276 Addendum Even though the side effects of dexamethasone are well-known and negatively impact quality of life during ALL treatment, currently no pharmacological treatment to overcome dexamethasone-induced side effects exists. Glucocorticoids can bind to two receptor types: the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Dexamethasone has a high affinity for the GR, but no affinity for the MR. Furthermore, dexamethasone suppresses the endogenous production of cortisol, which has a high affinity for the MR. We previously hypothesized that the neurobehavioral side effects of dexamethasone are due to cortisol depletion of the MR, caused by dexamethasone, which might be overcome by hydrocortisone (the synthetic equivalent of cortisol) addition. Our previous randomized controlled trial (RCT) investigated the effect of physiological hydrocortisone addition to dexamethasone treatment. In those patients who suffered most, hydrocortisone diminished neurobehavioral and sleep problems, but these results required further validation before implementation in clinical practice. The second aim of this thesis was therefore to validate the finding that hydrocortisone addition to dexamethasone treatment leads to a significant reduction of clinically relevant dexamethasone-induced neurobehavioral and sleep problems. We performed a doubleblind RCT with cross-over design in 52 children with ALL who suffered from clinically relevant neurobehavioral problems (Chapters 3 and 6). We found no difference between hydrocortisone and placebo in reducing dexamethasone-induced neurobehavioral problems. However, the neurobehavioral problems decreased equally during both hydrocortisone and placebo treatment, suggesting a placebo-effect which influences both patient and family. This placebo-effect may be used in clinical practice to alleviate some of the burden of dexamethasone-induced neurobehavioral problems. Finally, we aimed to describe the role of the MR in steroid-induced cytotoxicity and to evaluate the cytotoxic effect of hydrocortisone (Chapter 7). In a preclinical study, we showed that hydrocortisone can induce the expression of steroid-regulated genes through both GR and MR, and effectively induces cell death in Reh cell lines that by doxycyclineinduction express the GR or MR. Moreover, dexamethasone induces cell death in MRexpressing Reh cells that lack an endogenous functional GR gene. These results highlight that the MR is a potent receptor to induce leukemic cell death after activation by steroid treatment, and that hydrocortisone treatment can induce cell death in leukemic cells. In patient samples, the role of the mineralocorticoid receptor in steroid-induced cytotoxicity seems less pronounced, possibly due to the (relative) low expression of MR in ALL patients. Still, hydrocortisone may be considered as a potential anti-leukemic agent, especially for those patients who suffer from severe dexamethasone-induced side effects.
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