Personalized therapy tests for the monitoring of chronic lymphocytic leukemia development.

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.

In vitro antileukemic activity of novel adenosine derivatives bearing boron cluster modification.

A series of adenosine derivatives bearing a boron cluster were synthesized and evaluated for their cytotoxicity against primary peripheral mononuclear cells from the blood of 17 patients with leukemias (16 CLL and 1 very rare PLL), as well as from 5 healthy donors used as a control. Among the tested agents, two, i.e.

Relationship between in vitro drug sensitivity and clinical response of patients to treatment in chronic lymphocytic leukemia.

To improve the efficacy of therapeutic options in chronic lymphocytic leukemia (CLL) an in vitro system to determine the response of mononuclear blood cells from blood of patients was elaborated. The study combines four approaches, i.e.

In vivo and ex vivo responses of CLL cells to purine analogs combined with alkylating agent.

Background: The heterogeneity of chronic lymphocytic leukemia (CLL) is thought to be due to differences in the expression of factors that regulate apoptosis and cell cycle, giving rise to diverse apoptotic disturbances and tumor properties. Therefore, the primary goal in CLL treatment is to overcome resistance to apoptosis and efficiently trigger this process in leukemic cells.

Methods: Mononuclear cells were obtained from the blood of CLL patients by Histopaque-1077 sedimentation.

Promising anti-leukemic activity of atorvastatin.

There is a current need for novel therapeutic strategies for the treatment of chronic lymphocytic leukemia (CLL), a still incurable hematological cancer involving mainly deregulated apoptosis. The purpose of the present study was to determine ex vivo the effect of the synthetic statin, atorvastatin, a known cholesterol-lowering drug, on peripheral blood mononuclear cells obtained from CLL patients. Using flow cytometry, we investigated the viability and induction of apoptosis in leukemic cells exposed to statin by the Vybrant apoptosis assay kit #4, compared with untreated control cells.

Toward personalized therapy for chronic lymphocytic leukemia: DSC and cDNA microarray assessment of two cases.

The differences in clinical course of chronic lymphocytic leukemia could have an impact on variations in a patient's response to therapy. Our published results revealed that thermal transition (95 ± 5°C) in differential scanning calorimetry profiles appear to be characteristic for the advanced stage of CLL. Moreover, a decrease/loss of this transition in nuclei from leukemic cells exposed to drugs ex vivo could indicate their diverse efficacy.

PUMA, a critical mediator of cell death--one decade on from its discovery.

PUMA (p53 upregulated modulator of apoptosis) is a pro-apoptotic member of the BH3-only subgroup of the Bcl-2 family. It is a key mediator of p53-dependent and p53-independent apoptosis and was identified 10 years ago. The PUMA gene is mapped to the long arm of chromosome 19, a region that is frequently deleted in a large number of human cancers.

Targeting Bcl-2 in CLL.

Chronic lymphocytic leukemia (CLL) is a common adult leukemia in the Western world with an incidence of 4.2/100,000/year. The clinical course of disease is highly heterogenous; it affects people over 65-70 years of age.

Lipoprotein lipase: a new prognostic factor in chronic lymphocytic leukaemia.

The clinical course of patients with chronic lymphocytic leukemia (CLL) is highly heterogeneous. Gene expression analyses have revealed that leukemic cells with unmutated immunoglobulin heavy chain genes (IgV H ) differ from CLL cells with mutated IgV H in the expression level of some genes, i.e.

Can ex vivo evaluation (testing) predict the sensitivity of CLL cells to therapy with purine analogs in conjunction with an alkylating agent? A comparison of in vivo and ex vivo responses to treatment.

Malfunctions in the regulation of apoptosis cause the accumulation of malignant, long-lived B CD19+/CD5+ cells in chronic lymphocytic leukemia (CLL). The primary goal in CLL therapy is to overcome resistance to apoptosis and efficiently trigger programmed cell death in leukemic cells. This study demonstrated that the in vivo responses of malignant cells from CLL patients after administration of purine analogs (cladribine/fludarabine) with cyclophosphamide vary significantly.

Potential new agents for chronic lymphocytic leukemia treatment.

Chronic lymphocytic leukemia (CLL) is the most frequent type of hematological cancer in the Western World. An accumulation of leukemic cells in peripheral blood of patients is a result of apoptosis disturbances as well as an increase in germinal centers CLL cell proliferation. The differences between CLL patients in the course and response to therapy reflects personal variability between patients in their genetic material.

Dietary D-glucarate effects on the biomarkers of inflammation during early post-initiation stages of benzo[a]pyrene-induced lung tumorigenesis in A/J mice.

Previous studies showed that dietary calcium D-glucarate (CG) inhibited benzo[a]pyrene (B[a]P)-induced A/J mouse lung tumorigenesis, suppressing cell proliferation and chronic inflammation and inducing apoptosis during late post-initiation stages. The present study aimed to investigate changes in the homeostasis of cytokines in blood serum, as well as alterations in biomarkers of inflammation and apoptosis in lung tissue caused by dietary CG during early post-initiation stages of B[a]P-induced lung tumorigenesis. Two doses of 3 mg of B[a]P were given intragastrically to A/J mice 2 weeks apart.

[Biological activity of poly(ADP-ribose)polymerase-1].

Poly(ADP-ribose)polymerase-1 (PARP-1) catalyzes the polymerization of ADP-ribose units from NAD+ modules on target proteins, resulting in the attachment of linear or branched polymers. PARP-1 and its product poly(ADP-ribose)--PAR have recently received considerable attention because of their involvement in a wide range of cellular processes including chromatin modification, metabolism of nucleic acids, transcription regulation, and cell death. This review summarizes recent work on modular structure of six functional domains (A-F) of PARP-1 molecule in the context of three classic domains, i.

[Role of heat shock proteins in cell apoptosis].

Apoptosis is, apart from necrosis and autophagy, one of the possible cell death mechanisms eliminating needless, not normal or infected cells. This process ensures quantitative and qualitative cell control of organisms. Apoptosis is tightly regulated, it requires both activation of a large number of genes and energy input.

[The pleiotropic activity of heat-shock proteins].

Stress or heat-shock proteins (HSPs) are highly conserved proteins present in cells of both prokaryotes and eukaryotes, providing them with protection from cellular and environmental stress factors.Based on molecular-weight, HSPs can be divided into the large (HSP100: 100-110 kDa and HSP90: 75-96 kDa), intermediate (HSP70: 66-78 kDa, HSP60, and HSP40), and small (sHSP:8.5-40 kDa) subfamilies.

R-roscovitine (Seliciclib) affects CLL cells more strongly than combinations of fludarabine or cladribine with cyclophosphamide: Inhibition of CDK7 sensitizes leukemic cells to caspase-dependent apoptosis.

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of malignant, apoptosis-resistant B CD19(+)/CD5(+) cells. Populations of CLL cells are heterogeneous and consist primarily of quiescent cells with a minor subset of dividing cells. In this study the efficacy of a first-line in vivo therapy was compared with treatment by R-roscovitine (ROSC) alone or by purine analogues (cladribine and fludarabine) combined with maphosphamide for 14 CLL patients under ex vivo conditions.

Roscovitine triggers apoptosis in B-cell chronic lymphocytic leukemia cells with similar efficiency as combinations of conventional purine analogs with cyclophosphamide.

B-cell chronic lymphocytic leukemia (CLL) is characterized by an accumulation in peripheral blood of many long-lived lymphocytes that do not die because of the deregulation of apoptosis. Most CLL cells are quiescent, and therefore the leukemic lymphocytes are resistant to conventional chemotherapy. The aim of this study was to evaluate in vitro the chemosensitivity of CLL cells to cladribine or fludarabine used alone or in combinations with mafosfamide (Mf; the active form of cyclophosphamide) as well as to roscovitine, a potent inhibitor of cyclin-dependent kinases with proapoptotic potential.

[The biological role of D-glucaric acid and its derivatives: potential use in medicine].

D-glucaric acid is a natural non-toxic compound produced in small amounts by mammals, including humans. In mammals, D-glucaric acid and D-glucaro-l,4-lactone are end-products of the D-glucuronic acid pathway. The enzyme D-glucuronolactone dehydrogenase has been found to be responsible for the oxidation of the lactone of D-glucuronic acid to D-glucaro-l,4;6,3-dilactone.

Calorimetric study as a potential test for choosing treatment of B-cell chronic lymphocytic leukemia.

Differential scanning calorimetry (DSC) and complementary techniques were utilized to evaluate the sensitivity of B-cell chronic lymphocytic leukemia (B-CLL) cell samples in vitro exposed to cladribine or fludarabine in combination with mafosfamide. Mafosfamide, the active in vitro form of cyclophosphamide with both purine analogs produced the cytotoxic effect on mononuclear cell probes, however, to a different degree. Our results indicated that higher sensitivity of examined leukemic cell samples to the used drug combinations was usually accompanied by a marked decrease or even a complete loss of thermal transition at 95+/-3 degrees C in DSC scans of nuclear preparations as well as by more significant reduction of cell viability, higher extent of DNA damage estimated by the comet assay and by dropping/disappearance of anti-apoptotic protein Mcl-1 in comparison with untreated cells.

[New face of antiapoptotic proteins. II. Survivin].

Survivin (mol.wt. 16.

[New face of antiapoptotic proteins. I. Protein Mcl-1].

Main regulators of apoptosis belong to Bcl-2 protein family and apoptosis inhibitory proteins--IAPs. In this review the apoptosis inhibitor--Mcl-1 protein is profoundly characterized. It is important that this unique short-living protein--the member of Bcl-2 family may also operate as apoptosis promoting agent, which results of alternative splicing of its pre-mRNA, posttranslational modifications or proteolysis.

In vitro sensitivity of B-cell chronic lymphocytic leukemia to cladribine and its combinations with mafosfamide and/or mitoxantrone.

We examined in vitro sensitivity of B-CLL cells exposed to cladribine, mafosfamide, mitoxantrone and combinations ofcladribine with mafosfamide and/or mitoxantrone. The results revealed that each applied treatment of leukemic cells, besides having a cytotoxic effect, affected the events associated with apoptosis. All drugs used alone, and cladribine combinations with mafosfamide and/or mitoxantrone induced DNA fragmentation and the changes in expression/proteolysis level of caspase-3, caspase-9 precursors, PARP-1, lamin B, Bax and Bcl-2; however, each to a different degree.

[Mitochondrial intermembrane space proteins in apoptosis process].

Mitochondria, despite their function in cellular energy metabolism, play an important role in the apoptotic signaling pathways. These organelles in response to the death signal undergo changes resulting in the release of proteins which are essential to conduct apoptosis via mitochondrial pathway. This article is focused on the properties and functions of apoptogenic proteins released from the mitochondrial intermembrane space, i.

Changes in leukemic cell nuclei revealed by differential scanning calorimetry.

Using differential scanning calorimetry we analyzed the thermal profiles of nuclei from normal and B-cell chronic lymphocytic leukemia mononuclear cells. Intact nuclear fraction of normal mononuclear cells is characterized by four thermal transitions, i.e.

Proapoptotic activity of alemtuzumab alone and in combination with rituximab or purine nucleoside analogues in chronic lymphocytic leukemia cells.

Proapoptotic activity of anti-CD52 monoclonal antibody, alemtuzumab (ALT) as well as ALT-affected apoptosis-regulatory mechanisms were assessed in tumor cells from 36 patients with chronic lymphocytic leukemia (CLL). Cells were treated in vitro for 24-48 h with ALT alone or in combination with rituximab (RTX), or purine nucleoside analogues (PNA), fludarabine and cladribine. Moreover, eight ALT-treated patients were examined in vivo.