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(1/46) Inhibition of growth, production of insulin-like growth factor-II (IGF-II), and expression of IGF-II mRNA of human cancer cell lines by antagonistic analogs of growth hormone-releasing hormone in vitro.

Antagonistic analogs of growth hormone-releasing hormone (GHRH) suppress growth of various tumors in vivo. This effect is exerted in part through inhibition of the GHRH-GH-insulin-like growth factor (IGF)-I axis. Nevertheless, because autocrine/paracrine control of proliferation by IGF-II also is a major factor in many tumors, the interference with this growth-stimulating pathway would offer another approach to tumor control. We thus investigated whether GHRH antagonists MZ-4-71 and MZ-5-156 also act on the tumor cells directly by blocking the production of IGF-II. An increase in the IGF-II concentration in the media during culture was found in 13 of 26 human cancer cell lines tested. Reverse transcription-PCR studies on 8 of these cell lines showed that they also expressed IGF-II mRNA. Antagonists of GHRH significantly inhibited the rate of proliferation of mammary (MDA-MB-468 and ZR-75-1), prostatic (PC-3 and DU-145), and pancreatic (MiaPaCa-2, SW-1990, and Capan-2) cancer cell lines as shown by colorimetric and [3H]thymidine incorporation tests and reduced the expression of IGF-II mRNA in the cells and the concentration of IGF-II secreted into the culture medium. Growth and IGF-II production of lung (H-23 and H-69) and ovarian (OV-1063) cancer cells that express mRNA for IGF-II and excrete large quantities of IGF-II also was marginally suppressed by the antagonists. These findings suggest that antagonistic analogs of GHRH can inhibit growth of certain tumors not only by inhibiting the GHRH-GH-IGF-I axis, but also by reducing the IGF-II production and by interfering with the autocrine regulatory pathway.  (+info)

(2/46) The GH response to low-dose bolus growth hormone-releasing hormone (GHRH(1-29)NH2) is attenuated in patients with longstanding post-irradiation GH insufficiency.

OBJECTIVE: Previous studies have suggested that post-irradiation GH insufficiency results from a loss of GHRH secretion, since many patients were able to release GH following exogenous GHRH stimulation. However, supramaximal doses of GHRH were used and the response may decline with time after radiotherapy. We re-evaluated the GHRH dose-response curve in patients post cranial irradiation and in controls. DESIGN: Randomized controlled study. METHODS: Five adult male long-term survivors of childhood brain tumours (median age 21.8 years (18.4-26.7); 13.7 years (11.4-15.7) post-radiotherapy, >30Gy) and five matched controls were studied. An intravenous bolus of GHRH(1-29)NH(2) was administered in doses at the lower (0.05 microg/kg) and upper (0.15 microg/kg) range of the dose-response curves for young males, as well as the standard supramaximal dose (1. 0 microg/kg). GH was measured before stimulation, every 2min for the first hour and every 5min for the second hour. All studies were conducted in a random fashion. RESULTS: Significantly lower peak and area under the curve (AUC) GH concentrations occurred in the irradiated group using 0.15 microg/kg (median peak Irradiated, 4. 5mU/l vs median Controls, 37.4mU/l; P<0.01) and 1.0 microg/kg (median peak Irradiated, 4.8mU/l vs median Controls, 15.2mU/l; P<0. 05) GHRH(1-29)NH(2). In irradiated subjects there was an incremental rise in GH output with increasing doses of GHRH(1-29)NH(2 )(median AUC: 122mU/l.min vs 179mU/l.min vs 268mU/l.min; P=0.007) reflecting altered pituitary sensitivity and reduced responsiveness. CONCLUSION: The GH response to bolus GHRH(1-29)NH(2) is attenuated in adult long-term survivors of childhood brain tumours. This may reflect direct pituitary damage and/or the loss of the tropic effects of chronic GHRH deficiency.  (+info)

(3/46) Antagonists of growth hormone-releasing hormone (GH-RH) inhibit IGF-II production and growth of HT-29 human colon cancers.

Insulin-like growth factors (IGFs) I and II are implicated in progression of various tumours including colorectal carcinomas. To interfere with the production of IGFs, we treated male nude mice bearing xenografts of HT-29 human colon cancer with various potent growth hormone-releasing hormone (GH-RH) antagonists. Twice daily injections of antagonist MZ-4-71, 10 microg intraperitoneally or 5 microg subcutaneously (s.c.) resulted in a significant 43-45% inhibition of tumour growth. Longer acting GH-RH antagonists, MZ-5-156 and JV-1-36 given once daily at doses of 20 microg s.c. produced a 43-58% decrease in volume and weight of cancers. Histological analyses of HT-29 cancers demonstrated that both a decreased cell proliferation and an increased apoptosis contributed to tumour inhibition. GH-RH antagonists did not change serum IGF-I or IGF-II levels, but significantly decreased IGF-II concentration and reduced mRNA expression for IGF-II in tumours. In vitro studies showed that HT-29 cells produced and secreted IGF-II into the medium, and addition of MZ-5-156 dose-dependently decreased IGF-II production by about 40% as well as proliferation of HT-29 cells. Our studies demonstrate that GH-RH antagonists inhibit growth of HT-29 human colon cancers in vivo and in vitro. The effect of GH-RH antagonists may be mediated through a reduced production and secretion of IGF-II by cancer cells.  (+info)

(4/46) Antagonists of growth hormone-releasing hormone inhibit the growth of U-87MG human glioblastoma in nude mice.

Antagonists of growth hormone-releasing hormone(GH-RH)inhibit the growth of various cancers by mechanisms that involve the suppression of the insulin-like growth factor (IGF)-I and/or IGF-II. In view of the importance of the IGF system in glioma tumorigenesis, the effects of GH-RH antagonists MZ-5-156 and JV-1-36 were investigated in nude mice bearing subcutaneous and orthotopic xenografts of U-87MG human glioblastomas. After 4 weeks of therapy with MZ-5-156 or JV-1 -36 at the dose of 20 microg/day per animal, the final volume of subcutaneous U-87MG tumors was significantly (P < .01) decreased by 84% and 76%, respectively, as compared with controls. Treatment with GH-RH antagonists also reduced tumor weight and the levels of mRNA for IGF receptor type I (IGFR-I). A reduction in the mRNA levels for IGF-II was found in tumors of mice treated with MZ-5-156. Treatment with MZ-5-156 or JV-1 -36 also extended the survival of nude mice implanted orthotopically with U-87MG glioblastomas by 81% (P < .005) and 18%, respectively, as compared with the controls. Exposure in vitro to GH-RH antagonists MZ-5-156 or JV-1 -36 at 1 microM concentration for 24 hours decreased the tumorigenicity of U-87MG cells in nude mice by 10% to 30% and extended the latency period for the development of subcutaneous palpable tumors by 31% to 56%, as compared with the controls. Exposure of U-87MG cells to GH-RH antagonists in vitro also resulted in a time-dependent increase in the mRNA levels of IGFR-II or a decrease in the mRNA levels of IGFR-I. mRNA for GH-RH was detected in U-87MG cells and xenografts implying that GH-RH may play a role in the pathogenesis of this tumor. Our results suggest that GH-RH antagonists MZ-5-156 and JV-1-36 inhibit the growth of U-87MG human glioblastoma by mechanisms that involve the suppression of IGF system. Antagonistic analogs of GH-RH merit further development for the treatment of malignant glioblastoma.  (+info)

(5/46) The hexapeptide KP-102 (D-ala-D-beta-Nal-ala-trp-D-phe-lys-NH(2)) stimulates growth hormone release in a cichlid fish (Ooreochromis mossambicus).

Abstract Studies in mammals have shown that synthetic Met-enkephalin derivatives, called growth hormone-releasing peptides (GHRPs), stimulate growth hormone (GH) release. The present study was conducted to determine whether the GHRP, KP-102, specifically stimulates GH release in a teleost. Tilapia (Oreochromis mossambicus) were given a single intraperitoneal injection of KP-102 (D-Ala-D-beta;-Nal-Ala-Trp-D-Phe-Lys-NH(2)) or bovine GHRH(1-29)-amide or vehicle and blood was sampled at 1, 6 and 12 h after injection. KP-102 was administered at two doses of 1 ng/g and 10 ng/g body weight, whereas GHRH (positive control) was administered at a single dose of 10 ng/g body weight. Plasma levels of tilapia GH and prolactins (tPRL(177) and tPRL(188)) were determined by radioimmunoassay. As expected, GHRH injection significantly (P<0.001) elevated plasma GH levels (ng/ml) in tilapia at 6 h post-injection. KP-102 also significantly elevated GH levels (at the low dose) at 6 (P<0.05) and 12 (P<0.01) hours post-injection. There were no significant effects on plasma PRL(s) levels, although mean levels of both PRLs were elevated at 6 h post-injection. These results show for the first time that GHRPs stimulate GH release in teleosts and suggest that the GHRP receptor and possibly a "Ghrelin-like" ligand are also present in lower vertebrates.  (+info)

(6/46) The growth hormone-insulin-like growth factor I axis and renal glomerular function.

This study examined whether maneuvers that chronically raise or lower serum insulin-like growth factor I (IGF-I), within physiological and pathophysiological ranges, will affect glomerular hemodynamics. Pair-fed Munich Wistar rats received, for 6 to 7 days, continuous s.c. infusions of human recombinant IGF-I (rhIGF-I; 125 micrograms/day), vehicle, or s.c. injection of a synthetic growth hormone-releasing hormone antagonist (GHRH-ANT) (N = 7 in each group). Infusion of rhIGF-I raised serum IGF-I to about 180% of control values, and GHRH-ANT injections lowered serum IGF-I to about 33% of control. The IGF-I infusion induced an increase in left kidney weight when expressed in absolute units but not when expressed as a percentage of body weight; there was also an increase in glomerular volume in the IGF-I treated rats. GFR, single nephron GFR, and single nephron plasma flow also rose with IGF-I infusion, and these changes were associated with decreased afferent and efferent arteriolar resistance and increased glomerular ultrafiltration coefficient. GHRH-ANT injection did not affect kidney weight or glomerular volume; however, GFR, single nephron GFR, and single nephron plasma flow were reduced in association with an increase in efferent arteriolar resistance. There also was a tendency, not significant, for the glomerular ultrafiltration coefficient to decrease. The findings that a low dose of rhIGF-I, which raised the serum IGF-I only modestly, increased glomerular ultrafiltration and that reducing serum IGF-I below control values decreased glomerular dynamics suggest that physiological or pathophysiological changes in IGF-I may affect and possible help to regulate glomerular function.(ABSTRACT TRUNCATED AT 250 WORDS)  (+info)

(7/46) Antagonists of growth hormone-releasing hormone inhibit the proliferation of experimental non-small cell lung carcinoma.

Recent studies show that antagonists of growth hormone-releasing hormone (GH-RH) inhibit proliferation of various cancers indirectly through blockage of the endocrine GH-insulin-like growth factor (IGF) I axis and directly by an action on tumor cells involving the suppression of autocrine/paracrine IGF-I, IGF-II, or GH-RH. The effectiveness of therapy with GH-RH antagonist JV-1-38 and its mechanisms of action were investigated in NCI-H838 non-small cell lung carcinoma (NSCLC) xenografted s.c. into nude mice and in vitro. Treatment with GH-RH antagonist JV-1-38 significantly (P < 0.05-0.001) inhibited tumor growth as demonstrated by a 58% decrease in final tumor volume, 54% reduction in tumor weight, and the extension of tumor-doubling time from 8.5 +/- 1.38 to 12 +/- 1.07 days as compared with controls. Using ligand competition assays with (125)I-labeled GH-RH antagonist JV-1-42, specific high-affinity binding sites for GH-RH were found on tumor membranes. Reverse transcription-PCR revealed the expression of mRNA for GH-RH and splice variant 1 (SV(1)) of GH-RH receptor in H838 tumors. Reverse transcription-PCR analysis also demonstrated that H838 tumors express IGF-I and IGF-I receptors. Tumoral concentration of IGF-I and its mRNA expression were significantly decreased by 25% (P = 0.05) and 65% (P < 0.001), respectively, in animals receiving JV-1-38, whereas serum IGF-I levels remained unchanged. In vitro studies showed that H838 cells secreted GH-RH and IGF-I into the medium. The growth of tumor cells in vitro was stimulated by IGF-I and inhibited by GH-RH antagonist JV-1-38 and a GH-RH antiserum. Our results extend the findings on the involvement of IGF-I in NSCLC and suggest that GH-RH may be an autocrine growth factor for H838 NSCLC. The antitumorigenic action of GH-RH antagonists could be partly direct and mediated by SV(1) of tumoral GH-RH receptors. The finding of GH-RH and SV(1) of GH-RH receptors in NSCLC provides a new approach to the treatment of this malignancy based on the use of antagonistic analogues of GH-RH.  (+info)

(8/46) Blockade of endogenous growth hormone-releasing hormone receptors dissociates nocturnal growth hormone secretion and slow-wave sleep.

OBJECTIVES: A temporal association between non-rapid eye movement (NREM) sleep stages 3 and 4 and nocturnal augmentation of GH release was found long ago, yet the precise mechanism for this association has not been identified. It has been shown, however that pulsatile GHRH administration increases both slow-wave sleep (SWS) and GH. Based on these data, a role for GHRH as an inducer of SWS was proposed. To test this hypothesis, we have performed the corollary experiment whereby the action of endogenous GHRH has been antagonized. DESIGN: Healthy men (20-33 years old) had an infusion of GHRH antagonist ((N-Ac-Tyr(1), D-Arg(2)) GHRH-29 (NH(2))) or saline for a 12-h period, between 2100 and 0900 h. An i.v. bolus of GHRH was given at 0700 h and GH samples were drawn from 0700 to 0900 h to document the efficacy of GH suppression by the GHRH antagonist. METHODS: A limited montage sleep study was recorded from 2300 to 0700 h during each admission. Plasma GH concentrations were analyzed by the use of a sensitive chemiluminometric assay. RESULTS: Effectiveness of the GHRH antagonist was validated in all subjects by demonstrating 93+/-1.8% (P=0.012) suppression of GH response to a GHRH bolus. Polysomnography demonstrated that the percentage of SWS was not different when saline and GHRH antagonist nights were compared (P=0.607); other quantifiable sleep parameters were also unchanged. CONCLUSIONS: We conclude that endogenous GHRH is indispensable for the nocturnal augmentation of GH secretion, but that it is unlikely to participate in the genesis of SWS.  (+info)