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PubMed1990

Selective and nonselective stimulation of central cholinergic and dopaminergic development in vitro by nerve growth factor, basic fibroblast growth factor, epidermal growth factor, insulin and the insulin-like growth factors I and II.

To study the selectivity of neurotrophic actions in the brain, we analyzed the actions of several known growth factors on septal cholinergic, pontine cholinergic, and mesencephalic dopaminergic neurons in culture. Similar to nerve growth factor (NGF), basic fibroblast growth factor (bFGF) stimulated choline acetyltransferase activity in septal cultures. In contrast to NGF, bFGF also enhanced dopamine uptake in mesencephalic cultures and stimulated cell proliferation in all 3 culture types. Insulin and the insulin-like growth factors I and II stimulated transmitter-specific differentiation and cell proliferation in all culture types. Epidermal growth factor (EGF) produced a small increase in dopamine uptake by mesencephalic cells and stimulated cell proliferation in all culture types. In septal cultures, bFGF was most effective when given at early culture times, NGF at later times. The stimulatory actions of bFGF and insulin did not require the presence of glial cells and were not mediated by NGF. In mesencephalic cultures, the stimulation of dopamine uptake by bFGF and EGF was dependent on glial proliferation. The results suggest different degrees of selectivity of the neurotrophic molecules. NGF and, very similarly, bFGF seem to influence septal cholinergic neurons directly and rather selectively, whereas the neurotrophic actions of insulin and the insulin-like growth factors appear to be more general.

Animals↗

PubMed2001

Growth hormone/insulin-like growth factor-1 response to acute and chronic growth hormone-releasing peptide-2, growth hormone-releasing hormone 1-44NH2 and in combination in older men and women with decreased growth hormone secretion.

To better appreciate the interactions of GHRP-2 and GHRH 1-44NH2 on the release of GH in normal adult men and women with decreased GH secretion and low serum IGF-1 levels, a series of acute and chronic studies have been performed (n = 5 men, 5 women). The acute iv bolus GH responses of these subjects to the two peptides alone and together suggest that the decreased GH secretion may be primarily due to a deficiency of the natural endogenous GHRP, ghrelin, rather than a decreased secretion of endogenous GHRH or excess secretion of SRIF. To determine whether the low GH response to GHRH was due to a limited capacity of pituitary to release GH, higher dosages of GHRP-2 alone were administered. At a dose of 1 microg/kg GHRP-2 the GH response was essentially the same as that elicited by 1 microg/kg GHRH + 0.1 microg/kg GHRP-2 while the GH response to 10 microg/kg GHRP-2 sc was about twice as high in both men and women. Although these subjects have a limited pituitary capacity to release GH, which is also an indication of decreased GH secretion in the presence of low serum IGF-1 levels, this alone would not explain the low GH response to GHRH. Furthermore, the finding that a low dose of 0.1 microg/kg GHRP-2 augments the GH response to 1 microg/kg GHRH is strongly against an excess secretion of SRIF. Twenty-four hour profiles of GH secretion during placebo, GHRP-2, and various doses of GHRH alone and together with GHRP-2 were studied. In addition, 1 microg/kg/h GHRP-2 was infused continuously sc to these subjects for 30 d. The normal pulsatile secretion of GH as well as the serum IGF-1 level was increased after 24 h and remained elevated for 30 d. With a deficiency of endogenous GHRH, the GH response of GHRP-2 would be little to none, while in subjects with a deficiency of the natural GHRP, the GH response to GHRH would be more attenuated. Thus, in chronic deficiency the GH response would be expected to depend on the degree of the capacity of the pituitary to release GH as well as the type(s) of hormonal deficiency.

Area Under Curve↗

PubMed1992

Insulin-like growth factor-1, growth hormone-dependent insulin-like growth factor-binding protein and growth in children with chronic renal failure.

Insulin-like growth factor-binding protein-3 (IGFBP-3) and insulin-like growth factor-1 (IGF-1) levels were measured by specific radioimmunoassays in children with all degrees of chronic renal failure (CRF). Study group 1 comprised 29 children (10 on dialysis) who had been studied one to four times over 2 years to determine whether IGF-1 and IGFBP-3 levels differed from those in age-matched healthy children and to examine the relationship between these levels and heights. IGF-1 and IGFBP-3 levels did not differ from those in normal children. IGF-1 and IGFBP-3 were significantly correlated, increased with pubertal stage in all children and with age in non-dialysis patients. IGF-1, but not IGFBP-3, correlated with age in dialysis patients. There was no correlation between IGF-1 or IGFBP-3 levels (corrected for age) and height standard deviation score (SDS) in either non-dialysis or dialysis patients. Study group 2 comprised 19 children (7 on dialysis) who were studied prospectively for 1-2 years to examine the relationship between IGF-1 and IGFBP-3 levels, growth rates and nutritional parameters. Mean values of IGF-1 and IGFBP-3 (corrected for age) did not change over 1-year periods, while height SDS fell by -0.38 +/- 0.21 SD/year in dialysis patients and by -0.11 +/- 0.29 SD/year in non-dialysis patients. No significant correlations were found between IGF-1 or IGFBP-3 levels and growth rates or nutritional parameters. Thus growth retardation in children with CRF is not related to circulating levels of IGF-1 or IGFBP-3.

Adolescent↗

PubMed2001

Effect of transforming growth factor-beta1, insulin-like growth factor-I and insulin-like growth factor-II on cell growth and oestrogen metabolism in human breast cancer cell lines.

Oestrogens play an important role in the development of breast cancer. Oestrone sulphate (E1S) acts as a huge reservoir of oestrogens in the breast and is converted to oestrone (E1) by oestrone sulphatase (E1STS). E1 is then reversibly converted to the potent oestrogen, oestradiol (E2) by oestradiol-17beta hydroxysteroid dehydrogenase (E2DH). The aim of this study was to assess the effects of transforming growth factor-beta1 (TGFbeta1), insulin-like growth factor-I (IGF-I) and insulin-like growth factor-II (IGF-II) on cell growth, E1STS and E2DH activities in the MCF-7 and MDA-MB-231 human breast cancer cell lines. TGFbeta1, IGF-I and IGF-II alone or in combination inhibited cell growth of both cell lines but no additive or synergistic effects were observed. The treatments significantly stimulated E1STS activity in the MCF-7 cell line, except for TGFbeta1 alone and TGFbeta1 and IGF-I in combination, where no effects were seen. Only TGFbeta1 and IGF-II acted synergistically to stimulate E1STS activity in the MCF-7 cells. There was no significant effect on E1STS activity in the MDA-MB-231 cells with any of the treatments. In the MCF-7 cells, TGFbeta1 and IGF-I, IGF-I and IGF-II, and TGFbeta1, IGF-I and IGF-II acted synergistically to stimulate the reductive E2DH activity, while only TGFbeta1, IGF-I and IGF-II synergistically stimulated the oxidative E2DH activity. There were no additive or synergistic effects on both oxidative and reductive E2DH activities in the MDA-MB-231 cells. In conclusion, TGFbeta1, IGF-I and IGF-II may have effects on oestrogen metabolism, especially in the MCF-7 cell line where they stimulated the conversion of E1S to E1 and E1 to E2 and, thus, may have roles to play in the development of breast cancer.

Breast Neoplasms↗

PubMed1995

Dose-dependent responses in insulin-like growth factors, insulin-like growth factor-binding protein-3 and parameters of bone metabolism to growth hormone therapy in young adults with growth hormone deficiency.

There is increasing awareness that growth hormone (GH) replacement therapy is also essential in adult patients with growth hormone deficiency (GHD). There are little data available on the dose requirements for replacement therapy in this age group. In childhood, the growth response to GH therapy can serve as an indicator for correct replacement dose. Because this indicator does not exist in adults, we analyzed growth factors and biochemical markers of bone metabolism by specific radioimmunoassays in a group (n = 12) of adult patients (age, 20.0-31.6 years) with GHD with childhood onset before and after a 4-week treatment period (daily, s.c.) with recombinant, human GH at different doses (0.125, 0.25 and 0.5 IU/kg body weight/week). Comparing the basal levels to those on low-dose GH (0.125 IU/kg/week) and on a high dose (0.5 IU/kg/week), the following results were obtained. Insulin-like growth factor-I (IGF-I) in serum: basal, 68.6 +/- 37 ng/ml; low dose, 176.9 +/- 65 ng/ml (p < or = 0.05); high dose, 380.6 +/- 200 ng/ml (p < or = 0.01). IGF-binding protein-3 in serum: basal, 2.13 +/- 0.58 mg/l; low dose, 3.23 +/- 0.84 mg/l (p < or = 0.01); high dose, 3.97 +/- 0.82 mg/l. Osteocalcin in serum: basal, 3.88 +/- 1.27 ng/ml; low dose, 7.01 +/- 2.20 ng/ml (p < or = 0.01); no further increase. Procollagen-I peptide in serum: basal, 113.6 +/- 36.7 microgram/l; low dose, 211.6 +/- 90.4 microgram/l (p < or = 0.01); no further increase.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1997

Postnatal catch-up growth induced by growth hormone and insulin-like growth factor-I in rats with intrauterine growth retardation caused by maternal protein malnutrition.

In this study, we examined the effects of exogenous IGF-I and GH on postnatal growth of rat pups with intrauterine growth retardation due to gestational protein restriction. From birth until weaning (d 23), pups born from dams fed ad libitum a low (5% casein; P5 pups) or a normal protein diet (20% casein; P20 controls) were cross-fostered to well nourished lactating dams. On d 2, the litters (n = 6/dietary group) were reduced in size to 6 pups, and littermates received, through postnatal d 23, two daily s.c. injections of bovine GH (2.5 microg/g of body weight (BW)/day), human IGF-I (1.8 microg/g of BW/day), or saline. At birth, BW and tail length (TL) of P5 pups were markedly decreased (to 72 and 70% of controls, respectively; p < 0.001). Despite food rehabilitation, stunting of body growth was still apparent on d 23 in the saline-injected P5 rats (BW and TL: 76 and 83% of age-matched saline-injected controls; p < 0.01). Serum IGF-I (-51%; p < 0.001) and weight of liver, heart, kidney, brain, and thymus (-13 to -35%; p < 0.01) were also reduced. Administration of GH in P5 rats raised their serum IGF-I (1-fold) to levels observed in saline-injected controls, and restored normal BW and TL (94 and 98% of controls, respectively), and organ weight (91-107% of those of controls). Injections of IGF-I in P5 rats increased after 1 h their serum IGF-I to levels 3 times greater than in saline-injected controls, and resulted in normalization of BW and TL (94 and 96% of controls), and organ weight (92-111% of controls). In P20 controls, 3-wk GH and IGF-I injections significantly increased serum IGF-I (0.6- and 2-fold increases, respectively), BW (14 and 11%), TL (12 and 11%), and organ weight (+10 to 30%) compared with saline-injected rats (p < 0.01). We conclude that under conditions of adequate nutrition, both GH and IGF-I may equally promote postnatal catch-up growth in rats with intrauterine growth retardation caused by gestational protein malnutrition.

Animal Feed↗

PubMed1989

Purification of a growth factor related to platelet-derived growth factor and a type beta transforming growth factor secreted by mouse neuroblastoma cells. A general strategy for the purification of basic polypeptide growth factors.

A general strategy was developed for the purification of basic polypeptide growth factors. This method is a combination of gel filtration, weak-cation-exchange h.p.l.c. and reverse-phase h.p.l.c., separating the proteins according to size, charge and hydrophobicity respectively. All steps are carried out at low pH with exclusively volatile acidic buffer solutions. The sterile conditions and easy removal of salt by freeze-drying facilitate the detection of the growth factors by biological assays. By using this method, homogeneous preparations of two basic growth factors were purified in high yield from mouse-neuroblastoma-Neuro-2A-cell-conditioned medium. It is shown that these purified factors are biochemically and immunologically related to platelet-derived growth factor and type beta transforming growth factor from human platelets.

Animals↗

PubMed2000

Placental growth hormone (GH), GH-binding protein, and insulin-like growth factor axis in normal, growth-retarded, and diabetic pregnancies: correlations with fetal growth.

We previously described significant changes in GH-binding protein (GHBP) in pathological human pregnancy. There was a substantial elevation of GHBP in cases ofnoninsulin-dependent diabetes mellitus and a reduction in insulin-dependent diabetes mellitus. GHBP has the potential to modulate the proportion of free placental GH (PGH) and hence the impact on the maternal GH/insulin-like growth factor I (IGF-I) axis, fetal growth, and maternal glycemic status. The present study was undertaken to investigate the relationship among glycemia, GHBP, and PGH during pregnancy and to assess the impact of GHBP on the concentration of free PGH. We have extended the analysis of specimens to include measurements of GHBP, PGH, IGF-I, IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2, and IGFBP-3 and have related these to maternal characteristics, fetal growth, and glycemia. The simultaneous measurement of GHBP and PGH has for the first time allowed calculation of the free component of PGH and correlation of the free component to indexes of fetal growth and other endocrine markers. PGH, free PGH, IGF-I, and IGF-II were substantially decreased in IUGR at 28-30 weeks gestation (K28) and 36-38 weeks gestation (K36). The mean concentration (+/-SEM) of total PGH increased significantly from K28 to K36 (30.0 +/- 2.2 to 50.7 +/- 6.2 ng/mL; n = 40), as did the concentration of free PGH (23.4 +/- 2.3 to 43.7 +/- 6.0 ng/mL; n = 38). The mean percentage of free PGH was significantly less in IUGR than in normal subjects (67% vs. 79%; P < 0.01). Macrosomia was associated with an increase in these parameters that did not reach statistical significance. Multiple regression analysis revealed that PGH/IGF-I and IGFBP-3 account for 40% of the variance in birth weight. IGFBP-3 showed a significant correlation with IGF-I, IGF-II, and free and total PGH at K28 and K36. Noninsulin-dependent diabetes mellitus patients had a lower mean percentage of free PGH (65%; P < 0.01), and insulin-dependent diabetics had a higher mean percentage of free PGH (87%; P < 0.01) than normal subjects. Mean postprandial glucose at K28 correlated positively with PGH and free PGH (consistent with the hyperglycemic action of GH). GHBP correlated negatively with both postprandial and fasting glucose. Although GHBP correlated negatively with PGH (r = -0.52; P < .001), free PGH and total PGH correlated very closely (r = 0.98). The results are consistent with an inhibitory function for GHBP in vivo and support a critical role for placental GH and IGF-I in driving normal fetal growth.

Adult↗

PubMed2004

Serum levels of growth factors HGF (Hepatocyte Growth Factor), TGFbeta1 (transforming growth factor beta1) and IGF-I (Insulin Like Growth Factor I) in parathyroid tumors.

INTRODUCTION: HGF (Hepatocyte Growth Factor), TGFbeta1 (Transforming Growth Factor beta1) and IGF-I (Insulin Like Growth Factor I) are cytokines that are involved in the parathyroid tumors formation and growth. We tried to determine, if there are changes and relationships in the production of these cytokines by tumor cells of parathyroid tumors. MATERIAL AND METHODS: We determined concentrations of HGF, TGFbeta1 and IGF-I in serum from peripheral blood of 16 patients with parathyroid adenoma and of 8 patients with parathyroid secondary hyperplasia before and after parathyroidectomy. Results were compared with serum levels in healthy people. RESULTS: Both preoperative and postoperative HGF serum levels in patients with parathyroid adenoma and secondary hyperplasia are significantly higher than in healthy people. Preoperative and postoperative serum levels of TGFbeta1 in parathyroid adenoma and postoperative TGFb1 serum levels in parathyroid secondary hyperplasia are higher, compared with those in the healthy population and in parathyroid secondary hyperplasia preoperatively. There are no significant differences of IGF-I serum levels among the all investigated groups of patients. CONCLUSIONS: Changes in the growth factors production by parathyroid tumor cells are reflected by their concentrations in peripheral blood. The elevation of HGF serum levels in patients with parathyroid adenoma and hyperplasia can be explained by very high HGF production by tumor cells. Nevertheless, there is no decrease of HGF serum levels after the parathyroidectomy. That may be the result of the extratumoral production of this cytokine. Also TGFbeta1 and IGF-I serum levels indicate high possibility of the extratumoral production of these cytokines. Higher postoperative IGF-I serum levels (but not significantly) in parathyroid secondary hyperplasia are in accordance with its bone production.

Adenoma↗

PubMed1999

Effect of menopause and different combined estradiol-progestin regimens on basal and growth hormone-releasing hormone-stimulated serum growth hormone, insulin-like growth factor-1, insulin-like growth factor binding protein (IGFBP)-1, and IGFBP-3 levels.

OBJECTIVE: To determine the effects of menopause and three different formulations of E2 plus medroxyprogesterone acetate on serum concentrations of basal and growth hormone-releasing hormone (GHRH)-stimulated growth hormone (GH), insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein (IGFBP)-1, IGFBP-3, insulin, and C peptide. DESIGN: Prospective, controlled trial. SETTING: Menopausal outpatient clinic at an academic tertiary care hospital. PATIENT(S): Nineteen postmenopausal women with different menopausal ages. Seventeen premenopausal women were included as controls. INTERVENTION(S): Oral estrogen (E2 valerate, 2 mg/d) or transdermal estrogen (50-microg or 100-microg E2 patch) was administered for 8 weeks. Medroxyprogesterone acetate (5 mg/d) was administered during weeks 3, 4, 7, and 8 of each protocol. Blood samples were collected before treatment and after the completion of each protocol from postmenopausal women, and on cycle days 6-8 from premenopausal women. MAIN OUTCOME MEASURE(S): Levels of GH, IGF-1, IGFBP-1, IGFBP-3, insulin, and C peptide. RESULT(S): Basal GH levels were negatively correlated with age in premenopausal women but not in postmenopausal women. The area under the GHRH-induced GH curve decreased in older postmenopausal women after the oral estrogen protocol. Levels of IGF-1 diminished after the oral E2 protocol in postmenopausal women. CONCLUSION(S): The administration of oral, but not transdermal, E2 plus medroxyprogesterone acetate at the usual clinical doses used in postmenopausal women decreased IGF-1 levels and the response of GH to GHRH in older women. No substantial changes were detected in IGFBP-1, IGFBP-3, insulin, or C peptide levels.

Adult↗

PubMed2001

Circadian rhythms of basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), cortisol, and melatonin in women with breast cancer.

BACKGROUND: Circadian rhythms in plasma concentrations of many hormones and cytokines determine their effects on target cells. METHODS: Circadian variations were studied in cortisol, melatonin, cytokines (basic fibroblast growth factor IbFGF], EGF, insulin-like growth factor-1 [IGF-1]), and a cytokine receptor (insulin-like growth factor binding protein-3 [IGFBP-3]) in the plasma of 28 patients with metastatic breast cancer. All patients followed a diurnal activity pattern. Blood was drawn at 3h intervals during waking hours and once during the night, at 03:00. The plasma levels obtained by enzyme-linked immunoassay (ELISA) or radioimmunoassay (RIA) were evaluated by population mean cosinor (using local midnight as the phase reference) and by one-way analysis of variance (ANOVA). RESULTS: Cortisol and melatonin showed a high-amplitude circadian rhythm and a superimposed 12h frequency. bFGF showed a circadian rhythm with an acrophase around 13:00 with a peak-to-trough interval (double amplitude) of 18.2% and a superimposed 12h frequency. EGF showed a circadian rhythm with an acrophase around 14:20, a peak-to-trough interval of 25.8%, and a superimposed 12h frequency. IGF-1 showed a high value in the morning, which is statistically different (t test) from the low value at 10:00, but a regular circadian or ultradian rhythm was not recognizable as a group phenomenon. IGFBP-3 showed a low-amplitude (peak-to-trough difference 8.4%) circadian rhythm with the acrophase around 11:00 and low values during the night. CONCLUSIONS: (1) Circadian periodicity is maintained in hospitalized patients with metastatic breast cancer. (2) Ultradian (12h) variations were superimposed on the circadian rhythms of the hormones and several of the cytokines measured. (3) Studies of hormones and cytokines in cancer patients have to take their biologic rhythms into consideration. (4) The circadian periodicity of tumor growth stimulating or restraining factors raises questions about circadian and/or ultradian variations in the pathophysiology of breast cancer.

Analysis of Variance↗

PubMed2005

Effect of zinc sulphate and zinc methionine on growth, plasma growth hormone concentration, growth hormone receptor and insulin-like growth factor-I gene expression in mice.

1. The current experiment was conducted to investigate the effect of zinc sulphate (ZnSO4) and zinc methionine (Zn-Met) on growth and their effect on plasma growth hormone (GH) concentration, growth hormone receptor (GHR) and insulin-like growth factor I (IGF-I) mRNA expression in mice. 2. Ninety male KunMing (KM) mice were randomly divided into three treatments. The control group was fed on a basal diet containing 11.67 mg/kg of zinc. The ZnSO4 group and Zn-Met group were fed on the diets supplemented with ZnSO4 or Zn-Met at 30 mg/kg (containing zinc of 40.05 and 40.75 mg/kg, respectively). The mice were offered the test diets for 10 days. Weight gains and food intake were measured at the end of the experiment, zinc contents in liver and serum were determined using atomic absorption spectrophotometry; GH was determined by radioimmunoassay, the levels of GHR and IGF-I mRNA were determined with reverse transcript polymerase chain reaction. 3. Both ZnSO4 and Zn-Met enhanced weight gain and food intake in the mice, Zn-Met improved the growth and food intake more effectively than ZnSO4 did (P < 0.05). The both forms of zinc had no effect on GH and the level of GHR mRNA expression (P > 0.05) and they up-regulated the expression of IGF-I mRNA (P < 0.05). As compared to ZnSO4, Zn-Met enhanced the level of IGF-I mRNA significantly (P < 0.05). 4. Both ZnSO4 and Zn-Met had no effect on plasma GH and the expression of GHR mRNA, but they enhanced the expression of IGF-I mRNA. Zinc methionine enhanced the weight gain and up-regulated IGF-I mRNA expression more effectively than ZnSO4.

Alkaline Phosphatase↗

PubMed1993

Modulation of transforming growth factor-beta 1 stimulated elastin and collagen production and proliferation in porcine vascular smooth muscle cells and skin fibroblasts by basic fibroblast growth factor, transforming growth factor-alpha, and insulin-like growth factor-I.

During tissue repair and development, matrix accumulation is modulated as multiple signals impinge on target cells. We have investigated the effects of combinations of the mitogenic cytokines, basic fibroblast growth factor (bFGF), transforming growth factor alpha (TGF-alpha), and insulin-like growth factor-1 (IGF-1) with transforming growth factor-beta 1 (TGF-beta 1) with respect to the production of two matrix components, elastin and type I collagen. Using specific enzyme-linked immunoassays for detection of secreted precursors in both vascular smooth muscle cells and skin fibroblasts from the domestic pig, production of these two fibrous proteins was shown to be strongly stimulated by TGF-beta 1. In the smooth muscle cell, both bFGF and TGF-alpha were potent antagonists of TGF-beta 1-mediated matrix production, whereas IGF-1 was only weakly additive with respect to elastin production. Antagonism was also evident to a lesser extent in skin fibroblasts. Reduced responsiveness to TGF-beta 1 did not appear to be due to a switch to a proliferative state, since TGF-beta 1 itself acted as a mitogen in confluent SMC, and TGF-alpha was only a weak mitogen in confluent fibroblast cultures. Although a predominant effect of TGF-beta is matrix accumulation, these findings suggest that this property will be significantly modified by the cytokine context.

Animals↗

PubMed1996

Linear growth in response to growth hormone treatment in children with short stature associated with intrauterine growth retardation: the National Cooperative Growth Study experience.

Short stature commonly follows intrauterine growth retardation (IUGR). Most patients are not growth hormone (GH)-deficient, but GH therapy has been used in IUGR. Early studies found a heterogeneous increase in initial growth rate that could not be maintained. Results of more recent studies with higher doses are more encouraging but do not establish whether final height is increased. Data from a large number of patients in the National Cooperative Growth Study were reviewed to evaluate the response to GH treatment in patients with IUGR-associated short stature. Two hundred seventy such patients were identified and were categorized as those with unclassified IUGR and those with Russell-Silver syndrome/primordial short stature (RSS/PSS). Patients were treated with standard doses of recombinant human GH (approximately 0.3 mg/kg per week) and were assessed periodically for up to 4 years. The height SD score at baseline in patients with unclassified IUGR was -3.49 +/- 1.16, and their relative height improved with each year of therapy. Patients who completed 4 years of treatment reached a height SD score of -1.32 +/- 0.79. Results were similar in patients with RSS/PSS; their baseline height SD score was -3.83 +/- 1.05 and improved to -2.10 +/- 0.99 by year 4. Despite these encouraging results, no change occurred in predicted adult heights. Furthermore the number of patients who remained in treatment for 4 years decreased substantially, thus limiting the interpretation of the data. These data suggest that a beneficial response to GH occurs in some patients with IUGR-associated short stature and that little difference exists in the responses in patients with RSS/PSS compared with those in patients with unclassified IUGR.

Adolescent↗

PubMed2006

Growth inhibition and induction of apoptosis in acute myeloid leukemia cells by new indolinone derivatives targeting fibroblast growth factor, platelet-derived growth factor, and vascular endothelial growth factor receptors.

In acute myeloid leukemia (AML), receptor tyrosine kinase ligands promote growth and survival and contribute to AML-associated marrow neoangiogenesis. We have tested simultaneous inhibition of vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor receptor signaling by novel indolinone derivatives using 14 myeloid, including 11 human leukemic, cell lines. Compounds inhibited colony formation of all cell lines in a dose-dependent fashion. Inhibitory concentrations for 50% of the colony formation/survival (IC50) for BIBF1000 were <100 nmol/L for 3 of 11, <or=500 nmol/L for 6 of 11, and <1,000 nmol/L for 10 of 11 leukemic cell lines, with one cell line being resistant in the dose range <1,000 nmol/L. BIBF1120 was less effective with 4 of 11 leukemic cell lines being resistant within the dose range <1,000 nmol/L. Testing of myeloid 32D cells transfected with empty vector, wild-type Flt3, or Flt3 carrying an internal tandem duplication mutation revealed higher resistance for the internal tandem duplication mutant. These effects of the compounds were associated with inhibition of tyrosine phosphorylation and the mitogen-activated protein kinase pathway. Furthermore, both compounds induced apoptosis in the sensitive cell lines. In Mono-Mac1 cells, the compounds had a direct proapoptotic effect that was increasing the proapoptotic effect of 1-beta-D-arabinofuranosylcytosine. The data provide a rationale for clinical evaluation of these tyrosine kinase inhibitors in AML.

Acute Disease↗

PubMedDate not supplied

Enterotrophic effect of insulin-like growth factor-I but not growth hormone and localized expression of insulin-like growth factor-I, insulin-like growth factor binding protein-3 and -5 mRNAs in jejunum of parenterally fed rats.

BACKGROUND: Administration of insulin-like growth factor (IGF)-I, but not growth hormone (GH), stimulates mucosal hyperplasia in surgically stressed rats with intestinal atrophy induced by hypocaloric total parenteral nutrition (TPN). Our aim was to characterize the basis for this disparity in enterotrophic action by assessing the relationships between stimulation of intestinal growth, nutritional adequacy, and localization of expression of IGF-I, insulin-like growth factor binding protein (IGFBP)-3 and IGFBP-5 mRNAs in jejunum. METHODS: Rats were maintained with TPN for 8 days and treated with IGF-I or GH and adequate nutrition for 5 days after recovery from surgery. Jejunal mass, morphology, and sucrase activity were assessed. Localization of expression of IGF-I, IGFBP-3, and IGFBP-5 mRNAs in jejunum was accomplished by in situ hybridization. RESULTS: Serum IGF-I and body weight gain were significantly increased by IGF-I or GH. Jejunal mucosal dry mass, morphology, and sucrase activity were improved with IGF-I but not GH. There were no differences in IGF-I mRNA. IGFBP-3 mRNA was localized in the lamina propria of the villi. IGF-I or GH stimulated IGFBP-3 expression. IGF-I strongly stimulated IGFBP-5 expression in the lamina propria and the muscularis and induced a twofold increase in IGFBP-5 mRNA based on RNase protection assay of intact jejunum total RNA. GH induced a modest increase in IGFBP-5 expression in the muscularis with no effect on intact jejunum total RNA. CONCLUSIONS: The GH resistance observed in the jejunal mucosa of TPN rats cannot be fully explained by inadequate nutrition. The expression of IGFBP-5 in the lamina propria suggests it may modulate the enterotrophic action of exogeneous IGF-I.

Animals↗

PubMed1992

Treatment with recombinant human insulin-like growth factor I of children with growth hormone receptor deficiency (Laron syndrome). Kabi Pharmacia Study Group on Insulin-like Growth Factor I Treatment in Growth Hormone Insensitivity Syndromes.

Twenty-seven patients (14 female, 13 male; 3 pubertal) with growth hormone receptor deficiency (Laron syndrome) were treated with recombinant insulin-like growth factor I (IGF-I), 40-120 micrograms/kg body weight b.d., for up to 12 months. Height SDS was between -9.1 and -3.2 at the start of treatment (age, 3.7-22.9 years). Before treatment, most patients had increased basal serum concentrations of growth hormone (2.4-208 mU/l) and low serum concentrations of IGF-I (< 20-69 micrograms/l), IGF-II (69-295 micrograms/l) and IGF binding protein-3 (0.16-1.59 mg/l). In all but the two oldest patients, the growth rate increased by more than 2 cm/year compared with that before treatment. Asymptomatic hypoglycaemia (blood glucose < 3.0 mmol/l) was recorded in ten patients in 0.7% of measurements. Four patients experienced symptomatic hypoglycaemia. A transient asymptomatic decrease in serum potassium occurred in most patients after injections.

Adolescent↗

PubMed2001

Effects of oral administration of ibutamoren mesylate, a nonpeptide growth hormone secretagogue, on the growth hormone-insulin-like growth factor I axis in growth hormone-deficient children.

Ibutamoren mesylate (MK-0677), an orally active nonpeptide growth hormone (GH) secretagogue, stimulates GH release through a pituitary and hypothalamic receptor that is different from the GH-releasing hormone receptor. We evaluated the safety and tolerability and the GH-insulin-like growth factor (IGF) responses to two dosages of oral ibutamoren mesylate given to children with GH deficiency for 7 to 8 days. The patients, 18 prepubertal children (15 male, 3 female) with idiopathic GH deficiency, had a chronologic age of 10.6 +/- 0.8 years (mean +/- SD), bone age of 7.4 +/- 0.7 years, growth velocity < 10th percentile for age, height < 10th percentile for age, and a maximum GH response of < or = 10 microg/L to two different GH stimulation tests. The children were assigned as follows to one of three treatment groups with ibutamoren mesylate: 0.2 mg/kg per day for 7 days (days 1-7 or 8-14) and matching placebo for the alternate 7 days (groups I and II, respectively) or 0.8 mg/kg per day for 7 days (days 8-14, group III). On day 15 all patients received an 0.8-mg/kg dose of ibutamoren mesylate. Patients in groups I and II were studied first to assess safety at the low dose before advancement to the high dose. Hormonal profiles were evaluated on day -1 (baseline) and day 15, and the results were expressed as the change from baseline within each group. After administration of ibutamoren mesylate 0.8 mg/kg for 8 days (group III), the median increases (on day 15) from baseline were as follows: 3.8 microg/L (range, 0 to 34.3) for serum GH peak concentration (P = .001), 4.3 microg x h/L (range, 1.3 to 35.6) for the GH area under the concentration-time curve from time zero to 8 hours (AUC(0-8)) (P < .001), 12 microg/L (range, -4 to 116) for serum IGF-I (P = .01), and 0.4 microg/L (range, -0.9 to 1.5) for serum IGF-binding protein 3 (IGFBP-3) (P = .01). There was no change in serum prolactin, glucose, triiodothyronine, thyroxine, thyrotropin, peak serum cortisol, and insulin concentrations or 24-hour urinary free cortisol after administration of 0.8 mg/kg per day of ibutamoren mesylate for 8 days. We conclude that short-term administration of ibutamoren mesylate can increase GH, IGF-I, and IGFBP-3 levels in some children with GH deficiency. Thus this compound is applicable for testing its effect on growth velocity.

Administration, Oral↗