title: 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.
abstract: BACKGROUND
  Glucocorticoids, particularly prednisone/ prednisolone and dexamethasone, play a prominent role in the treatment of pediatric patients with acute lymphoblastic leukemia due to their ability to induce apoptosis in susceptible cells. Current therapeutic protocols use prednisone for both the prophase and the induction phase of the therapy because the greater antileukemic activity of dexamethasone is compromised by its high frequency of serious adverse reactions.
  
  
  OBJECTIVE
  To compare, for the first time, the in vitro antileukemic activity of prednisolone alone to that of a combination of prednisolone and dexamethasone using dexamethasone at a very low and presumably safe dosage (1/50 w/w).
  
  
  METHODS
  Lymphoblasts were isolated from bone marrow and/or blood samples from children with newly diagnosed acute lymphoblastic leukemia. The cytotoxic activity of prednisolone, dexamethasone and the prednisolone/dexamethasone combination against isolated leukemia cells was analyzed using the MTT cytotoxicity assay.
  
  
  RESULTS
  We observed differences in the in vitro antileukemic activity of prednisolone and dexamethasone in 21% of the tested patients. 3% of the children were prednisolone sensitive but dexamethasone resistant, while 18% were prednisolone resistant and dexamethasone sensitive. 32% were sensitive to both glucocorticoids and 18% were resistant to both. Cells from patients with good in vivo responses to prednisone monotherapy were more responsive to prednisolone in vitro than were cells from patients with poor prednisone responses (P<0.07). Importantly, we demonstrated that the use of even a minimal dose (1/50 w/w) of dexamethasone with prednisolone dramatically increases the in vitro anti-leukemic activity of prednisolone (P<0.0006).
  
  
  CONCLUSIONS
  The high inter-individual variability of acute lymphoblastic leukemia responses to glucocorticoids suggest that either patients should be selected for prednisone or dexamethasone treatment on the basis of predictive biomarkers or that prednisone should be used directly in combination with a very low and safe dose of dexamethasone to potentiate its antileukemic activity. The latter option is likely to be cheaper and more efficient, and therefore warrants further clinical investigation to assess its efficacy and safety in treating childhood acute lymphoblastic leukemia.
authors.affiliation: Laboratory of Experimental Medicine, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Spenerova
authors.forename: Petr
authors.initials: P
authors.lastname: Dzubak
authors.forename: Josef
authors.initials: J
authors.lastname: Srovnal
authors.forename: Lenka
authors.initials: L
authors.lastname: Radova
authors.forename: Renata
authors.initials: R
authors.lastname: Burianova
authors.forename: Petr
authors.initials: P
authors.lastname: Konecny
authors.forename: Sona
authors.initials: S
authors.lastname: Salkova
authors.forename: Zbynek
authors.initials: Z
authors.lastname: Novak
authors.forename: Dagmar
authors.initials: D
authors.lastname: Pospisilova
authors.forename: Jan
authors.initials: J
authors.lastname: Stary
authors.forename: Bohumir
authors.initials: B
authors.lastname: Blazek
authors.forename: Jiri
authors.initials: J
authors.lastname: Hak
authors.forename: Tomas
authors.initials: T
authors.lastname: Votava
authors.forename: Pavel
authors.initials: P
authors.lastname: Timr
authors.forename: Emilia
authors.initials: E
authors.lastname: Kaiserova
authors.forename: Eva
authors.initials: E
authors.lastname: Bubanska
authors.forename: Vladimir
authors.initials: V
authors.lastname: Mihal
authors.forename: Marian
authors.initials: M
authors.lastname: Hajduch
mesh_terms: D002648:Child; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011239:Prednisolone / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D005938:Glucocorticoids; D003907:Dexamethasone; D011239:Prednisolone