CONCENTRATIONS OF INSULIN-LIKE GROWTH-FACTOR (IGF)-BINDING PROTEIN-3 (IGFBP-3), IGF, AND IGFBP-3 PROTEASE ACTIVITY IN CEREBROSPINAL-FLUID OF CHILDREN WITH LEUKEMIA, CENTRAL-NERVOUS-SYSTEM TUMOR, OR MENINGITIS

Insulin-like growth factor-II (IGF-II) is the major IGF in human cereb rospinal fluid (CSF), whereas IGF-I is only detectable in trace amount s. The major IGFBPs in CSF are IGFBP-2 and IGFBP-4. Normally, IGFBP-3 is a minor component in CSF of healthy subjects, but may be increased in pathological states. We investigated IGF-I, IGF-II, and IGFBP-3 lev els by specific RIAs in CSF from patients with central nervous system (CNS) tumor or leukemia and compared them with values in patients with meningitis. Further, as proteolysis of IGFBP-3 is part of the modulat ion of IGF activity, IGFBP-3 fragmentation was quantified by densitome tric analysis of [I-125]IGFBP-3 protease assays. We examined CSFs of 2 3 children with malignant CNS tumors, 18 children with leukemia, and 1 3 children with meningitis. The CSF from 38 children who received lumb ar punctures to exclude meningitis was used to define the normal range for IGF-I, IGF-II, IGFBP-3, and IGFBP-3 protease activity in CSF. CNS tumor and leukemia patients had normal levels of IGF-I and IGF-II in CSF, whereas the IGF-II concentration in CSF of meningitis patients wa s elevated (P < 0.0001). Only 2 of 13 (15%) meningitis patients had el evation of CSF IGFBP-3 concentrations, despite high numbers of inflamm atory cells. By comparison, elevated IGFBP-3 concentrations were found in the CSF of 16 of 23 (70%) CNS tumor patients and 6 of 7 (86%) CNS tumor patients with microscopically detectable malignant cells in CSF. Twelve of 13 (92%) patients with medulloblastoma or ependymoma and al l 7 medulloblastoma/ependymoma patients with malignant cells in CSF ha d elevated IGFBP-3 concentrations. IGFBP-3 protease activity in CSF wa s elevated in 15 of 16 (94%) patients with CNS tumors of high grade hi stological malignancy. Five of 6 patients (83%) with acute leukemia an d microscopically detectable malignant cells in CSF at the time of dia gnosis showed elevated IGFBP-3 concentrations, with normalization afte r chemotherapy. Leukemia patients without malignant cells in CSF had n ormal IGFBP-3 concentrations. We conclude that in CSF of children with highly malignant CNS tumor or CNS leukemia, IGFBP-3 is elevated. This phenomenon could be caused by disruption of the blood-CSF barrier and entry of IGFBP-3 from serum, although this appears unlikely, especial ly for CNS leukemia. More likely possibilities are 1) local production of IGFBP-3 by CNS tumor tissue and secretion into the CSF, or 2) loca l production of IGFBP-3 by malignant cells within the CSF.