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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.

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Whether the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis exerts cardioprotective effects remains controversial; and the underlying mechanism(s) for such actions are unclear.Here we tested the hypothesis that growth hormone-releasing hormone (GHRH) directly activates cellular reparative mechanisms within the injured heart, in a GH/IGF-1 independent fashion. After experimental myocardial infarction (MI), rats were randomly assigned to receive, during a 4-week period, either placebo (n = 14), rat recombinant GH (n = 8) or JI-38 (n = 8; 50 µg/kg per day), a potent GHRH agonist. JI-38 did not elevate serum levels of GH or IGF-1, but it markedly attenuated the degree of cardiac functional decline and remodeling after injury. In contrast, GH administration markedly elevated body weight, heart weight, and circulating GH and IGF-1, but it did not offset the decline in cardiac structure and function. Whereas both JI-38 and GH augmented levels of cardiac precursor cell proliferation, only JI-38 increased antiapoptotic gene expression. The receptor for GHRH was detectable on myocytes, supporting direct activation of cardiac signal transduction. Collectively, these findings demonstrate that within the heart, GHRH agonists can activate cardiac repair after MI, suggesting the existence of a potential signaling pathway based on GHRH in the heart. The phenotypic profile of the response to a potent GHRH agonist has therapeutic implications.cardiac stem cells | apoptosis | remodeling | heart failure C ongestive heart failure remains a leading cause of morbidity and mortality in developed countries. Despite major therapeutic advances, current therapies fail to fully reverse heart failure and/or left ventricular (LV) dysfunction. One major therapeutic avenue is that of cytokine and/or hormonal signaling pathways, and in this regard, various experimental and clinical studies have suggested an important role for the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis in the regulation of cardiac growth and function (1, 2). Moreover, several clinical studies have tested the impact of GH replacement on the failing human heart, with controversial results (3, 4).In addition to GH itself and IGF-1, GH-releasing peptides such as ghrelin and synthetic GH secretagogues (GHS) are also suggested to have cardiac effects (5-8), and growth hormone-releasing hormone (GHRH) mRNA is detected in peripheral tissues, including the heart (9, 10), consistent with widespread biologic signaling potential beyond the hypothalamic-pituitary axis.Recently, Granata et al. (10) reported that rat GHRH (1-44) promoted survival of cardiomyocytes in vitro and protected rat hearts from ischemia-reperfusion injury. The detection of the GHRH receptor (GHRHR) on the cardiomyocyte sarcolemmal membrane supports the view that GHRH may elicit direct signal transduction within the heart, independent of the GH/IGF-1 axis per se (10). Ghrelin and other GHS may have pharmacologic potential (10) but also have pleiotropic actions with a high possibility...

were initially developed to block growth hormone (GH) secretion from the pituitary glands, leading to inhibition of insulin-like growth factor I (IGF-I) production in the liver and other tissues (1-6). The reduction in the levels of serum IGF-I could inhibit the proliferation of various cancers dependent on IGF-I, in view of involvement of this growth factor and of IGF-II, which is GH independent, in malignant transformation of cells, tumor progression, and metastasis (1-3). GHRH antagonists were shown to effectively inhibit the in vivo growth of various experimental human cancers, including osteosarcomas, mammary, ovarian and prostatic cancers, renal adenocarcinomas, small-cell lung cancer (SCLC) and non-SCLC, pancreatic and colorectal carcinomas, and malignant gliomas (7-17). The proliferation of some of these human cancers in vitro was also suppressed by GHRH antagonists (7-10, 12-14, 16-18). This finding and the reduction in the concentration of IGF-I and IGF-II and the suppression of the gene expression of IGF-I and -II in the tumors suggested that GHRH antagonists, in addition to indirect action mediated by inhibition of GH-IGF-I axis, might exert direct effects on tumor growth through specific yet-to-be-identified GHRH receptors (3,19).The GHRH receptor is a G-protein-coupled transmembrane receptor found predominantly in the pituitary gland, and its mRNA has also been detected in rat placenta, kidney, testis, hypothalamus, and the gastrointestinal tract (20-23). Receptors for other GHRH-related peptides, such as vasoactive intestinal peptide (VIP) and secretin, also belong to the G-protein-linked superfamily and show homology to GHRH receptor proteins (23). Although VIP receptors have been detected in various tumors and could be involved in the regulation of tumor growth (21,(24)(25)(26), recent work showed that the antiproliferative effect of GHRH antagonists is exerted through a mechanism independent of VIP receptors (27). When primers for human GHRH (hGHRH) receptor mRNA were used (27), no expression of mRNA was found in LNCaP human prostatic and MiaPaCa-2 human pancreatic cancer cells (27), in accordance with an earlier report on ovarian tumors (28). In addition, specific binding sites for radioligand [His 1 , 125 I-Tyr 10 ,Nle 27 ]hGHRH(1-32)NH 2 could not be detected in human cancers (14,17,27), although this radioligand is widely used for the characterization of pituitary GHRH receptors (29-31). These observations indicate that peptide receptors on human tumors that respond to our GHRH antagonists should be different from the classic pituitary-type GHRH receptors.In this study, we report the presence of high-affinity binding sites for GHRH antagonists on CAKI-1 human renal cell carcinoma (RCC). The binding characteristics were investigated by ligand competition assays, using 125 I-labeled GHRH antagonist JV-1-42 as a specific radioligand. These binding sites appear to be isoforms of hGHRH receptor, as demonstrated by reverse transcription (RT)-PCR, and are also distinct from the VIP receptors. In a...