Serum IGFBP3, IGF-I, and MMP7 changes in advanced colorectal cancer (ACRC) patients (pts) treated with anti-EGFR therapy: A GEMCAD study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15109-e15109
Author(s):  
E. Pineda ◽  
C. Pericay ◽  
X. García-Albéniz ◽  
J. Augé ◽  
V. Alonso ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Serum Levels ◽  
Continuous Variable ◽  
Igf I ◽  
Matrix Metalloproteinase 7 ◽  
Igf Binding ◽  
Third Line ◽  
Igf Binding Protein ◽  
Apoptotic Effects

e15109 Background: Insulin-like growth factor-I (IGF-I) is a potent mitotic and anti-apoptotic peptide, whereas IGF binding protein-3 (IGFBP3) seems to have pro-apoptotic effects. Matrix metalloproteinase-7 (MMP7), an enzyme with in vitro ability to degrade IGFBP3, has been shown to be a prognostic factor in ACRC. Methods: This is a prospective single cohort traslational study. Pts undergoing second/third line with irinotecan plus anti-EGFR therapy were eligible as cases. Patients with ACRC not undergoing therapy were eligible as controls. IGFBP3 and MMP7 were measured in serum with immunoassays at baseline and at 48h after treatment start. KRAS mutation status in codons 12/13 was determined by sequencing in 53 pts. The primary endpoint is to define the IGFBP3 and MMP7 variation under anti-EGFR therapy. IGFBP3 was used as a continuous variable and MMP7 was used to create two groups by its third quartile. Results: Eighty-five cases and 25 controls were recruited. No significant changes at 48h in IGF-I and IGFBP3 were found, but a significant decrease in MMP7 from 10.8 (95%IC 8.3–13.3) to 8.4 ng/ml (95%IC 6–10.9) was observed in cases (p<0.001) in contrast with controls, where no changes were found. Splitting the sample by the third quartile of MMP7 interesting changes in IGFBP3 variations were found. In the group with low levels of MMP7, IGFBP3 increases from 1,859 to 1,959 ng/ml (p=0.043) 48h after treatment initiation; on the contrary, in the group with high levels of MMP7, IGFBP3 decreases from 1,811 to 1,757 ng/ml (p=0.741). We found no association with IGFBP3 and neither response rate, time to progression nor overall survival. This latter analysis was also done only in pts with wild-type KRAS, without any change in the results. Conclusions: In pts with ACRC treated with anti-EGFR therapy, serum levels of IGFBP3 variations depend on basal MMP7 levels. IGFBP3 failed to be a predictive/prognostic factor in our sample although the limited number of KRAS pts analyzed can influence our results. [Table: see text] No significant financial relationships to disclose.

scholarly journals Abnormal Sex Chromosome Constitution and Longitudinal Growth: Serum Levels of Insulin-Like Growth Factor (IGF)-I, IGF Binding Protein-3, Luteinizing Hormone, and Testosterone in 109 Males with 47,XXY, 47,XYY, or Sex-Determining Region of the Y Chromosome (SRY)-Positive 46,XX Karyotypes

2008 ◽  
Vol 93 (1) ◽  
pp. 169-176 ◽  
Author(s):  
Lise Aksglaede ◽  
Niels E. Skakkebaek ◽  
Anders Juul
Keyword(s):  
Sex Chromosome ◽  
Serum Levels ◽  
Reproductive Hormones ◽  
Chromosome Constitution ◽  
Sitting Height ◽  
Igf I ◽  
Igf Binding ◽  
Xx Males ◽  
Igf Binding Protein ◽  
Igfbp 3

Abstract Context: Growth is a highly complex process regulated by the interaction between sex steroids and the GH IGF-axis. However, other factors such as sex chromosome-related genes play independent roles. Aim: The aim of the study was to evaluate the role of abnormal chromosome constitution for longitudinal growth in relation to reproductive hormones, IGF-I, and IGF binding protein (IGFBP)-3. Setting: The study was conducted at an outpatient clinic, Copenhagen University Hospital. Participants: Participants included 86 47,XXY males, 14 46,XX-males, and nine 47,XYY. Main Outcome Measures: Standing and sitting height, serum levels of reproductive hormones, IGF-I, and IGFBP-3 were measured. Results: In boys with 47,XXY and 47,XYY karyotypes, growth was accelerated already in childhood, compared with healthy boys. 46,XX-males were significantly shorter than healthy boys but matched the stature of healthy girls. In 47,XXY sitting height to height ratios were lower than expected, whereas body proportions in 46,XX-males and 47,XYY were normal. In all subjects serum levels of IGF-I and IGFBP-3 were within normal limits. The boys with 46,XX and 47,XXY karyotypes presented with low normal testosterone and elevated LH levels after puberty, whereas the sex hormone secretion of the 47,XYY boys remained normal. Conclusion: We found accelerated growth in early childhood in boys with 47,XXY and 47,XYY karyotypes, whereas 46,XX-males were shorter than controls. These abnormal growth patterns were not reflected in circulating levels of IGF-I and IGFBP-3. The boys with 46,XX and 47,XXY karyotypes developed hypogonadism in puberty, but androgen secretion in 47,XYY boys remained normal. The abnormal stature of these patients may be a result of abnormal gene expression due to the underlying chromosome aberration resulting in excessive expression of growth-related genes.

Major secretory protein of human decidualized endometrium in pregnancy is an insulin-like growth factor-binding protein

1988 ◽  
Vol 118 (2) ◽  
pp. 317-328 ◽  
Author(s):  
S. C. Bell ◽  
S. R. Patel ◽  
J. A. Jackson ◽  
G. T. Waites
Keyword(s):  
Growth Factor ◽  
Amniotic Fluid ◽  
Incubation Medium ◽  
Binding Protein ◽  
Secretory Protein ◽  
Insulin Like Growth Factor ◽  
Igf I ◽  
Igf Binding ◽  
Igf Binding Protein

ABSTRACT Pregnancy-associated endometrial α1-globulin (α1-PEG) is quantitatively the major secretory protein product, synthesized and secreted in vitro, of the human decidualized endometrium during pregnancy. This protein has been purified from cytosolic extracts of this tissue and has now been characterized as a 32 kDa somatomedin/insulin-like growth factor (IGF)-binding protein. Immunoreactive α1-PEG isolated from amniotic fluid exhibited identical physiochemical properties and IGF-I-binding characteristics. In cytosolic extracts of pregnancy endometrium, in incubation medium of this tissue and in amniotic fluid, the 32 kDa protein represented the major α1-PEG immunoreactive protein and major IGF-I-binding component. Purified α1-PEG and incubation medium of pregnancy endometrium competed for IGF-I with placental membrane IGF receptors in vitro. The implications of the endometrial source of IGF-I-binding protein are dicussed with reference to the origin of the amniotic fluid and serum small Mr IGF-binding protein and to the suggested paracrine effect upon trophoblast proliferation. J. Endocr. (1988) 118, 317–328

scholarly journals Insulin infusion increases levels of free IGF-I and IGFBP-3 proteolytic activity in patients after surgery

2001 ◽  
Vol 281 (4) ◽  
pp. E736-E741 ◽  
Author(s):  
J. Nygren ◽  
C. Carlsson-Skwirut ◽  
K. Brismar ◽  
A. Thorell ◽  
O. Ljungqvist ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Growth Factor ◽  
Proteolytic Activity ◽  
Insulin Infusion ◽  
Serum Levels ◽  
Insulin Resistant ◽  
Igf I ◽  
Igf Binding ◽  
Igf Binding Protein ◽  
Igfbp 3

We have studied the effects of insulin on the bioavailability of insulin-like growth factor (IGF) I in insulin-resistant patients after surgery. Serum levels of total IGF-I (tIGF-I), free IGF (fIGF)-I, fIGF-II, and IGF-binding protein (IGFBP) 1 and IGFBP-3 proteolytic activity (IGFBP-3-PA), determined on the day before surgery and on the 1st postoperative day, were related to insulin sensitivity measured by a hyperinsulinemic, normoglycemic clamp. Before surgery, the decreased tIGF-I ( P < 0.05) in response to insulin infusion was accompanied by an 18% reduction of IGFBP-1 ( P < 0.001), while IGFBP-3-PA remained unchanged. Levels of fIGF-I and fIGF-II were not changed by insulin infusions. After surgery, IGFBP-3-PA increased ( P < 0.05) during insulin infusion, and this was associated with an increase in tIGF-I ( P < 0.001) and fIGF-I ( P < 0.01), while no significant change was found in fIGF-II. The reduction in IGFBP-1 in response to insulin infusion was not affected by surgery. The change in IGFBP-3-PA during insulin infusion after surgery was related to the corresponding change in fIGF-I ( r 2 = 0.26, P < 0.05) and postoperative insulin sensitivity ( r 2 = −0.22, P < 0.05). These data suggest that increased IGFBP-3-PA during insulin infusion after surgery governs the increased levels of fIGF-I, while insulin-induced suppression of IGFBP-1 was not affected by surgery. We propose that, in catabolic, postoperative patients, increased levels of insulin from exogenous or, possibly, endogenous sources (nutritionally induced) may be a signal to increase IGF-I bioavailability by increased expression of IGFBP-3-PA to counteract further deterioration in glucose metabolism.

scholarly journals Desmopressin increases IGF-binding protein-1 in humans.

2008 ◽  
Vol 158 (4) ◽  
pp. 479-482 ◽  
Author(s):  
S B Catrina ◽  
R Rotarus ◽  
I R Botusan ◽  
M Coculescu ◽  
K Brismar
Keyword(s):  
Binding Protein ◽  
Serum Levels ◽  
University Hospital ◽  
Placebo Administration ◽  
Plasma Osmolarity ◽  
Igf I ◽  
Igf Binding ◽  
Vasopressin Secretion ◽  
Igf Binding Protein ◽  
Clinical Potential

ContextIGF binding protein-1 (IGFBP-1) is essential for IGF-I bioavailability. High levels of IGFBP-1 are encountered in critically ill patients and are a good predictor marker in acute myocardial infarction. The mechanisms responsible for the elevated IGFBP-1 levels in these conditions are still unclear. Interestingly, high levels of vasopressin have been reported in the above-mentioned conditions.ObjectiveTo study the effect of vasopressin on IGFBP-1 in humans.DesignPlacebo-controlled cross-over study in patients with central diabetes insipidus (CDI) in whom potential interference from endogenous vasopressin secretion is minimized. After a 3-day desmopressin washout period, each patient received i.v. saline on day 1 and desmopressin (3 μg) on day 2. Blood samples were taken after administration, every 2 h during the whole night, starting at 2000 h.Patients and settingFourteen inpatients with CDI in an endocrinology department of a university hospital.ResultsSerum IGFBP-1 increased within 4 h after 1-desamino-8-d-arginine vasopressin (DDAVP) by 375±73%, compared with a spontaneous fasting increase by 252±46% following placebo administration (P<0.05). No changes were registered in the levels of either classically regulators of IGFBP-1 (insulin, glucagon, and cortisol) or of IGF-I and glucose. The decrease in plasma osmolarity induced by DDAVP did not precede the increase in IGFBP-1.ConclusionsDDAVP increases serum levels of IGFBP-1. Further investigation is essential to unravel the clinical potential of this interaction in conditions associated with high IGFBP-1 levels.

Changes induced by non-enzymatic glycosylation of IGF-binding protein-3: effects on its binding properties and on its modulatory effect on IGF-I mitogenic action

1995 ◽  
Vol 144 (1) ◽  
pp. 119-126 ◽  
Author(s):  
A M Cortizo ◽  
J J Gagliardino
Keyword(s):  
Binding Protein ◽  
Mitogenic Activity ◽  
Dependent Manner ◽  
Binding Properties ◽  
Igf I ◽  
Igf Binding ◽  
Igf Binding Protein ◽  
Enzymatic Glycosylation ◽  
Igfbp 3

Abstract The aim of this study was to demonstrate the feasibility of in vitro non-enzymatic glycosylation of IGF-binding protein-3 (IGFBP-3) and whether this process affects its binding properties and its modulatory effect on IGF-I mitogenic activity. Swiss 3T3 fibroblasts were cultured and the IGFBP-3 released into the medium (CM) glycated with either labelled or unlabelled glucose. Parallel glycation studies were performed using standard human IGFBP-3. Both species of IGFBP-3 became effectively glycated in a dose-dependent manner. Glycated IGFBP-3 bound larger amounts of 125I-labelled IGF-I than its non-glycated form. According to Scatchard analysis this effect might be due to an increase in the number of binding sites of the IGFBP-3 molecule rather than to changes in its affinity constants, which remain unchanged. Preincubation of fibroblasts with CM containing IGFBP-3 for 16 h before the addition of IGF-I enhanced the stimulatory effect of the hormone on thymidine incorporation into cell DNA. This potentiation was blunted when in vitro glycated instead of non-glycated IGFBP-3 was employed. These results provide further evidence of the in vitro glycation of IGFBP-3 and demonstrate that this process affects both its binding properties and its enhancing effect on IGF-I mitogenic activity. These changes may explain, at least partially, the development of many alterations observed in poorly controlled diabetic patients. Journal of Endocrinology (1995) 144, 119–126

scholarly journals Serum IGF-I, IGFBP-3, and matrix metalloproteinase-7 levels and acquired chemo-resistance in advanced colorectal cancer

2009 ◽  
Vol 16 (1) ◽  
pp. 311-317 ◽  
Author(s):  
Rosa Gallego ◽  
Jordi Codony-Servat ◽  
Xabier García-Albéniz ◽  
Enric Carcereny ◽  
Raquel Longarón ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Matrix Metalloproteinase ◽  
Progressive Disease ◽  
Advanced Colorectal Cancer ◽  
Serum Levels ◽  
Chemotherapy Treatment ◽  
Igf I ◽  
Matrix Metalloproteinase 7 ◽  
Igfbp 3

Insulin-like growth factor-I (IGF-I) is thought to have antiapoptotic and mitogenic properties in colorectal cancer, whereas IGF-binding protein-3 (IGFBP-3) seems to exert a pro-apoptotic effect. Additionally, matrix metalloproteinase-7 (MMP-7), an enzyme with in vitro ability to degrade IGFBP-3, has been shown to be a prognostic factor in advanced colorectal cancer (ACRC). We studied whether chemotherapy treatment for ACRC modulates IGF-I, IGFBP-3, and MMP-7 serum levels. In 41 patients undergoing first-line therapy for ACRC, serum levels of IGF-I, IGFBP-3, and MMP-7 were measured with immunoassays at baseline and every 3 months until progressive disease, or a maximum of five determinations, during a chemotherapy regimen of either FOLFOX or FOLFIRI therapies. Associations were assessed for paired samples, using t-test or Wilcoxon ranks test depending on normality of the variable, verified with Shapiro-Wilk test. An average of four extractions (range 3–5) were done, for a total of 157 determinations. Mean pretreatment values of IGF-I, IGFBP-3, and MMP-7 were 83 (95% CI, 73–92) ng/ml, 2372 (95% CI, 2121–2623) ng/ml, and 10.6 (95% CI, 7.21–13.98) ng/ml respectively. No significant changes in IGF-I were found, but a significant increase in IGFBP-3 serum concentrations was observed during or after chemotherapy treatment without progressive disease, compared with basal levels (P<0.001). A significant decrease in IGFBP-3 to 1983 ng/ml (95% CI, 1675–2292) and a significant increase in MMP-7 levels to 14.6 (7.6–21.7) ng/ml were observed at progression of disease compared with baseline and treatment levels (P<0.001). This study shows that IGFBP-3 and MMP-7 serum levels change during chemotherapy treatment. The increased MMP-7 levels at disease progression support the hypothesis that this protease could play a role in acquired resistance by degrading IGFBP-3.

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