Comparison of the antileukemic activity in vitro of dexamethasone and prednisolone in childhood acute lymphoblastic leukemia

Abstract

It is generally assumed that prednisolone (PRD) and dexamethasone (DXM) have equal glucocorticoid activity if PRD is given at sev enfold higher doses. Resuits of clinical studies of childhood acute lymphoblastic leukemia (ALL) suggested that DXM is more potent relative to PRD than assumed. The purpose of this study was to determine the relative antileukemic activ ity of PRD phosphate and DXM phosphate in 133 untreated childhood ALL samples in vitro, using the 3-(4,5-dimethylthiazol-2~y!)-2,5~diphenyltetrazolium-bromide (MTT) assay, There was a marked variation in antileukemic activity of both agents among the patient samples. The median LC50 (drug concentration lethal to 50% of the ALL cells) for PRD phosphate was 3.50 |jlM, for DXM phosphate 0,20 jxM. The individu ally calculated ratios oftheLCSO values for PRD and DXM phosphate showed a large range from 0.7 to > 5 0 0 ; with a median of 16.2. This 16-fold difference could not be explained by differences betw een these glucocorticoids in stability, hy drolysis into unesterified drug, adhesion to the wall o f the microculture plates, or protein bind ing. ALL cells were cross-resistant to PRD and DXM phosphate (correlation coefficient = 0.85, P < 0.000001).W e conclude that the in vitro antileukemic activity o f DXM phosphate is median 16-fold higher than that of PRD phosphate, which contrasts to the generally assumed factor of 7, Based on the higher potency of DXM, and its more favorable pharmacokinetics as reported in the literature, DXM may be pre ferred to PRD as the glucocorticoid in the treatment of ALL.

Dexamethasone versus prednisone for induction therapy in childhood acute lymphoblastic leukemia: a systematic review and meta-analysis

“…Our analysis suggests that this heterogeneity is largely related to different PRED/DEX dose ratios applied in the different trials, with greater efficacy with larger relative DEX dosing, indicating that the presumed equivalent anti-leukemic activity for PRED/ DEX is not a 6:1-7:1 dose ratio, but is higher, as some in vitro experiments suggest. 38 Although our study is able to provide further information in regard to relative corticosteroid doses, the impact of absolute doses on our findings remains unknown. Meta-regression would have been an optimal approach to further explore a dose-effect function of PRED and DEX; however, too few studies were available to consider such an analysis.…”

Combination of prednisolone and low dosed dexamethasone exhibits greater in vitro antileukemic activity than equiactive dose of prednisolone and overcomes prednisolone drug resistance in acute childhood lymphoblastic leukemia

“…Two of the most important glucocorticoids used for treating childhood ALL are PRED and DEX. Although DEX consistently shows higher antileukemic activity both in vitro and in vivo 4,[15][16][17] , PRED is used in most chemotherapy protocols due to its better toxicity profile. DEX administration is associated with higher risk of myopathy, adverse neuro-psychiatric events, osteonecrosis, sepsis, fungal infections, diabetes and pancreatitis 7 .…”

“…DEX administration is associated with higher risk of myopathy, adverse neuro-psychiatric events, osteonecrosis, sepsis, fungal infections, diabetes and pancreatitis 7 . Several studies, including ours [4][5][6]16 , have shown that leukemia cells from different patients can exhibit different responses to PRED and DEX. However, the development of personalized glucocorticoid therapies based on the in vitro response of leukemia cells to individual glucocorticoids is clinically challenging because of time constrains (MTT assay would delay onset of therapy for minimum 4 days).…”

“…A large number of publications have reported a correlation between the in vitro corticoid responses of leukemic lymphoblasts and in vivo responses to PRED monotherapy 4 . This includes our report published in 1999 which focused on differences in the antileukemic activities of PRED and DEX in vitro as assessed by the MTT cytotoxicity assay 5 .…”

Dexamethasone compared to prednisolone for adults with acute lymphoblastic leukemia or lymphoblastic lymphoma: final results of the ALL-4 randomized, phase III trial of the EORTC Leukemia Group

“…4,5 Dexamethasone is 6.5 times more potent than prednisolone as measured by conventional glucocorticoid activity, but it shows a 16-fold gain in potency against lymphoblasts in vitro, suggesting that it might be a more active corticosteroid in the treatment of ALL. 6,7 The better penetration in the central nervous system (CNS) 8 and the enhanced lymphoblastic cytotoxicity might explain the lower bone marrow relapse rate, the lower CNS relapse rate and the advantage in event-free survival recorded in children receiving dexamethasone . [9][10][11] However, attempts to increase the antileukemic effect of dexamethasone by increasing its dose have been associated with increased toxicity and early deaths, mostly due to severe infections.…”