Glucocorticoids are commonly used in the first-line treatment of hematological malignancies, such as acute lymphoblastic leukemia, due to the ability of these steroids to activate pro-apoptotic pathways in human lymphocytes. The goal of the current study was to examine the gene expression and enzyme activity of the microsomal enzyme, 11-β hydroxysteroid dehydrogenase type 2 (HSD11B2, HSD2), which is responsible for the oxidation of bioactive glucocorticoids to their inert metabolites. Using the glucocorticoid-sensitive human leukemic cell line, CEM-C7, we were able to detect the expression of HSD2 at the level of mRNA (via RT-PCR), protein (via immunohistochemistry and immunoblotting), and enzyme activity (via conversion of tritiated cortisol to cortisone). Furthermore, we observed that HSD2 enzyme activity is down regulated in CEM-C7 cells that were pretreated with the synthetic glucocorticoid, dexamethasone (100？nM, <15 hours), and that this down regulation of enzyme activity is blocked by the administration of the glucocorticoid receptor antagonist, RU-486. Taken collectively, these data raise the possibility that the effectiveness of glucocorticoids in the treatment of human leukemias may be influenced by: (1) the ability of these neoplastic cells to metabolize glucocorticoids via HSD2 and (2) the ability of these steroids to regulate the expression of this key enzyme. 1. Introduction Glucocorticoid (GC) therapy remains one of the first-line therapies in the treatment of a variety of leukemias, including acute lymphoblastic leukemia (ALL). Synthetic GCs, such as dexamethasone and prednisone, are effective in treating ALL due to their ability to induce cell cycle arrest and apoptosis. The microsomal enzyme, 11-beta hydroxysteroid dehydrogenase type 2 (HSD2), catalyzes the conversion of biologically active 11-hydroxy glucocorticoids (i.e., cortisol) to their inactive 11-keto metabolites (i.e., cortisone). This activity allows for the tissue-specific conversion of cortisol to inactive cortisone, thereby decreasing the local concentrations of active GCs. Loss of the ability to inactivate cortisol via HSD2 enzyme activity has been implicated in the pathogenesis of a number of human diseases [1]. Despite the widespread use of GCs to treat leukemia, relatively little is known about the metabolism of GCs in human leukemic cells. The CEM-C7 cell line is glucocorticoid-sensitive subclone of a human leukemic cell line derived from a 4-year-old female patient with late stage ALL [2, 3]. A previous study has reported that the synthetic GC, dexamethasone, was not
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