RESUMO
Abnormalities in insulin-like growth factor binding proteins (IGFBPs) have been reported in the cerebrospinal fluid (CSF) of children with acute leukemia. In the present study, we have further characterized the IGFBPs in whole CSF prospectively in 11 children with acute B-lineage lymphoblastic leukemia (ALL) undergoing chemotherapy. Western ligand blots Western immunoblots using a new anti-IGFBP-6 and a new IGFBP-rP1 (related protein-1 antibody and immunoassays (Diagnostic Systems Laboratories, Inc., Webster, TX) were used to characterize and measure IGFBP-6, IGFBP-2, IGFBP-3, and IGFBP-rP1 in children with ALL at diagnosis, and with treatment. Comparisons at baseline were made with 11 children with meningitis and 11 children with febrile convulsions (controls). The mean (+/- SE) CSF IGFBP-6 in ALL patients, 56 (+/- 7) ng/mL, was significantly lower than in meningitis, 97 (+/- 17) ng/mL; and in controls, 123 (+/- 24) ng/mL (P < 0.05, t test). In contrast, CSF IGFBP-3 was elevated in ALL patients, 29 (+/- 9) ng/mL; compared with meningitis, 11 (+/- 1) ng/mL; and controls, 10 (+/- 1) ng/mL (P < 0.05, t test); and IGFBP-2 did not differ among the three groups (47-59 ng/mL, P > 0.05). CSF IGFBP-6 remained very low in the patients with ALL, at 4 and 36 weeks of treatment; whereas IGFBP-3 decreased to control levels, and IGFBP-2 did not change significantly. At baseline, Western ligand blots and Western immunoblots identified a 25- to 28-kDa broad band as IGFBP-6 and a 30-kDa band as IGFBP-2 and showed that there was almost no intact IGFBP-3 in CSF. IGFBP-rP1 was also present in the CSF and was elevated in patients with ALL, compared with the 2 control groups. In conclusion, at diagnosis, IGFBP-rP1 and fragments of IGFBP-3 are elevated, and IGFBP-6 is significantly decreased, in the CSF of ALL children; and IGFBP-6 remained low, with treatment, up to 36 weeks. The role of the IGFBPs and IGFBP-rPs in central nervous system acute leukemia remain to be further elucidated.
Assuntos
Proteínas de Transporte/líquido cefalorraquidiano , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/líquido cefalorraquidiano , Leucemia-Linfoma Linfoblástico de Células Precursoras/líquido cefalorraquidiano , Criança , Pré-Escolar , Feminino , Humanos , Fator de Crescimento Insulin-Like II/metabolismo , Estudos Longitudinais , MasculinoRESUMO
OBJECTIVE: Children with steroid-dependent nephrotic syndrome (SDNS), despite being in remission on glucocorticoids, continue to have growth retardation and short stature. The mechanism is uncertain as both chronic glucocorticosteroids and the nephrotic syndrome may independently affect growth. We investigated the changes in the IGFs and IGF-binding proteins (IGFBPs) in a group of short SDNS children, and studied the changes prospectively with 1 year's treatment with GH. DESIGN AND METHODS: Total and 'free' IGF-I, IGFBP-3 and acid-labile subunit (ALS) were studied in eight SDNS boys (mean age=12.6 years; mean bone age=9.1 years) on long term oral prednisolone (mean dose 0.46 mg/kg per day) before, during, and after, 1 year's treatment with GH (mean dose 0.32 mg/kg per week). Pretreatment comparisons were made with two control groups, one matched for bone age (CBA; mean bone age=9.2 years), and another for chronological age (CCA; mean chronological age=13 years). Subsequently, three monthly measurements of serum and urine IGFBPs were carried out in the GH-treated SDNS patients using Western ligand blot and Western immunoblot. RESULTS: Pre-treatment serum total IGF-I levels and the IGF-I/IGFBP-3 ratio were elevated significantly in SDNS compared with CBA, and were similar to CCA. Serum free IGF-I levels were elevated significantly compared with both control groups, but serum IGFBP-3 did not differ significantly. Urinary IGFBP-2, IGFBP-3 and ALS were detectable in the SDNS children only. With GH treatment, IGF-I and IGFBP-3, but not IGF-II, increased significantly compared with pre-treatment values, and returned to baseline after cessation of GH treatment. Urinary IGFBPs did not change significantly with GH treatment. CONCLUSIONS: There is persistent urinary loss of IGFBP-2, IGFBP-3 and ALS in children with SDNS in remission with growth retardation. However, the significant elevation in serum IGF-I suggests that glucocorticoid-induced resistance to IGF is the main factor responsible for the persistent growth retardation in these children. Exogenous GH was able to overcome this resistance by further increasing serum IGF-I.