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

Changes in insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding proteins (IGEBPs) were correlated with protein synthesis and breakdown using [1-C-13]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 mu g l(-1), respectively). During FN, IGF-I fell to 156 +/- 22 mu g l(-1) (p = 0.02), and rose to 276 +/- 27 mu g 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 mu g 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.