Review GLUCOCORTICOID RESISTANCE IN CHILDHOOD LEUKAEMIA: MECHANISMS AND MODULATION Glucocorticoids (GCs) are a central component in contem- porary paediatric acute lymphoblastic leukaemia treatment protocols. GC resistance has an adverse impact on clinical outcome in childhood leukaemia. Mechanisms of GC resist- ance have been described in cell line models, but have largely remained elusive in clinical specimens. GCs exert their cytotoxic effect through the induction of apoptosis. Recent advances in knowledge about the apoptotic pathway have opened a whole new field of drug resistance research and identified a large number of potential targets for enhancing GC action. It is of importance, however, to realize that lymphoid tumours are among the few cell types that can respond to GC exposure by initiating their apoptotic programme (in several non-lymphoid tumours GCs induce proliferation or inhibit apoptosis). Very little is known about the GC-mediated gene-regulatory events preceding the apoptotic cascade. The main challenge facing today’s researchers in steroid resistance research is to unravel this part of the GC-induced apoptotic pathway. This review summarizes the efforts to elucidate the molecular mechanisms of GC-induced apoptosis and resist- ance, with particular reference to childhood leukaemia. Several strategies are also discussed for modulating or circumventing this type of drug resistance. GLUCOCORTICOIDS IN CHILDHOOD LEUKAEMIA The cytolytic effects of glucocorticoids (GCs) on thymocytes were first described in 1936 (Selye, 1936). GCs were first used in the treatment of childhood leukaemia in the late 1940s and early 1950s. Consecutive trials showed that, as single agents, GCs induced partial and complete responses in up to 80% of children suffering from newly diagnosed acute lymphoblastic leukaemia [initial (i)ALL]. In relapsed ALL (rALL) and acute myeloid leukaemia (AML) patients, however, response rates were much lower (35% and 20% respectively) (reviewed by Kaspers et al, 1994a). Today GCs are an integral part of ALL treatment protocols. Resistance to GC-induced cell kill (determined both in vivo and in vitro) has been identified as a major adverse prognostic factor in iALL. The Berlin–Frankfurt– Mu ¨ nster (BFM) study group showed a worse treatment outcome for patients who responded poorly to a 7-d regimen of prednisolone (PRD) monotherapy in the ALL-BFM-83 study, despite the subsequent use of usually effective combination chemotherapy (Riehm et al, 1987). Compared with PRD poor responders, defined by a cut-off point of more than 1 · 10 9 leukaemic cells ⁄ l in the peripheral blood after 7d PRD, good responders had a significantly higher probability of achieving complete remission (99% vs 92%) and a higher probability of event-free survival at 3 years (75% vs 43%). The prognostic significance of the in vivo PRD response was retained in the ALL-BFM-86 and -90 trials (Fig 1), even though, thanks to improvements in treatment, the overall probability of event-free survival at 5 years increased from 64% to 78% (Schrappe et al, 2000). Our group (Fig 2; Kaspers et al, 1997) and Hongo et al (1997) reported significant correlations between in vitro GC resist- ance, determined with the total cell kill methyl-thiazol- tetrazolium (MTT) assay, and clinical outcome in childhood iALL. GCs also form an integral part of rALL, and some AML treatment protocols. However, in line with the lower response rate to GC monotherapy in vivo, our laboratory demonstrated that these leukaemias were > 75-fold more resistant to GCs in vitro (Klumper et al, 1995; Zwaan et al, 2000). This may at least partly explain their relatively low cure rate (Henze et al, 1991; Stevens et al, 1998). During the past decades, extensive studies have been performed in the attempt to elucidate the molecular mechanisms of GC-induced cell lysis and GC resistance. This review includes an overview of the results obtained to date. In the first section of this review, background information is given about glucocorticoid hormones, the glucocorticoid receptor and the apoptotic pathway. In the second part, the molecular events in GC-induced apoptosis are linked to GC resistance, and the third section discusses several strategies for modulating GC resistance. GLUCOCORTICOID HORMONES, THE GLUCOCORTICOID RECEPTOR AND GLUCOCORTICOID-INDUCED APOPTOSIS Glucocorticoid hormones The family of steroid hormones comprises four major types: the progestins, androgens, oestrogens and corticosteroids. These lipophilic compounds are all derived from cholesterol but differ structurally and functionally. The corticosteroids can be subdivided into mineralocorticoids, which regulate electrolyte and fluid balance, and GCs, which have a wide range of biological activities, including inhibition of the immune and inflammatory responses and induction of apoptosis in lymphoid cells. The predominant naturally occurring GC in humans is cortisol. Correspondence: E. G. Haarman, Department of Paediatric Haematology ⁄ Oncology, VU University Medical Centre, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. E-mail: EG.Haarman@VUmc.nl British Journal of Haematology, 2003, 120, 919–929 Ó 2003 Blackwell Publishing Ltd 919