scholarly journals Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD/SCID mice

2015 ◽  
Vol 112 (44) ◽  
pp. 13651-13656 ◽  
Author(s):  
Xianyang Zhang ◽  
Tengjiao Cui ◽  
Jinlin He ◽  
Haibo Wang ◽  
Renzhi Cai ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Cell Proliferation ◽  
Serum Insulin ◽  
Severe Combined Immunodeficiency ◽  
Scid Mice ◽  
Growth Hormone Releasing Hormone ◽  
Releasing Hormone ◽  
Rat Islets ◽  
Therapeutic Benefits ◽  
Glucose Challenge

Agonists of growth hormone-releasing hormone (GHRH) have been previously reported to promote growth, function, and engraftment of islet cells following transplantation. Here we evaluated recently synthesized GHRH agonists on the proliferation and biological functions of rat pancreatic β-cell line (INS-1) and islets. In vitro treatment of INS-1 cells with GHRH agonists increased cell proliferation, the expression of cellular insulin, insulin-like growth factor-1 (IGF1), and GHRH receptor, and also stimulated insulin secretion in response to glucose challenge. Exposure of INS-1 cells to GHRH agonists, MR-356 and MR-409, induced activation of ERK and AKT pathways. Agonist MR-409 also significantly increased the levels of cellular cAMP and the phosphorylation of cAMP response element binding protein (CREB) in INS-1 cells. Treatment of rat islets with agonist, MR-409 significantly increased cell proliferation, islet size, and the expression of insulin. In vivo daily s.c. administration of 10 μg MR-409 for 3 wk dramatically reduced the severity of streptozotocin (STZ)-induced diabetes in nonobese diabetic severe combined immunodeficiency (NOD/SCID) mice. The maximal therapeutic benefits with respect to the efficiency of engraftment, ability to reach normoglycemia, gain in body weight, response to high glucose challenge, and induction of higher levels of serum insulin and IGF1 were observed when diabetic mice were transplanted with rat islets preconditioned with GHRH agonist, MR-409, and received additional treatment with MR-409 posttransplantation. This study provides an improved approach to the therapeutic use of GHRH agonists in the treatment of diabetes mellitus.

scholarly journals Polyethylene glycol-conjugated growth hormone-releasing hormone is long acting and stimulates GH in healthy young and elderly subjects

2005 ◽  
Vol 153 (2) ◽  
pp. 249-256 ◽  
Author(s):  
A Munafo ◽  
T X Q Nguyen ◽  
O Papasouliotis ◽  
H Lécuelle ◽  
A Priestley ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Polyethylene Glycol ◽  
Serum Insulin ◽  
Repeated Administration ◽  
The Elderly ◽  
Elderly Subjects ◽  
Growth Hormone Releasing Hormone ◽  
Releasing Hormone ◽  
Young Subjects ◽  
Long Acting

Objective: The clinical use of growth hormone-releasing hormone (GHRH) is limited by its short half-life. Polyethylene glycol-conjugated GHRH (PEG-GHRH) was developed to provide increased stability compared with the currently available GHRH(1–29). This study aimed to evaluate the safety, tolerability and pharmacodynamics of PEG-GHRH. Design: PEG-GHRH was administered by subcutaneous injection to young healthy men (n = 12) and elderly men and women (aged > 60 years; n = 20). Results: In both groups, administration of PEG-GHRH generated a clear increase in circulating GH compared with placebo. Following single-dose (0.25, 0.5, 2 or 4 mg) administration to young subjects, the effect persisted for 12 h, but a sustained increase was observed on repeated administration to the elderly. Serum insulin-like growth factor-I also increased in response to PEG-GHRH treatment. Injection-site reactions were more frequent with PEG-GHRH compared with placebo, but these were mild and transient; other adverse events were similar to those observed after placebo. Some impairment of glucose tolerance was observed in the elderly following repeated administration of PEG-GHRH. Antibodies to GHRH were not observed. Conclusions: PEG-GHRH offers the possibility of less frequent dosing compared with GHRH. This possibility deserves further clinical testing.

Preclinical efficacy of growth hormone-releasing hormone antagonist MIA-602 for androgen-dependent and castration-resistant human prostate cancer.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 221-221
Author(s):  
Ferenc G. Rick ◽  
Cale D. Fahrenholtz ◽  
Maria I. Garcia ◽  
Norman L. Block ◽  
Andrew V. Schally ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Growth Hormone ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Growth Hormone Releasing Hormone ◽  
Releasing Hormone ◽  
Castration Resistant ◽  
Ghrh Antagonists

221 Background: Advanced hormone-sensitive prostate cancer (PCa) responds to androgen deprivation therapy (ADT). However, therapeutic options for castration-resistant disease are limited. As growth hormone-releasing hormone receptor (GHRH-R) and ligand GHRH are regulated in an autocrine fashion in PCa, GHRH-R inhibition represents a novel approach to PCa treatment. We investigated the effects of a new, highly potent GHRH antagonist, MIA-602, on growth of androgen-dependent and castration-resistant PCa cells in vitro/in vivo. Methods: All three cell lines used in this study expressed androgen receptors (ARs). 22Rv1 cells are castration-resistant and also express clinically relevant AR splice variants. LNCaP and VCaP lines are androgen dependent models that progress to castration resistance following ADT. Protein and mRNA levels of GHRH-R and its biologically active splice variant, SV1, were evaluated in cell lines and tumors by immunoblot and real-time RT-PCR. The influence of MIA-602 on cell proliferation and tumor formation was examined. Results: GHRH-R and SV1 were present in 22Rv1, LNCaP, and VCaP. LNCaP and VCaP cells expressed higher levels of GHRH-R protein compared to 22Rv1. However, 22Rv1 expressed higher levels of SV1. Inhibition of GHRH-R using MIA-602 decreased cell proliferation in vitro of 22Rv1, LNCaP, and VCaP PCa cell lines respectively by 70.4%, 60.7% and 20.3% (P<0.05 for all). MIA-602 decreased 22Rv1 xenograft volumes in mice by 63% after 3 weeks of treatment. VCaP showed a substantial inhibition of xenograft growth following therapy with MIA-602 in vivo. MIA-602 effectively inhibited VCaP xenografts as a single agent or in combination with ADT by surgical castration. Conclusions: The effectiveness of the novel Miami class GHRH antagonist, MIA-602, in inhibiting growth of androgen-dependent and castration-resistant PCa models in vitro and in vivo was demonstrated. The inhibitory effect of GHRH antagonists appear to be due to effects exerted through GHRH receptors on cancer cells and/or possibly by indirect mechanisms. Further investigations of GHRH antagonists for PCa treatment are warranted.

Association of pituitary adenoma with neuronal christoma: A TEM study

1994 ◽  
Vol 52 ◽  
pp. 232-233
Author(s):  
Eva Horvath ◽  
Kalman Kovacs ◽  
B. W. Scheithauer ◽  
R. V. Lloyd ◽  
H. S. Smyth
Keyword(s):  
Growth Hormone ◽  
Pituitary Adenoma ◽  
Pituitary Tumor ◽  
Nervous Tissue ◽  
Alternative Explanation ◽  
Growth Hormone Releasing Hormone ◽  
Cell Hyperplasia ◽  
Releasing Hormone ◽  
Secretory Neurons

The association of a pituitary adenoma with nervous tissue consisting of neuron-like cells and neuropil is a rare abnormality. In the majority of cases, the pituitary tumor is a chromophobic adenoma, accompanied by acromegaly. Histology reveals widely variable proportions of endocrine and nervous tissue in alternating or intermingled patterns. The lesion is perceived as a composite one consisting of two histogenetically distinct parts. It has been suggested that the neuronal component, morphologically similar to secretory neurons of the hypothalamus, may initiate adenoma formation by releasing stimulatory substances. Immunoreactivity for growth hormone releasing hormone (GRH) in the neuronal component of some cases supported this view, whereas other findings such as consistent lack of growth hormone (GH) cell hyperplasia in the lesions called for alternative explanation.Fifteen tumors consisting of a pituitary adenoma and a neuronal component have been collected over a 20 yr. period. Acromegaly was present in 11 patients, was equivocal in one, and absent in 3.

Treatment with growth hormone-releasing hormone (GHRH) 1-44 stimulates growth velocity in growth hormone-deficient children

1989 ◽  
Vol 120 (3_Suppl) ◽  
pp. S85-S86
Author(s):  
Y.-F. SHI ◽  
X.-L. BAO ◽  
R. Liu ◽  
J.-Y. DENG ◽  
W. REINHARDT ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Velocity ◽  
Growth Hormone Releasing Hormone ◽  
Releasing Hormone
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