Monoclonal antibodies to growth hormone (GH) prolong liver GH binding and GH-induced IGF-I/IGFBP-3 synthesis

1999 ◽  
Vol 277 (2) ◽  
pp. E308-E315 ◽  
Author(s):  
V. Beauloye ◽  
S. M. Muaku ◽  
P. Lause ◽  
D. Portetelle ◽  
R. Renaville ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Monoclonal Antibodies ◽  
Growth Factor ◽  
Time Course ◽  
Serum Insulin ◽  
Mrna Levels ◽  
Insulin Like Growth Factor ◽  
Igf I ◽  
Time Course Study ◽  
Igfbp 3

This time-course study further explored the mechanisms whereby monoclonal antibodies (MAbs) may enhance growth hormone (GH) effects. Hypophysectomized rats were killed 0, 1, 3, 6, 12, 24, and 48 h after a single injection of bovine (b) GH alone or complexed with an anti-bGH MAb. Serum insulin-like growth factor I (IGF-I) concentrations were increased more and for a longer period after MAb-GH complexes (peak at 24 h: 295 ± 24 ng/ml) than after bGH alone (peak at 12 h: 219 ± 37 ng/ml; P < 0.01), whereas liver IGF-I mRNA was similar at 12 h in both groups but remained higher at 24 h (by 65%, P < 0.001) and 48 h (by 64%, P < 0.001) in the presence of the MAb. Induction of serum insulin-like growth factor-binding protein (IGFBP)-3 and liver IGFBP-3 mRNA by bGH also was markedly amplified by the MAb (3.6- and 2-fold at 24 h, respectively; P < 0.01). GH receptors (GHR) remained occupied for a longer period after MAb-GH injection (36 ± 16 and 35 ± 8% at 6 and 12 h, respectively) compared with bGH alone (0 ± 28 and −15 ± 11%), whereas total liver GH-binding sites and GHR mRNA levels were not affected by the MAb. We conclude that MAbs against GH amplify and prolong the serum IGF-I response to GH, which may result from both a prolongation of liver IGF-I synthesis and an enhanced induction of IGFBP-3. These two effects may in turn be the consequences of sustained GH binding to its liver receptors in the presence of MAb.

scholarly journals Dose-response effects of a new growth hormone receptor antagonist (B2036-PEG) on circulating, hepatic and renal expression of the growth hormone/insulin-like growth factor system in adult mice

2000 ◽  
Vol 167 (2) ◽  
pp. 295-303 ◽  
Author(s):  
JW van Neck ◽  
NF Dits ◽  
V Cingel ◽  
IA Hoppenbrouwers ◽  
SL Drop ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Receptor Antagonist ◽  
Growth Hormone Receptor ◽  
Binding Protein ◽  
Mrna Levels ◽  
Insulin Like Growth Factor ◽  
Gh Receptor ◽  
Igf I ◽  
Igfbp 3

The effects of growth hormone (GH) in regulating the expression of the hepatic and renal GH and insulin-like growth factor (IGF) system were studied by administering a novel GH receptor antagonist (GHRA) (B2036-PEG) at different doses (0, 1.25, 2.5, 5 and 10 mg/kg/day) to mice for 7 days. No differences were observed in the groups with respect to body weight, food consumption or blood glucose. However, a dose-dependent decrease was observed in circulating IGF-I levels and in hepatic and renal IGF-I levels at the highest doses. In contrast, in the 5 and 10 mg/kg/day GHRA groups, circulating and hepatic transcriptional IGF binding protein-3 (IGFBP-3) levels were not modified, likely resulting in a significantly decreased IGF-I/IGFBP-3 ratio. Hepatic GH receptor (GHR) and GH binding protein (GHBP) mRNA levels increased significantly in all GHRA dosage groups. Endogenous circulatory GH levels increased significantly in the 2.5 and 5 mg/kg/day GHRA groups. Remarkably, increased circulating IGFBP-4 and hepatic IGFBP-4 mRNA levels were observed in all GHRA administration groups. Renal GHR and GHBP mRNA levels were not modified by GHRA administration at the highest doses. Also, renal IGFBP-3 mRNA levels remained unchanged in most GHRA administration groups, whereas IGFBP-1, -4 and -5 mRNA levels were significantly increased in the 5 and 10 mg/kg/day GHRA administration groups. In conclusion, the effects of a specific GHR blockade on circulating, hepatic and renal GH/IGF axis reported here, may prove useful in the future clinical use of GHRAs.

Long-term treatment of Laron type dwarfs with insulin-like growth factor-1 increases serum insulin-like growth factor-binding protein-3 in the absence of growth hormone activity

1993 ◽  
Vol 128 (2) ◽  
pp. 144-149 ◽  
Author(s):  
Hannah Kanety ◽  
Avraham Karasik ◽  
Beatrice Klinger ◽  
Aviva Silbergeld ◽  
Zvi Laron
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Binding Protein ◽  
Serum Insulin ◽  
Continuous Treatment ◽  
Insulin Like Growth Factor ◽  
Factor Binding ◽  
Long Term Treatment ◽  
Igf I ◽  
Igfbp 3

Insulin-like growth factor binding protein-3 (IGFBP-3) is the major carrier of insulin-like growth factor I (IGF-1) in serum, and its production is growth hormone (GH) dependent. It is unclear whether in humans IGFBP-3 production is directly regulated by GH or mediated via IGF-I. We addressed this question in six patients with Laron-type dwarfism, a syndrome characterized by the absence of GH receptor activity (LTD), who were chronically treated with recombinant IGF-I. Analysis of the electrophoretic profiles of serum IGFBPs in these patients by Western ligand blotting revealed an extremely low IGFBP-3 level. A striking progressive increase in serum IGFBP-3 was observed with continuous treatment, despite the absence of GH action. In LTD children, serum IGFBP-3 increased up to 19-fold after six months of therapy and equalled levels observed in controls, whereas in adult LTD patients the increase was smaller. A rise in serum levels of 34, 30 and 24 kDa BPs (presumably IGFBP-2, -1 and -4, respectively was also noted with chronic IGF-I therapy. This proof of GH-independent induction of IGFBP-3 by IGF-1 may be a major advantage in the therapeutic use of biosynthetic IGF-I in several types of short stature children.

scholarly journals Insulin-like Growth Factor II Signaling in Neoplastic Proliferation Is Blocked by Transgenic Expression of the Metalloproteinase Inhibitor Timp-1

1999 ◽  
Vol 146 (4) ◽  
pp. 881-892 ◽  
Author(s):  
David C. Martin ◽  
John L. Fowlkes ◽  
Bojana Babic ◽  
Rama Khokha
Keyword(s):  
Growth Factor ◽  
T Antigen ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Early Event ◽  
Mrna Levels ◽  
Insulin Like Growth Factor ◽  
Igf Binding Proteins ◽  
Protein Levels ◽  
Igf I ◽  
Igfbp 3

Insulin-like growth factor (IGF) II is overexpressed in many human cancers and is reactivated by, and crucial for viral oncogene (SV40 T antigen, [TAg])–induced tumorigenesis in several tumor models. Using a double transgenic murine hepatic tumor model, we demonstrate that tissue inhibitor of metalloproteinase 1 (TIMP-1) blocks liver hyperplasia during tumor development, despite TAg-mediated reactivation of IGF-II. Because the activity of IGFs is controlled by IGF-binding proteins (IGFBPs), we investigated whether TIMP-1 overexpression altered the IGFBP status in the transgenic liver. Ligand blotting showed that IGFBP-3 protein levels were increased in TIMP-1–overexpressing double transgenic littermates, whereas IGFBP-3 mRNA levels were not different, suggesting that TIMP-1 affects IGFBP-3 at a posttranscriptional level. IGFBP-3 proteolysis assays demonstrated that IGFBP-3 degradation was lower in TIMP-1–overexpressing livers, and zymography showed that matrix metalloproteinases (MMPs) were present in the liver homogenates and were capable of degrading IGFBP-3. As a consequence of reduced IGFBP-3 proteolysis and elevated IGFBP-3 protein levels, dissociable IGF-II levels were significantly lower in TIMP-1–overexpressing animals. This decrease in bioavailable IGF-II ultimately resulted in diminished IGF-I receptor signaling in vivo as evidenced by diminished receptor kinase activity and decreased tyrosine phosphorylation of the IGF-I receptor downstream effectors, insulin receptor substrate 1 (IRS-1), extracellular signal regulatory kinase (Erk)-1, and Erk-2. Together, these results provide evidence that TIMP-1 inhibits liver hyperplasia, an early event in TAg-mediated tumorigenesis, by reducing the activity of the tumor-inducing mitogen, IGF-II. These data implicate the control of MMP-mediated degradation of IGFBPs as a novel therapy for controlling IGF bioavailability in cancer.

Growth hormone and parathyroid hormone stimulate IGFBP-3 in rat osteoblasts

1994 ◽  
Vol 267 (2) ◽  
pp. E226-E233 ◽  
Author(s):  
C. Schmid ◽  
I. Schlapfer ◽  
M. Peter ◽  
M. Boni-Schnetzler ◽  
J. Schwander ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Parathyroid Hormone ◽  
Growth Factor ◽  
Culture Media ◽  
Insulin Like Growth Factor ◽  
Igf I ◽  
Conditioned Cell Culture Medium ◽  
Rat Osteoblasts ◽  
Igfbp 3

Osteoblast-like cells prepared from calvaria of newborn rats produce insulin-like growth factor (IGF) I and several insulin-like growth factor binding proteins (IGFBPs) in vitro. Among the IGFBPs found in conditioned cell culture medium, IGFBP-3 is the most abundant. Intact IGFBP-3, as assessed by 125I-labeled IGF-II ligand blot analysis, is more abundant in culture media of cells exposed to growth hormone (GH) or to parathyroid hormone (PTH), both at 5 x 10(-9) mol/l, for 24 h. At the same time, concentrations of IGF-I are increased in media of cells exposed to PTH but not to GH, compared with hormone-free control cultures. IGFBP-3 mRNA is increased in osteoblasts exposed to PTH or to GH but not in response to 5 x 10(-9) mol/l IGF-I. PTH exerts a rapid (within 2 h) stimulatory effect on IGF-I and IGFBP-3 production, both at the message and peptide levels, whereas GH increases only IGFBP-3, both at the message and peptide levels (after 24 h). We conclude that IGF-I does not mediate increased IGFBP-3 production by rat osteoblasts in response to GH and PTH.

Abnormality of growth hormone and insulin-like growth factor I axis in advanced cancer patients

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 19671-19671
Author(s):  
T. Takahata ◽  
M. Munakata ◽  
Y. Sakata ◽  
K. Nakagawa ◽  
T. Mukaiyama ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Thyroid Hormones ◽  
Cancer Patients ◽  
Performance Status ◽  
Insulin Like Growth Factor ◽  
Igf I ◽  
Cancer Anorexia ◽  
Cachexia Syndrome ◽  
Igfbp 3

19671 Background: Pituitary and thyroid hormones are known to be altered in anorexia nervosa, but few hormonal studies have been performed in cancer anorexia-cachexia syndrome. This study focused on growth hormone (GH) and Insulin-like Growth Factor (IGF)-I axis in cancer patients. Methods: To investigate the relationship among performance status (PS), nutritional and hormonal status, blood sampling was performed to measure GH, IGF-I, IGF-binding protein 3(IGFBP-3), T3, T4, complete blood counts and blood chemistry profiles for 15 cancer patients in each of PS0–1, PS2, PS3 and PS4 after the informed consent was obtained. Results: A total of 58 patients were evaluated including 15 patients in PS0–1, PS2 and PS3 and 13 in PS4. Hemoglobin and albumin levels went down along with progression of PS. GH level was high and T3 was low in poor PS. T4 and IGFBP-3 were lower in PS4 than those of other PS. There is a tendency of low IGF-I and thyroid hormones and high GH levels in poor PS as compared with those of good PS (p=0.0064 for IGF-I, p<0.001 for T3, and T4, not significant for GH analyzed by ANOVA). Conclusions: Abnormal GH - IGF-I axis was more pronounced in poor PS. It is conceivable that normalization of this abnormality can improve cancer anorexia-cachexia syndrome and new drug development for such normalizing agents is warranted. No significant financial relationships to disclose.

Effects of octreotide on insulin-like growth factor I and metabolic indices in growth hormone-treated growth hormone-deficient patients

1993 ◽  
Vol 129 (5) ◽  
pp. 399-408 ◽  
Author(s):  
Torben Laursen ◽  
Jens OL Jorgensen ◽  
Hans Ørskov ◽  
Jens Møller ◽  
Alan G Harris ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Animal Studies ◽  
Area Under The Curve ◽  
Insulin Like Growth Factor ◽  
Gh Secretion ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I ◽  
Igfbp 3

Animal studies have demonstrated that in addition to inhibiting growth hormone (GH) secretion octreotide inhibits in a direct manner hepatic or peripheral insulin-like growth factor I (IGF-I) generation. To test this hypothesis in humans we studied ten GH-deficient patients with frequent blood sampling during 38 h on two occasions. Regular GH therapy was discontinued 72 h prior to each study period. At the start of each study a subcutaneous (sc) injection of GH (3 IU/m2) was given (at 18.00 h). In a single-blinded crossover design, patients received a continuous sc infusion of either octerotide (200 μg/24 h) or placebo (saline). The pharmacokinetics of GH were similar on the two occasions. The area under the curve±sem of serum GH was 142.5±53.6 μg·l−1·h−1 (octreotide) and 144.8±41.8 μg·l−1·h−1 (placebo), (p=0.73); Cmax (μg/l) was 12.5±1.47 (octreotide) and 12.8±1.42 (placebo) (p=0.83), and Tmax (h) was 6.1±0.97 (octreotide) and 5.2±0.65 (placebo) (p=0.49). Growth hormone administration was associated with an increase in serum IGF-I (μg/l), which was identical during the two studies, from 85.3±19.4 to 174.25±30.3 for octreotide and from 97.0±26.4 to 158.8±28.2 for placebo. Mean IGF-I levels (μg/l) were 138.2±25.1 (octreotide) and 134.5±28.6 (placebo) (p=0.78). Similarly, the increase in IGF binding protein 3 (IGFBP-3) levels was identical. Mean IGFBP-3 levels (μg/l) were 2303±323 (octreotide) and 2200±361 (placebo) (p=0.25). Mean insulin levels were significantly lower during octreotide treatment (39.9±17.9 mU/l) than during placebo (59.7±17.8 mU/l) (p<0.05). Mean blood glucose levels were elevated significantly during octreotide infusion (5.98±0.23 mmol/l for octreotide and 5.07±0.16 mmol/l for placebo; p=0.001). Glucagon levels decreased non-significantly (p=0.07) and IGFBP-1 levels tended to increase during infusion of octreotide although not significantly (p=0.41). Levels of the lipid intermediates were identical on the two occasions. Alanine and lactate levels were significantly increased during octreotide infusion. Mean levels of blood alanine (μmol/l) were 470.8±24.2 (octreotide) and 360.1±17.8 (placebo) (p<0.02). Mean levels of blood lactate were 1038±81.0 (octreotide) and 894.4±73.8 (placebo) (p<0.04). We conclude that short-term continuous sc infusion of octreotide has no direct effect on the generation of IGF-I or the pharmacokinetics of exogenous GH in GH-deficient man.

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