In vitro topo II–DNA complex accumulation and cytotoxicity of etoposide in leukaemic cells from patients with acute myelogenous and chronic lymphocytic leukaemia

2001 ◽  
Vol 25 (2) ◽  
pp. 133-140 ◽  
Author(s):  
Yuying Wang ◽  
Rong Zhou ◽  
Jan Liliemark ◽  
Astrid Gruber ◽  
Synnöve Lindemalm ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
Lymphocytic Leukaemia ◽  
Leukaemic Cells ◽  
Acute Myelogenous ◽  
Topo Ii ◽  
Dna Complex

scholarly journals EZN-2208 treatment suppresses chronic lymphocytic leukaemia by interfering with environmental protection and increases response to fludarabine

Open Biology ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 190262
Author(s):  
Roberta Valsecchi ◽  
Nadia Coltella ◽  
Daniela Magliulo ◽  
Lucia Bongiovanni ◽  
Lydia Scarfò ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Chronic Lymphocytic Leukaemia ◽  
Environmental Protection ◽  
Lymphocytic Leukaemia ◽  
Therapeutic Approaches ◽  
Leukaemic Cells ◽  
Induced Apoptosis ◽  
Early Phases

The transcription factor HIF-1α is overexpressed in chronic lymphocytic leukaemia (CLL), where it promotes leukaemia progression by favouring the interaction of leukaemic cells with protective tissue microenvironments. Here, we tested the hypothesis that a pharmacological compound previously shown to inhibit HIF-1α may act as a chemosensitizer by interrupting protective microenvironmental interactions and exposing CLL cells to fludarabine-induced cytotoxicity. We found that the camptothecin-11 analogue EZN-2208 sensitizes CLL cells to fludarabine-induced apoptosis in cytoprotective in vitro cultures; in vivo EZN-2208 improves fludarabine responses, especially in early phases of leukaemia expansion, and exerts significant anti-leukaemia activity, thus suggesting that this or similar compounds may be considered as effective CLL therapeutic approaches.

The Local Sanarelli-Shwartzman Phenomenon in Rats Induced by Human Leukaemic Cells

1973 ◽  
Vol 29 (02) ◽  
pp. 353-362
Author(s):  
J Lisiewicz ◽  
A Pituch ◽  
J. A Litwin
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
Intravenous Injection ◽  
Peripheral Blood ◽  
Lymphocytic Leukaemia ◽  
Acute Myeloblastic Leukaemia ◽  
Demarcation Line ◽  
E Coli ◽  
Leukaemic Cells ◽  
Shwartzman Phenomenon

SummaryThe local Sanarelli-Shwartzman phenomenon (SSP-L) in the skin of 30 rats was induced by an intr a cutaneous sensitizing injection of leukaemic leucocytes isolated from the peripheral blood of patients with chronic lymphocytic leukaemia (CLL), acute myeloblastic leukaemia (AL) and chronic granulocytic leukaemia (CGL) and challenged by an intravenous injection of 100(μ of E. coli endotoxin. SSP-L was observed in 7 rats after injection of CLL lymphocytes and in 6 and 2 rats after AL myeloblasts and the CGL granulocytes, respectively. The lesions in the skin after AL myeloblasts appeared in a shorter time and were of longer duration compared with those observed after CLL lymphocytes and CGL granulocytes. Histologically, the lesions consisted of areas of destruction in the superficial layers of the skin ; the demarcation line showed the presence of neutrophils, macrophages and erythrocytes. Haemorrhages and fibrin deposits near the demarcation line were larger after injection of CLL lymphocytes and AL myeloblasts than after CGL granulocytes. The possible role of leucocyte procoagulative substances in the differences observed have been discussed.

In vitro differentiation of chronic lymphocytic leukaemia cells with a small pre-B-like phenotype

1983 ◽  
Vol 7 (2) ◽  
pp. 133-138 ◽  
Author(s):  
John Gordon ◽  
Pierre Aman ◽  
Hakan Mellstedt ◽  
Peter Biberfeld ◽  
George Klein
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
Lymphocytic Leukaemia ◽  
In Vitro Differentiation

scholarly journals Topoisomerase II levels and drug sensitivity in adult acute myelogenous leukemia

Blood ◽  
1994 ◽  
Vol 83 (2) ◽  
pp. 517-530 ◽  
Author(s):  
SH Kaufmann ◽  
JE Karp ◽  
RJ Jones ◽  
CB Miller ◽  
E Schneider ◽  
...  
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Topoisomerase Ii ◽  
Drug Sensitivity ◽  
Myelogenous Leukemia ◽  
Clinical Samples ◽  
Immunoperoxidase Staining ◽  
Acute Myelogenous ◽  
Topo Ii

Abstract The topoisomerase (topo) II-directed agents etoposide, daunorubicin (DNR), and amsacrine (m-AMSA) are widely used in the treatment of acute myelogenous leukemia (AML). In the present study, multiple aspects of topo II-mediated drug action were examined in marrows from adult AML patients. Colony-forming assays revealed that the dose of etoposide, DNR, or m-AMSA required to diminish leukemic colony formation by 90% (LD90) varied over a greater than 20-fold range between different pretreatment marrows. Measurement of nuclear DNR accumulation in the absence and presence of quinidine revealed evidence of P-glycoprotein (Pgp) function in 8 of 82 samples at diagnosis and 5 of 36 samples at first relapse, but the largest quinidine-induced increment in DNR accumulation (< 2-fold) was too small to explain the variations in drug sensitivity. Restriction enzyme-based assays and sequencing of partial topo II alpha and topo II beta cDNAs from the most highly resistant specimens failed to demonstrate topo II gene mutations that could account for resistance. Western blotting of marrow samples containing greater than 80% blasts revealed that the content of the two topo II isoenzymes varied over a greater than 20-fold range, but did not correlate with drug sensitivity in vitro or in vivo. In addition, levels of topo II alpha and topo II beta in 46 of 47 clinical samples were lower than in human AML cell lines. Immunoperoxidase staining showed that these low topo II levels were accompanied by marked cell-to- cell heterogeneity, with topo II alpha being abundant in some blasts and diminished or absent from others. There was a trend toward increasing percentages of topo II alpha-positive cells in pretreatment marrows that contained more S-phase cells. Consistent with this observation, treatment of patients with granulocyte-macrophage colony- stimulating factor for 3 days before chemotherapy resulted in increases in topo II alpha-positive cells concomitant with increases in the number of cells traversing the cell cycle. These observations have implications for the regulation of topo II in AML, for the use of topo II-directed chemotherapy, and for future attempts to relate drug sensitivity to topo II levels in clinical material.

scholarly journals UGT2B17 modifies drug response in chronic lymphocytic leukaemia

2020 ◽  
Vol 123 (2) ◽  
pp. 240-251 ◽  
Author(s):  
Eric P. Allain ◽  
Michèle Rouleau ◽  
Katrina Vanura ◽  
Sophie Tremblay ◽  
Joanie Vaillancourt ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
Drug Response ◽  
Lymphocytic Leukaemia ◽  
Term Treatment ◽  
Cell Models ◽  
Short Term Treatment ◽  
Enzymatic Assays ◽  
Respective Treatment ◽  
Leukaemic Cells ◽  
Amp Activated Protein Kinase

Abstract Background High UGT2B17 is associated with poor prognosis in untreated chronic lymphocytic leukaemia (CLL) patients and its expression is induced in non-responders to fludarabine-containing regimens. We examined whether UGT2B17, the predominant lymphoid glucuronosyltransferase, affects leukaemic drug response and is involved in the metabolic inactivation of anti-leukaemic agents. Methods Functional enzymatic assays and patients’ plasma samples were analysed by mass-spectrometry to evaluate drug inactivation by UGT2B17. Cytotoxicity assays and RNA sequencing were used to assess drug response and transcriptome changes associated with high UGT2B17 levels. Results High UGT2B17 in B-cell models led to reduced sensitivity to fludarabine, ibrutinib and idelalisib. UGT2B17 expression in leukaemic cells involved a non-canonical promoter and was induced by short-term treatment with these anti-leukaemics. Glucuronides of both fludarabine and ibrutinib were detected in CLL patients on respective treatment, however UGT2B17 conjugated fludarabine but not ibrutinib. AMP-activated protein kinase emerges as a pathway associated with high UGT2B17 in fludarabine-treated patients and drug-treated cell models. The expression changes linked to UGT2B17 exposed nuclear factor kappa B as a key regulatory hub. Conclusions Data imply that UGT2B17 represents a mechanism altering drug response in CLL through direct inactivation but would also involve additional mechanisms for drugs not inactivated by UGT2B17.

Spontaneous programmed death (apoptosis) of B-chronic lymphocytic leukaemia cells following their culture in vitro

2008 ◽  
Vol 71 (3) ◽  
pp. 343-350 ◽  
Author(s):  
Russell J. Collins ◽  
Louise A. Verschuer ◽  
Brian V. Harmon ◽  
Roger L. Prentice ◽  
John H. Pope ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
Lymphocytic Leukaemia ◽  
Culture In Vitro ◽  
Programmed Death

scholarly journals Isolation from human chronic-lymphocytic-leukaemia cells of membrane glycoproteins associated with Fc-receptor functions. Physical parameters and production of polyclonal antibodies

1987 ◽  
Vol 245 (1) ◽  
pp. 75-83 ◽  
Author(s):  
G Gorini ◽  
G A Medgyesi ◽  
M Garavini ◽  
K J Dorrington ◽  
J Down
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
Gel Electrophoresis ◽  
Lymphocytic Leukaemia ◽  
Polyclonal Antibodies ◽  
Polyacrylamide Gel Electrophoresis ◽  
Fc Receptor ◽  
Polyacrylamide Gel ◽  
Two Dimensional ◽  
Membrane Glycoproteins

Two membrane glycoproteins that bound immune complexes and inhibited Fc-receptor- (FcR-)mediated functions in vitro were purified from human FcR+ chronic-lymphocytic-leukaemia cells. A multi-step purification was developed, consisting essentially in: (i) Tween 40 extraction of crude cell membranes; (ii) solubilization of membrane fragments by Renex-30; (iii) isolation of glycoproteins by affinity chromatography on Lens culinaris haemagglutinin-Sepharose; (iv) papain treatment of the eluted glycoproteins followed by gel-filtration chromatography; (v) purification by polyacrylamide-gel electrophoresis of two molecular species from the protein-size fraction enriched for immune-complex-binding activity. The two electrophoretically isolated components displayed apparent molecular masses of 70 and 45 kDa by SDS/polyacrylamide-gel electrophoresis and restricted charge heterogeneity by two-dimensional analysis. Two-dimensional peptide mapping revealed the presence of many peptides in common between the two proteins and the absence of a number of peptides in the 45 kDa component. These two polypeptides were used as immunogens to produce polyclonal antibodies that cross-reacted with both proteins and specifically inhibited FcR-mediated reactions in vitro. Furthermore, FcR-related components from detergent-extracted lysates of the human K562 and U937 cell lines or human placental membranes were revealed by the putative anti-FcR antibodies adsorbed on Protein A-Sepharose.

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