Antagonists of growth-hormone-releasing hormone: an emerging new therapy for cancer

Growth-hormone-releasing hormone (GHRH) and its receptors are expressed in a wide variety of normal and malignant tissues. This article describes various GHRH antagonists, their mechanisms of action, and in vivo studies. These antagonists are a promising potential therapy for a wide range of cancers, and perhaps other diseases. This article reviews the potential clinical uses of antagonists of growth-hormone-releasing hormone (GHRH) for tumor therapy. GHRH antagonists suppress the growth of various human cancer lines xenografted into nude mice; such tumors include breast, ovarian, endometrial and prostate cancers, lung cancers (small-cell lung carcinomas and non-small-cell lung carcinomas), renal, pancreatic, gastric and colorectal carcinomas, brain tumors (malignant gliomas), osteogenic sarcomas and non-Hodgkin's lymphomas. The antitumor effects of GHRH antagonists are exerted in part indirectly through the inhibition of the secretion of GH from the pituitary and the resulting reduction in the levels of hepatic insulin-like growth factor I (IGF-I). The main effects of the GHRH antagonists are, however, exerted directly on tumors. GHRH ligand is present in various human cancers and might function as an autocrine and/or paracrine growth factor. Pituitary-type GHRH receptors and their splice variants are also found in many human cancers. The inhibitory effects of GHRH antagonists seem to be due to the blockade of action of tumoral GHRH. Antagonists of GHRH can also suppress cancer growth by blocking production of IGF-I and/or IGF-II by the tumor. Further development of GHRH antagonists that are still-more potent should lead to potential therapeutic agents for various cancers. Key Points The presence of growth-hormone-releasing hormone (GHRH) ligand has been demonstrated in various cancers, suggesting that GHRH could be an autocrine growth factor GHRH antagonists inhibit the growth of various human cancer lines xenografted into nude mice; such lines include breast cancers, prostate cancers, small cell lung carcinomas (SCLC) and non-SCLC, malignant gliomas, renal cell carcinomas, pancreatic cancers, colorectal carcinomas and lymphomas Splice variants of GHRH receptors and pituitary-type GHRH receptors that might mediate effects of tumoral GHRH and of GHRH antagonists have been demonstrated in many human cancers GHRH antagonists seem to be devoid of major adverse effects, which would offer a distinct advantage over other classes of antitumor agents