Schally Andrew V, Varga Jozsef L
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Centers, New Orleans, LA 70112, USA.
Comb Chem High Throughput Screen. 2006 Mar;9(3):163-70. doi: 10.2174/138620706776055449.
The development of antagonists of growth hormone (GH) - releasing hormone (GH-RH) is reviewed. GH-RH antagonists bind with a high affinity to pituitary receptors for GH-RH and inhibit the release of GH in vitro and in vivo. The main applications of GH-RH antagonists would be for tumor therapy. The antitumor effects of GH-RH antagonists are exerted in part indirectly through the inhibition of the secretion of pituitary GH and the reduction in the levels of hepatic insulin like growth factor (IGF-I). However, principal effects of the GH-RH antagonists are exerted directly on tumors. Antagonists of GH-RH inhibit the proliferation of various cancer cell lines in vitro and suppress in vivo the levels and the expression of mRNA for IGF-I and IGF-II in tumors. In many human cancers, the effects of GH-RH antagonists appear to be due to the blockade of the action of tumoral GH-RH. GH-RH ligand is present in various human cancers indicating that it may be an autocrine/paracrine growth factor. Splice variants (SVs) of GH-RH receptors and pituitary type of GH-RH receptors that might mediate effects of tumoral GH-RH and of GH-RH antagonists were demonstrated in many human cancers. This suggests the presence of a stimulatory loop based on GH-RH and SVs or pituitary type of GH-RH receptors in diverse tumors. It was shown that GH-RH antagonists inhibited the growth of various human cancer lines xenografted into nude mice including mammary, ovarian, endometrial and prostate cancers, small cell lung carcinomas (SCLC) and non-SCLC, renal, pancreatic, gastric and colorectal carcinomas, malignant gliomas, osteosarcomas and Non-Hodgkin's lymphomas. Further development of GH-RH antagonists should lead to potential therapeutic agents for various cancers.
本文综述了生长激素释放激素（GH-RH）拮抗剂的研发情况。GH-RH拮抗剂能与垂体中GH-RH的受体高亲和力结合，在体内外均能抑制生长激素（GH）的释放。GH-RH拮抗剂的主要应用将是肿瘤治疗。GH-RH拮抗剂的抗肿瘤作用部分是通过抑制垂体GH的分泌以及降低肝脏胰岛素样生长因子（IGF-I）的水平间接发挥的。然而，GH-RH拮抗剂的主要作用是直接作用于肿瘤。GH-RH拮抗剂在体外可抑制多种癌细胞系的增殖，在体内可抑制肿瘤中IGF-I和IGF-II的水平及mRNA表达。在许多人类癌症中，GH-RH拮抗剂的作用似乎是由于阻断了肿瘤源性GH-RH的作用。GH-RH配体存在于多种人类癌症中，表明它可能是一种自分泌/旁分泌生长因子。在许多人类癌症中已证实存在GH-RH受体的剪接变体（SVs）以及可能介导肿瘤源性GH-RH和GH-RH拮抗剂作用的垂体型GH-RH受体。这表明在多种肿瘤中存在基于GH-RH和SVs或垂体型GH-RH受体的刺激环路。研究表明，GH-RH拮抗剂可抑制移植到裸鼠体内的多种人类癌症细胞系的生长，包括乳腺癌、卵巢癌、子宫内膜癌和前列腺癌、小细胞肺癌（SCLC）和非小细胞肺癌、肾癌、胰腺癌、胃癌和结直肠癌、恶性胶质瘤、骨肉瘤和非霍奇金淋巴瘤。GH-RH拮抗剂的进一步研发应能产生针对多种癌症的潜在治疗药物。
