Ex Vivo Drug Resistance Profile in Childhood Acute Myelogenous Leukemia: No Drug is More Effective in Comparison to Acute Lymphoblastic Leukemia

Styczyński, Jan; Wysocki, Mariusz; Dębski, Robert; Juraszewska, Edyta; Malinowska, Iwona; E, Stańczak; Płoszyńska, A; Stefaniak, Jolanta; Mazur, Benigna; Szczepański, Tomasz

doi:10.1080/1042819021000006394

Cited by 11 publications

(22 citation statements)

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“…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 .…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

Section: Discussionmentioning

confidence: 99%

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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

Spenerova¹,

Džubák²,

Srovnal³

et al. 2014

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Spenerova¹,

Džubák²,

Srovnal³

et al. 2014

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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“…Several studies suggest that the intrinsic resistance in many tumor types, including acute myeloid leukemia (AML), is closely associated with the capacity to undergo robust cell cycle arrest in G 2 /M. [1][2][3] Generally, prolonged cell cycle arrest following DNA damage relies on p53-dependent mechanisms leading to increased expression of cell cycle regulators such as p21 and 14-3-3s. 4,5 However, a subset of tumor cells with nonfunctional p53 is also able to undergo DNA damage-induced G 2 arrest mediated by the DNA damage checkpoint.…”

Section: Introductionmentioning

confidence: 99%

Dual Inhibition of PI3K/Akt Signaling and the DNA Damage Checkpoint in p53-Deficient Cells with Strong Survival Signaling: Implications for Cancer Therapy

Składanowski¹,

Bożko²,

Sabisz³

et al. 2007

Cell Cycle

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ABBreviAtionS ABStrActNatural (intrinsic) resistance of many tumor types to DNA damaging agents is closely associated with their capacity to undergo robust cell cycle arrest in G 2 /M. G 2 arrest is regulated by the DNA damage checkpoint and by survival signaling, with a potential role of PI3K/Akt in checkpoint function. In this work, we wanted to clarify if inhibition of multiple checkpoint/survival pathways may confer better efficacy in the potentiation of genotoxic agents compared to inhibition of either pathway alone. We compared the influence of UCN-01, which affects both the DNA damage checkpoint and PI3K/ Akt-mediated survival signaling, with the PI3K inhibitors wortmannin and LY294002 in p53-deficient M1 acute myeloid leukemia cells treated with the DNA damaging agent cisplatin. Our results show that direct inhibition of PI3K/Akt in G 2 -arrested cells by wortmannin or LY294002 strongly enhanced the cytotoxicity of cisplatin without influencing the G 2 checkpoint. Unexpectedly, dual inhibition of both survival and checkpoint signaling by UCN-01, also increased the cytotoxicity of cisplatin, but to a lesser degree than wortmannin or LY294002. The differences in cytotoxicity were accompanied by differences in cell death pathways: direct inhibition of PI3K/Akt was accompanied by rapid apoptotic cell death during G 2 , whereas cells underwent mitotic transit and cell division followed by cell death during G 1 when both checkpoint and survival signaling were inhibited. Our results elucidate a novel function for PI3K/Akt as a survival factor during DNA damage-induced G 2 arrest and could have important pharmacological consequences for the application of response modulators in p53-deficient tumors with strong survival signaling.

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“…1, P=0.010). However, differences in each drug sensitivity were not significant between clinical responder and nonresponder in both this study and other studies [20].…”

Section: Discussionmentioning

confidence: 45%

“…For AML, high in vitro drug resistance could partially explain unfavorable clinical results of therapy, when compared to ALL [1,20]. One of the reasons for the poor therapeutic outcomes may be cellular drug resistance to chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Relationship between In Vitro Chemosensitivity assessed with MTT Assay and Clinical Outcomes in 103 Patients with Acute Leukemia

et al. 2007

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Background : Cellular drug resistance is supposed to play a major role in chemotherapy failure or relapse. The purpose of this study was to analyze the relationship between in vitro chemosensitivity test results using a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and clinical response on chemotherapy, and to find the possibility of optimizing the treatment protocol for individual patients according to their actual drug resistance.Methods : For MTT assay, we obtained bone marrow aspirates from 103 patients with acute leukemia at the time of initial diagnosis or relapse. The following drugs were tested: cytarabine, vincristine, methotrexate, daunorubicin, dexamethasone, L-asparaginase, and mitoxantrone. To evaluate clinical responses after induction chemotherapy, we followed up on their bone marrow study.Results : In our study, in vitro chemosensitivity test with the MTT assay significantly predicted whether patients with AML remained continuous complete remission or went into relapse. It also predicted whether or not child patients with ALL would acquire complete remission after induction chemotherapy.Conclusions : Although it does not provide the insight into the mechanisms that cause drug resistance, the MTT assay may be a useful tool in individually optimizing the chemotherapy of patients with acute leukemia. (Korean J Lab Med 2007;27:89-95)

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Ex Vivo Drug Resistance Profile in Childhood Acute Myelogenous Leukemia: No Drug is More Effective in Comparison to Acute Lymphoblastic Leukemia

Cited by 11 publications

References 10 publications

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

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

Dual Inhibition of PI3K/Akt Signaling and the DNA Damage Checkpoint in p53-Deficient Cells with Strong Survival Signaling: Implications for Cancer Therapy

Relationship between In Vitro Chemosensitivity assessed with MTT Assay and Clinical Outcomes in 103 Patients with Acute Leukemia

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