Ghrh

Benign prostatic hyperplasia (BPH) is a pathologic condition of the prostate described as a substantial increase in its number of epithelial and stromal cells. BPH may significantly reduce the quality of life due to the initiation of bladder outlet obstruction and lower urinary tract syndromes. Current medical therapies mostly consist of inhibitors of 5α-reductase or α1-adrenergic blockers; their efficacy is often insufficient. Antagonistic analogs of neuropeptide hormones are novel candidates for the management of BPH. At first, antagonists of luteinizing hormone-releasing hormone (LHRH) have been introduced to the therapy aimed to reduce serum testosterone levels.  However, they have also been found to produce an inhibitory activity on local LHRH receptors in the prostate as well as impotence and other related side effects. Since then, several preclinical and clinical studies reported the favorable effects
of LHRH antagonists in BPH. In contrast, antagonists of growth hormone-releasing hormone (GHRH) and gastrin-releasing peptide (GRP) have been tested only in preclinical settings and produce significant reduction in prostate size in experimental models of BPH. They act at least in part, by blocking the action of respective ligands produced locally on prostates through their respective receptors in the prostate, and by inhibition
of autocrine insulin-like growth factors-Ⅰ/Ⅱ and epidermal growth factor production. GHRH and LHRH antagonists were also tested in combination resulting in a cumulative effect that was greater than that of each alone. This article will review the numerous studies that demonstrate the beneficial effects of antagonistic analogs of LHRH, GHRH and GRP in BPH, as well as
suggesting a potential role for somatostatin analogs in experimental therapies.

In preclinical studies, antagonists of growth hormone-releasing hormone (GHRH) have demonstrated inhibitory effects on the growth of various types of cancers expressing the pituitary type of GHRH receptors (pGHRH-R) and/or its active splice variant 1 (SV1). In this study, we investigated the effectiveness of the treatment of MDA-MB-231 human triple-negative breast cancer (TNBC) with GHRH antagonist JMR-132 alone or in combination with docetaxel. Receptor expression in the MDA-MB-231 human breast cancer cell line was evaluated by reverse transcription-polymerase chain reaction (RT-PCR). Cell viability assays were performed on MDA-MB-231 cells treated with JMR-132, docetaxel or in combination. For studies in vivo, a subcutaneous nude mouse xenograft model was used. JMR-132 was administered s.c. at a dose of 10 μg/day and docetaxel at a dose of 10 mg/kg i.p. given on day 1 and 5. Similar regimens were used for the combination of both substances. At the end of the experiment, an mRNA-based human cancer pathway array including 84 major genes was performed on the tumor tissue of mice treated with JMR-132 to elucidate the mechanism of action of GHRH antagonists in vivo. The in vitro proliferation studies revealed that JMR-132 and docetaxel decreased the cell viability in a dose-dependent manner. The combination of both treatments produced a significantly greater inhibition of cell viability compared to the single agents. Treatment of nude mice bearing MDA-MB-231 xenografts with JMR-132 and docetaxel significantly (p<0.05) inhibited tumor growth by 46 and 50%, respectively. Treatment with the combination of JMR-132 and docetaxel led to an inhibition of tumor volume by 71.6% (p<0.001). Polymerase chain reaction array analysis revealed that JMR-132 interacts with signal transduction pathways involved in proliferation, apoptosis and angiogenesis. Our results suggest that GHRH antagonists in combination with taxanes may enhance the efficacy of treatment for patients with TNBC expressing the SV1 and/or the pGHRH receptor.

The introduction of new cytotoxic substances as well as agents that target vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling has improved clinical outcome of patients with metastatic colorectal cancer (mCRC). In this review we summarize the most relevant clinical data on VEGF and EGFR targeting regimens in mCRC. The effects of available treatment strategies for mCRC are often temporary, with resistance and disease progression developing in most patients. Thus, new treatment strategies are urgently needed. Some GI peptides including gastrin and gastrin releasing peptide, certain growth factors such as insulin-like growth factor-I and II and neuropeptides such as growth hormone releasing hormone (GHRH) are implicated in the growth of CRC. Experimental investigations in CRC with antagonistic analogs of bombesin/gastrin-releasing peptide, GHRH, and with cytotoxic peptides that can be targeted to peptide receptors on tumors, are summarized in the second part of the review.

Malignant melanoma is the deadliest form of skin cancer; the treatment of advanced and recurrent forms remains a challenge. It has recently been reported that growth hormone-releasing hormone (GHRH) receptor is involved in the pathogenesis of melanoma. Therefore, we investigated the effects of our new GHRH antagonists on a human melanoma cancer cell line. Antiproliferative effects of GHRH antagonists, MIA-602, MIA-606 and MIA-690, on the human melanoma cell line, A-375, were studied in vitro using the MTS assay. The effect of MIA-690 (5 μg/day 28 d) was further evaluated in vivo in nude mice bearing xenografts of A-375. Subcellular localization of p27 was detected with Western blot and immunofluorescent staining. MIA-690 inhibited the proliferation of A-375 cells in a dose-dependent manner (33% at 10 μM, and 19.2% at 5 μM, P < 0 .05 vs. control), and suppressed the growth of xenografted tumors by 70.45% (P < 0.05). Flow cytometric analysis of cell cycle effects following the administration of MIA-690 revealed a decrease in the number of cells in G2/M phase (from 19.7% to 12.9%, P < 0.001). Additionally, Western blot and immunofluorescent studies showed that exposure of A-375 cells to MIA-690 triggered the nuclear accumulation of p27. MIA-690 inhibited tumor growth in vitro and in vivo, and increased the translocation of p27 into the nucleus thus inhibiting progression of the cell cycle. Our findings indicate that patients with malignant melanoma could benefit from treatment regimens, which combine existing chemotherapy agents and novel GHRH-antagonists.

Introduction: This study evaluated the effects of an ntagonistic analog of growth hormone-releasing hormone, MIA-602, on tumor growth, response to doxorubicin, expression of drug resistance genes, and efflux pump function in human triple negative breast cancers.
Methods: HCC1806 (doxorubicin-sensitive) and MX-1 doxorubicin-resistant), cell lines were xenografted into nude mice and treated with MIA-602, doxorubicin, or their combination. Tumors were evaluated for changes in volume and the expression of the drug resistance genes MDR1 and NANOG. In-vitro cell culture assays were used to analyze the effect of MIA-602 on efflux pump function.
Results: Therapy with MIA-602 significantly reduced tumor growth and enhanced the efficacy of doxorubicin in both cell lines. Control HCC1806 tumors grew by 435%, while the volume of tumors treated with MIA-602 enlarged by 172.2% and with doxorubicin by 201.6%. Treatment with the combination of MIA-602 and doxorubicin resulted in an increase in volume of only 76.2%. Control MX-1 tumors grew by 907%, while tumors treated with MIA-602 enlarged by 434.8% and with doxorubicin by 815%. The combination of MIA-602 and doxorubicin reduced the increase in tumor volume to 256%. Treatment with MIA-602 lowered the level of growth hormonereleasing hormone and growth hormone-releasing hormone receptors and significantly reduced the expression of multidrug resistance (MDR1) gene and the drug resistance
regulator NANOG. MIA-602 also suppressed efflux pump function in both cell lines.
Conclusions: We conclude that treatment of triple negative breast cancers with growth hormone-releasing hormone antagonists reduces tumor growth and potentiates the effects of cytotoxic therapy by nullifying drug resistance.

Novel drugs are required for the treatment of
CRPC. The best option may not be the agents
that target androgen receptors or compounds
which inhibit enzymes involved in androgen
biosynthesis. This is because the androgen
deprivation created by these compounds
can be overcome by mutations in androgen
receptors, the appearance of splice variants
of these receptors or alternate biochemical
pathways.
The use of currently available cytotoxic
analogs of LHRH, or somatostatin that can
be targeted to prostate cancers may lead to
an improvement in the treatment of CRPC
and an increase in the survival rate. A new
modality based on GHRH antagonists also
appears to be useful for the treatment of
metastatic CRPC.

Both cardiac myocytes and cardiac stem cells (CSCs) express the
receptor of growth hormone releasing hormone (GHRH), activation
of which improves injury responses after myocardial infarction (MI).
Here we show that a GHRH-agonist (GHRH-A; JI-38) reverses ventricular
remodeling and enhances functional recovery in the setting
of chronic MI. This response is mediated entirely by activation of
GHRH receptor (GHRHR), as demonstrated by the use of a highly
selective GHRH antagonist (MIA-602). One month after MI, animals
were randomly assigned to receive: placebo, GHRH-A (JI-38), rat
recombinant GH, MIA-602, or a combination of GHRH-A and
MIA-602, for a 4-wk period. We assessed cardiac performance and
hemodynamics by using echocardiography and micromanometry
derived pressure-volume loops. Morphometric measurements were
carried out to determine MI size and capillary density, and the
expression of GHRHR was assessed by immunofluorescence and
quantitative RT-PCR. GHRH-A markedly improved cardiac function
as shown by echocardiographic and hemodynamic parameters. MI
size was substantially reduced, whereas myocyte and nonmyocyte
mitosis was markedly increased by GHRH-A. These effects occurred
without increases in circulating levels of growth hormone and
insulin-like growth factor I and were, at least partially, nullified by
GHRH antagonism, confirming a receptor-mediated mechanism.
GHRH-A stimulated CSCs proliferation ex vivo, in a manner offset
by MIA-602. Collectively, our findings reveal the importance of the
GHRH signaling pathway within the heart. Therapy with GHRH-A
although initiated 1 mo after MI substantially improved cardiac performance
and reduced infarct size, suggesting a regenerative process.
Therefore, activation of GHRHR provides a unique therapeutic
approach to reverse remodeling after MI.