Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2014, 158(3):422-427 | DOI: 10.5507/bp.2012.059

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

Michaela Spenerova^a,b,#, Petr Dzubak^a,b,#, Josef Srovnal^a,b, Lenka Radova^a, Renata Burianova^a, Petr Konecny^a, Sona Salkova^a, Zbynek Novak^b, Dagmar Pospisilova^b, Jan Stary^c, Bohumir Blazek^d, Jiri Hak^e, Tomas Votava^f, Pavel Timr^g, Emilia Kaiserova^h, Eva Bubanskaⁱ, Vladimir Mihal^a,b, Marian Hajduch^a

^a Laboratory of Experimental Medicine, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Czech Republic

^b Department of Pediatrics, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc

^c Department of Pediatric Haematology and Oncology, University Hospital Motol, Prague

^d Department of Pediatrics, University Hospital in Ostrava

^e Department of Pediatrics, University Hospital in Hradec Kralove

^f Department of Pediatrics, Faculty Hospital in Pilsen

^g Department of Pediatrics, Hospital in Ceske Budejovice

^h Department of Pediatric Oncology, University Hospital in Bratislava, Slovak Republic

ⁱ Department of Pediatric Oncology and Hematology, Children's Medical University Department, Banska Bystrica, Slovak Republic

^# These authors equally contributed to the work

Introduction: 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.

Aim: 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).

Conclusion: 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.

Keywords: acute lymphoblastic leukemia, glucocorticoids, prednisone, prednisolone, dexamethasone, drug resistance, MTT assay

Received: February 22, 2012; Prepublished online: October 31, 2012; Published: September 30, 2014  Show citation