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
Spenerova M.,Palacky University |
Dzubak P.,Palacky University |
Srovnal J.,Palacky University |
Radova L.,Palacky University |
And 12 more authors.
Biomedical Papers | Year: 2014
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. © 2014 PALACKY UNIV. All rights reserved.
Cholujova D.,Slovak Academy of Sciences |
Jakubikova J.,Slovak Academy of Sciences |
Czako B.,University Hospital in Bratislava |
Martisova M.,University Hospital in Bratislava |
And 4 more authors.
Cancer Immunology, Immunotherapy | Year: 2013
Dendritic cells (DCs) and natural killer (NK) cells are central components of innate immunity for controlling tumor growth. The therapeutic effects of certain anti-myeloma drugs are partially mediated by targeting the innate immune response. In addition, novel types of natural compounds have been developed that efficiently modulate the activity of both the cellular and humoral compartments of immunity. MGN-3 is known as an activator of natural killer cells, inducer of apoptosis and cytokine production, and modulator of dendritic cell maturation and differentiation in vitro. We have performed a randomized, placebo-controlled study to examine the effects of MGN-3 on innate immune system parameters in 48 multiple myeloma patients. We performed immunophenotypic analysis of peripheral blood samples, determined NK cell activity, and assessed the cytokine profiles of plasma before and during 3 months of treatment. The results demonstrate a clear increase in NK activity in MGN-3-treated patients compared to the placebo group, an increased level of myeloid DCs in peripheral blood, and augmented concentrations of T helper cell type 1-related cytokines. The present study suggests that MGN-3 may represent an immunologically relevant product for activating innate immunity in multiple myeloma patients and warrants further testing to demonstrate clinical efficacy. © 2012 Springer-Verlag.
Oravcova I.,National Cancer Institute NCI |
Czako B.,University Hospital in Bratislava |
Demeckova E.,University Hospital in Bratislava |
Demitrovicova L.,National Cancer Institute NCI |
And 8 more authors.
Neoplasma | Year: 2010
The results of treatment of acute promyelocytic leukemia, when combination ATRA + chemotherapy is used in induction and maintainance therapy and risk adapted strategy applied in consolidation, improved at present time. Enhanced supportive therapy also contribute to improved outcome of APL patients. 3 - year relapse free, overall survival and clinical and biological presenting features of APL patients were evaluated. Since january 2001 till march 2009 32 patients treated with modified spanish treatment scheme were assesed. After june 2003 risk adapted strategy in protocol therapy according to spanish treatment group with ATRA and anthracyclines in consolidation therapy in high and intermediate risk patients was used. Cytoreduction therapy in patients with initially high leukocyte count was the modification of spanish treatment scheme. 29 (90,6 %) patients achieved complete hematologic remission, 2 (6,3 %) molecular relapses were observed, death was observed in 4 patients (12,5 %). The estimated 3-year OS was 90,6 %; 95 % CI (80,5 % - 100,0 %), and estimated 3- year RFS was 95,5 %; 95 % CI (86,8 % - 100,0 %). Survival results correspond with other published clinical studies. The number of relapses was slightly lower and the incidence of ATRA syndrome (50 %) was higher when compare with the results of other study groups. Current recommendations for treatment with risk-adapted strategy for patients with newly diagnosed acute promyelocytic leukemia resulted in our patients group to comparable outcome and good compliance like in other published studies.