Changes in protein turnover, IGF-I and IGF binding proteins in children with cancer

Abstract

Changes in insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding proteins (IGFBPs) were correlated with protein synthesis and breakdown using [1-13C]leucine before chemotherapy and during subsequent febrile neutropenia (FN) in eight children with cancer, aged 6.3-17.5 y. IGF-I levels were similar to age-matched controls before chemotherapy (mean +/- SEM: 250+/-28 and 228+/-22 microg l(-1), respectively). During FN, IGF-I fell to 156+/-22 microg l(-1) (p = 0.02), and rose to 276+/-27 microg l(-1) with recovery at 6 months (p = 0.004). Similarly, IGFBP-3 decreased from 4.0+/-0.2 mg l(-1) before chemotherapy to 3.0+/-0.3 mg l(-1) during FN (p = 0.01), and returned to 4.1+/-0.2 mg l(-1) at 6 months (p = 0.01). IGF-I correlated with IGFBP-3 (r = +0.7, p < 0.001). Scanning densitometry showed a decrease in IGFBP-3 from 94 to 54% during FN, when the presence of IGFBP-3 protease activity was observed. Compared with normal human serum, IGFBP-2 was elevated throughout the study. IGFBP-1 increased from 14.6+/-3.5 to 30.6+/-2.8 microg l(-1) (p = 0.004), whereas serum insulin decreased from 26.5+/-6.8 to 7.8+/-0.8 mU l(-1) (p = 0.03) before and during FN, respectively. Whilst IGF-I and IGFBP-3 fell, daytime growth hormone increased from 3.3+/-0.6 to 6.7+/-0.8 mU l(-1) (p=0.01), and cortisol from 197+/-48 to 594+/-98 nmol l(-1) (p = 0.005). Albumin decreased from 47+/-2 to 38+/-2 g l(-1) (p = 0.004) and improved to 47+/-2 g l(-1) with recovery (p = 0.003). Protein synthesis increased from 4.5+/-0.4 to 5.0+/-0.6 g kg(-1)d(-1) before chemotherapy and during FN, while protein breakdown rose from 5.4+/-0.4 to 6.3+/-0.4 kg(-1)d(-1). Increasing protein breakdown was related to falling IGF-I and IGFBP-3 levels. Modification of IGFBP-3 by circulating proteolytic activity may alter IGF bioavailability, allowing protein synthesis to increase during periods of severe catabolic stress.

IGF-1 is downregulated in experimental cancer cachexia

“…The observation that transgenic mice overexpressing IGF-1 specifically in the skeletal muscle show a hypertrophic phenotype is consistent with the role played by this growth factor in the regulation of muscle mass (44). Finally, catabolic states such as sepsis and cancer have been associated with reduced levels of circulating IGF-1 (4,29).…”

Changes of serum growth factors (IGF-I,-II and IGFBP-2,-3) prior to and after stem cell transplantation in children with acute leukemia

“…[13][14][15][16] To our knowledge, we present for the first time results that show the changes of insulin-like growth factors and their binding protein during long-term follow-up after stem cell transplantation. 17,18 Especially, the significant increase of IGFBP-2 serum levels up to 100 days after transplantation has never been shown before. About 89% (n ¼ 24) of patients with AML and 66% (n ¼ 16) of ALL patients showed increased serum concentration greater than +2 SDS at day 100 (in some cases up to five times greater than the normal levels at day 100).…”

High insulinlike growth factor binding protein 1 level predicts incident congestive heart failure in the elderly

“…Our results suggest the importance of adjustment for obesity and other risk factors in assessing the independent association of IGFBP-1 levels with vascular endpoints. Elevated circulating IGFBP-1 occurs in catabolic states including AIDS wasting (20), end-stage renal disease (17), cancer (16), energy deficiency during military training (18), and dietary restriction (21).…”

“…IGFBP-1 has a very different system of regulation than IGFBP-3, with hepatic IGFBP-1 production strongly (inversely) regulated by insulin. Aging, cachectic conditions, malnutrition, inflammatory cytokines, and oxidative stress all increase IGFBP-1 expression (15)(16)(17)(18)(19)(20)(21), which may in turn lead to inhibition of anabolic IGF-I effects by IGFBP-1 during catabolic states. High circulating IGFBP-1 levels predict cardiovascular events after myocardial infarction (22) and cardiovascular mortality among apparently healthy older men (23).…”