Toward personalized therapy for chronic lymphocytic leukemia

Rogalińska, Małgorzata; Franiak-Pietryga, Ida; Błoński, Jerzy Z.; Góralski, Paweł; Maciejewski, Henryk; Janus, Agnieszka; Robak, Paweł; Mirowski, Marek; Piekarski, Henryk; Robak, Tadeusz; Kiliańska, Zofia M.

doi:10.4161/cbt.22623

Cited by 7 publications

(11 citation statements)

References 36 publications

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“…Our results confirmed that DSC technique combined with other approaches could be helpful in the choice of anti-leukemic strategy of CLL patients' therapy to avoid ineffective drug application [22,24].…”

Section: Decrease/lack Of Thermal Transition At 95 ± 5°c Accompanies supporting

confidence: 79%

The differences in thermal profiles between normal and leukemic cells exposed to anticancer drug evaluated by differential scanning calorimetry

Góralski

Rogalińska

Błoński

et al. 2014

J Therm Anal Calorim

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Chronic lymphocytic leukemia (CLL) is a heterogenous disease with an imbalance between apoptosis and cell proliferation. Therefore, the main goal in CLL therapy is to induce apoptosis and effectively support this process in transformed B lymphocytes. In the current study, we have compared differential scanning calorimetry (DSC) profiles of nuclei isolated from CLL cells and normal mononuclear cells exposed to cladribine or fludarabine combined with mafosfamide (CM; FM), and additionally to CM combined with monoclonal antibody-rituximab (RCM) for 48 h, as well as in culture medium only (controls). Under current study, the mononuclear cells from peripheral blood (PBMCs) of healthy individuals have been included. The obtained results have shown the presence of thermal transition at 95 ± 5°C in most of nuclear preparations (92.2 %) isolated from blood of CLL patients. This thermal characteristic parameter was changed after drug exposure, however, to a different extent. These thermal changes were accompanied by the decrease of cell viability, an elevation of apoptosis rate and the changes in expression/proteolysis of poly(ADP-ribose)polymerase-1-main marker of apoptosis. Importantly, in DSC profiles of nuclear preparations of PBMCs from blood of healthy donors exposed to investigated drug combinations and control CLL cells, the lack of such changes was observed. Our results confirmed that DSC technique complemented with other biological approaches could be helpful in tailoring therapy for CLL patients. Keywords Chronic lymphocytic leukemia Á Differential scanning calorimetry Á Anti-leukemic tailored therapy Á Purine analogs Á Mafosfamide Á Rituximab Paweł Góralski and Małgorzata Rogalińska should be considered jointly as the first authors.

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Section: Decrease/lack Of Thermal Transition At 95 ± 5°c Accompanies supporting

confidence: 79%

The differences in thermal profiles between normal and leukemic cells exposed to anticancer drug evaluated by differential scanning calorimetry

Góralski

Rogalińska

Błoński

et al. 2014

J Therm Anal Calorim

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“…Considerable differences in leukemic cell reactivity were observed in cell samples incubated with Rit, with the cells appearing resistant to Rit in the stable form of the disease. Previous studies have reported that in progressive CLL, additional thermal transition occurs at ~95±5°C (15,19,20,26,28,29), which decreases in the case of the apoptotic activity. The presence of a thermal transition at 95°C following CLL incubation with ≥1 of the agents indicates that the leukemic cells in the stable form of the disease are resistant to Rit.…”

Section: Resultsmentioning

confidence: 98%

Personalized therapy tests for the monitoring of chronic lymphocytic leukemia development

et al. 2017

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There is individual variation in the course of disease development and response to therapy of patients with chronic lymphocytic leukemia (CLL). Novel treatment options for CLL include a new generation of purine analogs, antibodies and inhibitors of specific cell signaling pathways, which typically induce apoptosis or necrosis. A prospective analysis of patient blood samples revealed that a combination of four tests allowed the most appropriate and effective type of treatment to be selected prior to drug administration, and for the analysis of leukemic cell sensitivity to anticancer drug(s) during disease development. The comparative analysis of blood from the stable and progressive form of CLL in an individual patient revealed diversity in the response to anticancer agents. CLL peripheral blood mononuclear cells were incubated with cladribine + mafosfamide (CM), fludarabine + mafosfamide, CM + rituximab, rituximab alone (Rit) or kinetin riboside (RK). A combination of cell viability, differential scanning calorimetry (DSC) profiles of nuclear preparations and poly(ADP-ribose) polymerase 1 (PARP-1) protein expression analysis of the leukemic cells was performed to evaluate the anticancer effects of the tested agents during CLL development. The results of the present study indicate that such studies are effective in determining the most appropriate anticancer drug and could monitor disease progression on an individual level. In addition, the results of the current study suggest that CLL progression leads to diversification of the cellular drug response. The most efficient apoptosis inducer for the patient was purine analog RK when the disease was stable, while the CM combination was the most effective agent for the progressive form of disease.

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“…Since the disease could transform into an active form, the coexistence of quiescent and cycling cell populations complicate the diagnostics and prediction of therapy efficacy (5,6). Therefore, an analysis of the chemosensitivity profile of patient cells prior to therapy followed by the use of personalized medicine based on apoptosis induction would markedly reduce the ineffective treatment (8,13–15).…”

Section: Discussionmentioning

confidence: 99%

“…This microRNA is associated with the progression of CLL and weak response to therapy (12). The presence of several factors important for disease development reveals the necessity for the use of personalized medicine, by testing the potential reaction of the patient's cells to anticancer drugs before treatment, to avoid administration of an ineffective regimen (8,13–16). Therefore, it is very important to search for new anticancer agents with the potential to induce apoptosis in CLL cells (17–20).…”

Section: Introductionmentioning

confidence: 99%

Dose and drug changes in chronic lymphocytic leukemia cell response in�vitro: A comparison of standard therapy regimens with two novel cyclin‑dependent kinase inhibitors

et al. 2019

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Chronic lymphocytic leukemia (CLL) treatment is improving; however, some patients do not respond to therapy. Due to the high heterogeneity in disease development, there is an urgent need for personalization of therapy. In the present study, the response of leukemic mononuclear cells to anticancer drugs used for CLL treatment (cladribine + mafosfamide; CM or CM combined with rituximab; RCM) was compared with the response to new cyclin-dependent kinase (CDK) inhibitors: BP14 and BP30. Viable apoptotic and necrotic cells were quantified by flow cytometry using propidium iodide and Yo-Pro stains. CDK inhibitors were studied in several doses to determine the reduction of necrosis and simultaneous increase of apoptosis in leukemic cell incubations with anticancer agents. The distinct cell response to applied doses/anticancer agents was observed. Results obtained in the current manuscript confirmed that modulation of doses is important. This was particularly indicated in results obtained at 24 h of cells incubation with anticancer agent. While an important time for analysis of anticancer response efficacy (monitoring of apoptosis induction potential) seems to be 48 h of cells exposition to anticancer agents. High variability in response to the drugs revealed that both the nature and the dose of the anticancer agents could be important in the final effect of the therapy. The present findings support the thesis that personalized medicine, before drug administration in the clinic, could be important to avoid the application of ineffective therapy.

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Toward personalized therapy for chronic lymphocytic leukemia

Cited by 7 publications

References 36 publications

The differences in thermal profiles between normal and leukemic cells exposed to anticancer drug evaluated by differential scanning calorimetry

The differences in thermal profiles between normal and leukemic cells exposed to anticancer drug evaluated by differential scanning calorimetry

Personalized therapy tests for the monitoring of chronic lymphocytic leukemia development

Dose and drug changes in chronic lymphocytic leukemia cell response in�vitro: A comparison of standard therapy regimens with two novel cyclin‑dependent kinase inhibitors

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