先前合成的一些人生长激素释放激素（hGH-RH）拮抗剂已被证明可在裸鼠体内抑制多种人类癌症的增殖。然而，这些类似物的活性需要提高以确保临床疗效。为了制备具有高活性和长效活性的hGH-RH拮抗剂，我们合成并对22种hGH-RH(1-29)NH2的拮抗类似物进行了生物学测试。在体外灌注大鼠垂体系统中以及静脉注射到大鼠体内后，评估了拮抗剂抑制hGH-RH诱导的生长激素（GH）释放的能力。还测定了这些肽与GH-RH受体的结合亲和力。所有拮抗类似物都具有共同的核心序列[苯乙酰基 - 酪氨酸1，D-精氨酸2，对氯苯丙氨酸6（对氯苯丙氨酸），α-氨基丁酸15（α-氨基丁酸），正亮氨酸27]hGH-RH(1-29)NH2，并含有精氨酸、D-精氨酸、高精氨酸（Har）、正亮氨酸（Nle）和其他取代基。以下类似物被确定具有高和/或长效拮抗活性：[苯乙酰基 - 酪氨酸1，D-精氨酸2，对氯苯丙氨酸6，精氨酸9，α-氨基丁酸15，正亮氨酸27，D-精氨酸29]hGH-RH(1-29)NH2（JV-1-10），[苯乙酰基 - 酪氨酸1，D-精氨酸2，对氯苯丙氨酸6，α-氨基丁酸15，正亮氨酸27，D-精氨酸28，高精氨酸29]hGH-RH(1-29)NH2（MZ-6-55），[苯乙酰基 - 酪氨酸1，D-精氨酸2，对氯苯丙氨酸6，精氨酸9，α-氨基丁酸15，正亮氨酸27，D-精氨酸28，高精氨酸29]hGH-RH(1-29)NH2（JV-1-36），以及[苯乙酰基 - 酪氨酸1，D-精氨酸2，对氯苯丙氨酸6，高精氨酸9，甲基酪氨酸10，α-氨基丁酸15，正亮氨酸27，D-精氨酸28，高精氨酸29]hGH-RH(1-29)NH2（JV-1-38）。在所测试的肽中，类似物JV-1-36在体外显示出最高的GH-RH拮抗活性，并且在体内也诱导了至少30分钟的强烈且持久的GH释放抑制。拮抗剂JV-1-38在体外和体内的效力略低于JV-1-36，但在体内被证明具有非常长效的作用，即使在60分钟后仍能抑制GH-RH诱导的GH释放。这些拮抗剂在体内的高活性和长效活性表明其优于早期的GH-RH类似物。其中一些hGH-RH拮抗剂可能在治疗依赖胰岛素样生长因子I和II的癌症中找到临床应用。
