223 The role of the MR 7 INTRODUCTION Glucocorticoids, also denoted as steroids, were among the first drug classes used in the treatment of childhood acute lymphoblastic leukemia (ALL) and are still regarded as cornerstone drugs in ALL therapy.1-3 Different synthetic glucocorticoids, with different molecular aspects and varying properties, are used.1 Dexamethasone is currently the preferred glucocorticoid in most ALL treatment protocols since its use is linked to less relapses and a higher event-free survival compared to prednisone.4 Two receptors exist which can bind glucocorticoids: the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), both nuclear receptors encoded by the NR3C1 and NR3C2 gene respectively. The cytotoxic effect of glucocorticoids seems to be mainly exerted through the GR, and previous steroid cytotoxicity studies in childhood ALL mainly focused on prednisone and dexamethasone in relation to the expression levels of and mutations in the NR3C1 gene.1,5,6 Clinical steroid resistance as well as in vitro steroid resistance, which have been shown to be a poor prognostic factor for the survival of ALL, are related to NR3C1 aberrations.6,7 Mutations in the NR3C2 gene are less frequently studied, maybe due to the fact that MR expression on leukemic cells is relatively low.8 The role of the MR in steroid cytotoxicity therefore has remained unclear. Synthetic glucocorticoids differ in their ability to bind and activate the GR and MR. Prednisone has a high affinity for both the GR and MR, whereas dexamethasone does not bind the MR and has a high potency to activate the GR.9 Hydrocortisone, which is identical to the natural occurring hormone cortisol, can bind both receptors, but has a higher affinity for the MR.9,10 Interestingly, hydrocortisone seems to potentiate the cytotoxic effect of both prednisolone and dexamethasone in steroid sensitive ALL cell lines.8 Moreover, when hydrocortisone was given as a single drug, it appeared to be as potent as dexamethasone or prednisolone in cytotoxicity assays.8 Hydrocortisone has never been considered as a potential cytotoxic steroid in ALL treatment protocols. Since hydrocortisone has far fewer side effects compared to dexamethasone or prednisone, and may even ameliorate certain neurobehavioral side effects of dexamethasone treatment,11 it would be of interest to investigate the cytotoxic effect of hydrocortisone, compared to prednisone and dexamethasone. The purpose of the present study was to establish the role of the MR in steroid-induced cytotoxicity in patients with ALL. Furthermore, we evaluated in vitro antileukemic activity of prednisolone, dexamethasone and hydrocortisone in cell lines that selectively can be induced to express the GR or the MR.
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