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NCI CANCERLIT® Search: Chronic Lymphocytic Leukemia - April 2002
National Cancer Institute®
Last Modified: April 1, 2002
Table of Contents
1
UI - 11716964
AU - Kozyr AV; Sashchenko LP; Kolesnikov AV; Zelenova NA; Khaidukov SV;
TI -
Ignatova AN; Bobik TV; Gabibov AG; Alekberova ZS; Suchkov SV; Gnuchev NV
Anti-DNA autoantibodies reveal toxicity to tumor cell lines.
SO - Immunol Lett 2002 Jan 1;80(1):41-7
AD - Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian
Academy of Sciences, Miklukho-Maklaya st., 16/10, Moscow, Russia.
Cytotoxicity of anti-DNA autoantibodies from sera of SLE and CLL
patients was assayed on permanent cell lines L929, HL-60, Raji, and
K562. L929 cells appeared to be the most sensitive to antibody
treatment. DNA-hydrolyzing properties of the same autoantibody
preparations were analyzed in parallel. The data obtained outlined the
correlation between cytotoxicity and DNA-hydrolyzing properties of these
autoantibodies. It was shown that treatment of the cells with cytotoxic
anti-DNA autoantibodies induced internucleosomal DNA fragmentation and
Annexin V binding to the cell surface characteristic of apoptotic
pathway of cell death. A time-dependent profile of antibody-mediated
toxicity to L929 cells suggested recruitment of at least two distinct
mechanisms of cell death. The first peak of cell death observed in 3 h
of incubation was completely inhibited by preincubation of cells with
caspase inhibitor YVAD-CHO, while the second increase in cell mortality
(18-30 h) persisted. Possible mechanisms for anti-DNA autoantibody
cytotoxicity are discussed.
2
UI - 11870564
AU - Hallek M
TI -
[What effects has the presence of prolymphocytes on prognosis and
therapy of CLL? ]
SO - Dtsch Med Wochenschr 2002 Mar 1;127(9):464
3
UI - 11760553
AU - O'Brien S
TI -
NCCN: New directions in chronic lymphocytic leukemia.
SO - Cancer Control 2001 Nov-Dec;8(6 Suppl 2):114-7
4
UI - 11896535
AU - Decker T; Schneller F; Hipp S; Miething C; Jahn T; Duyster J; Peschel C
TI -
Cell cycle progression of chronic lymphocytic leukemia cells is
controlled by cyclin D2, cyclin D3, cyclin-dependent kinase (cdk) 4 and
the cdk inhibitor p27.
SO - Leukemia 2002 Mar;16(3):327-34
AD - Third Department of Medicine, Technical University of Munich, Munich,
Germany.
B-CLL cells are arrested in G0/early G1 phase of the cell cycle and are
characterized by a marked hyporesponsiveness towards a variety of
polyclonal B cell activators. We have previously demonstrated that
costimulation with CpG-ODN and IL-2 can overcome this proliferative
defect. Cyclin D3 is the principal D-type cyclin which mediates G1
progression in normal B cells, but in B-CLL cells both cyclin D2 and
cyclin D3, were strongly upregulated upon stimulation. Both cyclins were
associated with cdk4 but not with cdk6, which is the catalytic partner
of D-type cyclins in normal B cells. Moreover, immune complexes
consisting of cyclin D2 and cdk4 or cyclin D3 and cdk4 were both
functional and phosphorylated the RB protein in vitro. The cell cycle
inhibitor p27 plays a pivotal role in cell cycle progression of B
lymphocytes and has been shown to be overexpressed in B-CLL cells. P27
was rapidly downregulated in B-CLL cells even when stimulated with a
non-CpG-ODN or IL-2 alone, while only moderate regulation could be
observed in normal B cells. Taken together, our findings demonstrate
that regulation of early cell cycle progression differs between B-CLL
cells and normal B cells. These findings do not only contribute to the
understanding of B-CLL pathophysiology, but might ultimately lead to the
identification of new therapeutic targets.
5
UI - 11896536
AU - Cioca DP; Kitano K
TI -
Apoptosis induction by hypercross-linking of the surface antigen CD5
with anti-CD5 monoclonal antibodies in B cell chronic lymphocytic
leukemia.
SO - Leukemia 2002 Mar;16(3):335-43
AD - Second Department of Internal Medicine, Shinshu University School of
Medicine, Matsumoto, Nagano, Japan.
We evaluated cells from 24 patients with B cell chronic lymphocytic
leukemia (B-CLL) to determine apoptosis induced by CD5
hypercross-linking. Following the CD5 hypercross-linking with anti-CD5
monoclonal antibodies (MoAbs), we identified 10 patients where CD5
hypercross-linking induced apoptosis (group A) and 14 patients whose
cells were resistant to the anti-CD5 MoAbs (group B). The programmed
cell death pathway of the cells from patient group A was caspase-3 and
poly (ADP-ribose) polymerase (PARP)-dependent, involved a reduction of
the mitochondrial transmembrane potential DeltaPsi and a down-regulation
of the anti-apoptotic Bcl-2, Mcl-1 and iNOS proteins. Early
activation-associated molecules such as CD25 and CD69 were expressed at
higher levels than in controls after 6 h of culture with anti-CD5 MoAb.
The expression of CD5 and of CD72, the ligand for CD5, were
significantly lower in group A compared with group B. Anti-CD20 MoAb had
similar activity with anti-CD5 MoAb and the combination of the two MoAbs
seemed to be additive. In this study, it is suggested that the cells
from some B-CLL patients can be induced into programmed cell death by
CD5 hypercross-linking with anti-CD5 MoAbs.
6
UI - 11801464
AU - Cuneo A; Bigoni R; Rigolin GM; Roberti MG; Bardi A; Cavazzini F; Milani
TI -
R; Minotto C; Tieghi A; Della Porta M; Agostini P; Tammiso E; Negrini M;
Castoldi G
Late appearance of the 11q22.3-23.1 deletion involving the ATM locus in
B-cell chronic lymphocytic leukemia and related disorders.
Clinico-biological significance.
SO - Haematologica 2002 Jan;87(1):44-51
AD - Institute of Hematology, University of Ferrara, via Savonarola 9, 44100
Ferrara, Italy. sse@dns.unife.it
BACKGROUND AND OBJECTIVES: Chromosome 11q22.3-23.1 deletions involving
the ataxia-teleangiectasia mutated (ATM) locus (11q-/ATM+/-) are
detected at diagnosis in 10-20% of cases of B-cell chronic lymphocytic
leukemia (CLL) and are associated with a relatively aggressive disease.
The aim of this study was to ascertain whether 11q-/ATM+/- may appear
late during the course of the disease and to analyze its possible
correlation with disease evolution. DESIGN AND METHODS: Eighty-two
patients with CLL and related disorders, i.e. CLL/PL and prolymphocytic
leukemia (PLL), without 11q- at diagnosis were sequentially ascertained
at 1-2 year intervals by conventional cytogenetic analysis (CCA) and
fluorescence in situ hybridization (FISH), using an ATM-specific probe.
RESULTS: Eight patients acquired a submicroscopic 11q deletion 13-43
months after diagnosis: the diagnosis at presentation was CLL in 3
cases, CLL/PL in 3 cases and PLL in 2 cases. A 13q14 deletion preceded
the development of 11q- in four patients; additional aberrations
included +12 (three cases), 17p13 deletion and 6q21 deletion (one case
each). The acquisition of the 11q deletion was more frequently found in
those patients presenting with CLL/PL and PLL than typical CLL
(p=0.0016) and with splenomegaly (p=0.003). Follow-up data showed that
karyotype evolution (p=0.009) and cytological transformation (p<0.001)
were associated with the acquisition of this cytogenetic lesion. The
variables predicting for a shorter survival in this series included the
11q deletion (p=0.03), along with other classical clinicobiological
parameters (performance status, advanced stage, splenomegaly, elevated
serum beta2 microglobulin and lactate dehydrogenase levels.
INTERPRETATION AND CONCLUSIONS: a) Submicroscopic 11q deletion involving
the ATM locus may, in some instances, represent a secondary change in
CLL, CLL/P and PLL, suggesting that sequential FISH analyses are
necessary to detect this chromosome anomaly in some patients; b) the
acquisition of 11q-/ATM deletion may play a role in determining
cytological transformation and disease progression of CLL and related
disorders.
7
UI - 11849209
AU - Karlsson K; Stromberg M; Liliemark J; Delannoy A; Johnson SA; Porwit A;
TI -
Kimby E; Larfars G; Cristiansen I; Nilsson G; Celsing F; Sundstrom G;
Luthman M; Tidefelt U; Wallvik J; Juliusson G
Oral cladribine for B-cell chronic lymphocytic leukaemia: report of a
phase II trial with a 3-d, 3-weekly schedule in untreated and pretreated
patients, and a long-term follow-up of 126 previously untreated
patients.
SO - Br J Haematol 2002 Mar;116(3):538-48
AD - Department of Haematology, University Hospital, Linkoping, Sweden.
karin.karlsson@lio.se
A phase II study was undertaken to evaluate the efficacy and toxicity of
a new schedule of cladribine administration (10 mg/m2 orally daily for 3
d every 3 weeks) in 107 patients with B-cell chronic lymphocytic
leukaemia (CLL). To minimize toxicity, treatment withdrawal criteria
were defined. The results of the 63 previously untreated patients were
retrospectively compared with 63 from an earlier study using a 5-d
monthly schedule. The compiled data were analysed for prognostic factors
for survival. No significant difference regarding response were seen in
the two cohorts of the 126 previously untreated patients. The complete
response (CR), nodular partial response (nPR) and partial response (PR)
rates were 15%, 21% and 41%. Quality of response had no impact on
survival. The 3- and 5-year overall survival for previously untreated
patients was 73% and 58%, respectively, with a median follow-up of 54
months. Pretreatment haemoglobin <11.0 g/dl and elevated
beta-2-microglobulin had a negative influence on survival. Major
infections occurred in 21% of patients in the 3-d study compared with
35% in the 5-d study. The overall response (OR) and CR rates in the 40
previously treated patients were 34% and 5% respectively. Median overall
survival was 24 months and median progression-free survival for
responding patients was 14 months. Cladribine used as a single agent is
an effective treatment with an acceptable safety profile for pretreated
and untreated B-CLL. The achievement of complete remission was not a
prerequisite for long-term survival.
8
UI - 11849210
AU - Buhl L; Szecsi PB; Gisselo GG; Schafer-Nielsen C
TI -
Surface immunoglobulin on B lymphocytes as a potential target for
specific peptide ligands in chronic lymphocytic leukaemia.
SO - Br J Haematol 2002 Mar;116(3):549-54
AD - Department of Clinical Biochemistry, Roskilde County Hospital, Roskilde,
Denmark.
With the aim of producing unique targets for malignant cells we have
identified peptide ligands for the clonal surface immunoglobulin
isolated from the B cells of a chronic lymphocytic leukaemia (CLL)
patient. The peptides were identified from random-peptide phage-display
libraries. The obtained ligands bound specifically to the surface of the
target lymphocytes as well as to clonal immunoglobulin in lysate from
the same cells. Peptide-based antigen mimotopes may have a future use in
targeted therapy of CLL and other B-cell-derived malignancies displaying
surface immunoglobulin.
9
UI - 11762819
AU - Seymour JF; Grigg AP; Szer J; Fox RM
TI -
Fludarabine and mitoxantrone: effective and well-tolerated salvage
therapy in relapsed indolent lymphoproliferative disorders.
SO - Ann Oncol 2001 Oct;12(10):1455-60
AD - Department of Haematology, The Peter MacCallum Cancer Institute, East
Melbourne, Victoria, Australia. jseymour@petermac.unimelb.edu.au
BACKGROUND: Prior studies of the combination of fludarabine,
mitoxantrone and dexamethasone have yielded high response rates but are
associated with a significant risk of opportunistic infections,
predominantly Pneumocystis Carinii pneumonia (PCP) requiring routine
prophylaxis. PATIENTS AND METHODS: We evaluated the combination of
fludarabine (25 mg/m2/day x 3) and mitoxantrone (10 mg/m2 x 1) without
corticosteroids or PCP prophylaxis in 29 patients with relapsed or
refractory indolent lymphoproliferative disorders; median age 56 years,
62% refractory to preceding chemotherapy. RESULTS: A median of four
cycles was administered without cumulative myelosuppression. Neutropenia
<0.5 x 10(9/)l was seen in 16% of cycles. Infections complicated 10.4%
of cycles. with impaired performance status (> or = ECOG 2) and
increased age ( > 56 years) significant risk factors (P < or = 0.01). No
cases of PCP were encountered. The response rate was 90%, median
remission duration 11.9 months and the median survival 57 months.
Peripheral blood progenitor cell mobilization was attempted in 11
patients and yielded > or = 2 x 10(6) CD34+ cells/kg in only 5 cases
(45%). CONCLUSIONS: High response rates can be attained with fludarabine
and mitoxantrone in combination without corticosteroids, and routine PCP
prophylaxis can safely be omitted. Peripheral blood progenitor
collections are problematic in these heavily pretreated patients.
10
UI - 11920534
AU - DiRaimondo F; Albitar M; Huh Y; O'Brien S; Montillo M; Tedeschi A;
TI -
Kantarjian H; Lerner S; Giustolisi R; Keating M
The clinical and diagnostic relevance of CD23 expression in the chronic
lymphoproliferative disease.
SO - Cancer 2002 Mar 15;94(6):1721-30
AD - Institute of Hematology, University of Catania, Italy.
BACKGROUND: CD23 antigen is a cell surface protein considered important
in the differentiation of chronic lymphocytic leukemia (CLL) from other
lymphoid leukemias. METHODS: To better clarify CD23 role as a diagnostic
tool, the authors retrospectively evaluated clinical and laboratory
features of 372 patients who were referred to M.D. Anderson Cancer
Center with a diagnosis of CLL or B-cell chronic lymphoproliferative
disease. RESULTS: Most of the patients (91%) were CD19+/CD5+. Only 6% of
these CD19+/CD5+ patients were CD23-. Overall, CD23- patients had the
worse prognostic features compared with CD23+ cases, including anemia (P
= 0.03), massive splenomegaly (P = 0.000), high lactate dehydrogenase (P
= 0.007), high beta2-microglobulin (P = 0.006), older age (P = 0.001),
and male gender (P = 0.02). Surface immunoglobulin expression was
moderate/strong in 19 (82%) patients, and FMC-7 was positive in 22 (96%)
patients. None of the 13 patients tested for CD10 expressed the antigen.
Based on morphology, of the CD23, 16 (70%) were diagnosed with mantle
cell leukemia (MCL) was diagnosed in 16 (70%) CD23- patients, 3 (13%)
with splenic marginal-zone leukemia, 3 (13%) with prolymphocytic
leukemia (PLL) or PLL/CLL, and 1 (4%) with CLL. No cyclin D1 protein
expression was noted by Western blot analysis in the one case that
showed typical CLL morphology, and this patient did not require therapy.
On the whole, the survival rate of CD23- patients was significantly
worse than that of patients with CD23+. In contrast, 15 of 32 (49%)
CD19+/CD5- patients were CD23-. CD23 negativity in this group was not
associated with distinct clinical features or outcome. Eleven (73%) of
these patients were classified as having splenic marginal-zone lymphoma
and 4 as having follicular lymphoma. CONCLUSIONS: These data indicate
that CD23 negativity is rare in typical B-cell CLL, and CD23 negativity
in patients with CD19+/CD5+ is suggestive of mantle cell leukemia a more
aggressive disease with poor response to conventional therapy in which
newer chemotherapy regimens such as hyper-CVAD may be more effective.
Copyright 2002 American Cancer Society.
11
UI - 11823048
AU - Briones J; Timmerman JM; Hilbert DM; Levy R
TI -
BLyS and BLyS receptor expression in non-Hodgkin's lymphoma.
SO - Exp Hematol 2002 Feb;30(2):135-41
AD - Division of Oncology, Stanford University Medical Center, Stanford, CA
94305-5151, USA.
OBJECTIVE: B Lymphocyte Stimulator (BLyS) protein and its receptor are
new members of the tumor necrosis factor family, with specific effects
exclusively on B cells. We have studied the tumor cell expression of the
BLyS-Receptor (BLyS-R) and the serum BLyS protein levels in patients
with different types of non-Hodgkin's lymphomas (NHL). METHODS: BLyS-R
expression was assessed by flow cytometry on B cells from 43 NHL
patients and 10 normal donors. BLyS protein serum levels were analyzed
by ELISA. RESULTS: All B cells, tumor and normal, expressed BLyS-R. The
mean fluorescence intensity (MFI +/- SD) of BLyS-R on normal B cells was
25.2 +/- 2.3 arbitrary units, while follicular NHL and chronic
lymphocytic leukemia (CLL) exhibited significantly lower expression of
the BLyS-R (17.7 +/- 3.1; 15.5 +/- 3.9, respectively, p < 0.0001 for
both); other lymphoma subtypes expressed levels comparable to normal B
cells (diffuse large cell, 24.8 +/- 4.3; mantle cell, 20 +/- 4.7;
marginal zone, 20.7 +/- 3.7). BLyS protein serum levels were analyzed in
15 normal donors and 17 patients with follicular NHL. Levels of BLyS
protein were, on average, threefold higher in patients with follicular
lymphoma compared to normal donors (mean +/- SD; 13.4 +/- 5.6 ng/mL vs
4.6 +/- 0.7 ng/mL; p < 0.0001). BLyS protein alone was unable to
stimulate proliferation in cultures of follicular lymphoma B cells or
normal B cells. CONCLUSION: The specificity of the expression of BLyS-R
by B-cell lymphomas opens new opportunities for the treatment of these
cancers by targeting this ligand-receptor pair.
12
UI - 11883499
AU - Feldt K S
TI -
Rethinking advanced directives.
SO - J Gerontol Nurs 2000 Oct;26(10):5
13
UI - 11242795
AU - Kroft SH; Dawson DB; McKenna RW
TI -
Large cell lymphoma transformation of chronic lymphocytic leukemia/small
lymphocytic lymphoma. A flow cytometric analysis of seven cases.
SO - Am J Clin Pathol 2001 Mar;115(3):385-95
AD - Dept of Pathology, University of Texas Southwestern Medical Center, 5323
Harry Hines Blvd, Dallas, TX 75390-9073, USA.
We studied 7 cases of large cell transformation of chronic lymphocytic
leukemia/small lymphocytic lymphoma (CLL/SLL) immunophenotyped by
multiparameter flow cytometry. The 6 women and 1 man ranged in age from
45 to 91 years. All had previous or concurrent evidence of CLL/SLL.
Morphologic features and sites of involvement of the diffuse large
B-cell lymphoma (DLBCL) were heterogeneous; 2 cases had
paraimmunoblastic morphologic features. Six DLBCLs had an
immunophenotype consistent with CLL: CD19+, CD5+, CD23+, and FMC7
negative (3 cases) or very dim (2 cases); 1 case was not studied for
FMC7. CD20 was dim in 3 of these, moderate to bright in 2, and variable
in 1. Surface immunoglobulin was dim in 2 cases and moderate or bright
in 4. Five of 6 expressed CD38. Comparison with the immunophenotypes of
the previous or coexistent CLL/SLL (4 of 6 cases) revealed minor
modulations in antigen expression but no major alterations. The seventh
DLBCL lacked CD5 expression, but otherwise had immunophenotypic features
similar to CLL. These findings indicate that DLBCL arising in CLL/SLL
tends to retain a CLL immunophenotype, in contrast with de novo CD5+
large cell lymphomas that uncommonly express such a phenotype.
14
UI - 11836167
AU - Ganeshaguru K; Wickremasinghe RG; Jones DT; Gordon M; Hart SM; Virchis
TI -
AE; Prentice HG; Hoffbrand AV; Man A; Champain K; Csermak K; Mehta AB
Actions of the selective protein kinase C inhibitor PKC412 on B-chronic
lymphocytic leukemia cells in vitro.
SO - Haematologica 2002 Feb;87(2):167-76
AD - Department of Hematology, Royal Free & University College Medical
School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK.
k.ganeshaguru@rfc.ucl.ac.uk
BACKGROUND AND OBJECTIVES: The staurosporine derivative PKC412
(CGP41251) is a more selective inhibitor of the conventional isoforms of
protein kinase C (PKC) than is the parent compound. In addition to its
growth inhibitory properties, PKC412 reverses the efflux function of the
multidrug resistance (MDR)-1 gene product, P-glycoprotein (P-gp). DESIGN
AND METHODS: The in vitro actions of PKC412 were investigated in
peripheral blood lymphocytes (PBL) from 4 normal volunteers, B-cell
isolates from 3 normal tonsils and 31 patients with B-cell chronic
lymphocytic leukemia (B-CLL). Following incubation with PKC412 for 2
days, the viability of B-CLL cells was decreased relative to that of
controls (63+/-23% at 1 micromole/L; 52+/-30% at 10 micromole/L; n=20).
Normal PBL were significantly more resistant to the drug (91+/-5% viable
cells at 1 micromole/L; 73+/-18% at 10 micromole/L; n=4). Thirteen of
the B-CLL patients were treated with oral PKC412 in a phase II trial.
RESULTS: PKC activity in malignant cells from these patients showed a
reduction post-treatment of 25-96% of their respective pre-treatment
levels. Morphologic analysis, as well as in situ assay for DNA strand
breaks (TUNEL assay) showed that B-CLL cells were killed by an apoptotic
mechanism. In B-CLL cells the mean IC50, for PKC412, as measured by the
reduction of 3-(4,5-dimethylthiozol-2-yl)-2,5-diphenyl tetrazolium
bromide (MTT), was 2.1 micromol/L in 16 samples in which the IC50 were
below the maximum concentration of PKC412 used for the assay. In
tonsillar B-cells, the mean IC50 was 11 micromol/L whereas PBL cells
were resistant. Four of eight and 1/3 B-CLL samples that were resistant
to chlorambucil and fludarabine, respectively, were sensitive to PKC412.
In 15/31 B-CLL samples a dose-dependent reversal of P-gp-mediated drug
efflux by PKC412 was observed. A statistically significant correlation
(p<0.001) was observed between P-gp protein expression as measured by
FACScan analysis and the reversal of efflux activity by either PKC412 or
verapamil. PKC412 increased the sensitivity of B-CLL cells to
2'-chlorodeoxyadenosine and chlorambucil. INTERPRETATION AND
CONCLUSIONS: This study establishes the in vitro cytotoxic and multidrug
resistance (MDR) modulatory properties of PKC412 towards malignant cells
from B-CLL patients. The direct antitumor activity combined with the
potential for P-gp modulation make PKC412 an attractive drug for the
treatment of malignancies expressing the MDR phenotype, or in
combination with conventional drugs.
15
UI - 11836173
AU - Morabito F; Mangiola M; Stelitano C; Deaglio S; Callea V; Malavasi F
TI -
Peripheral blood CD38 expression predicts time to progression in B-cell
chronic lymphocytic leukemia after first-line therapy with high-dose
chlorambucil.
SO - Haematologica 2002 Feb;87(2):217-8
CD38 expression by B-cell chronic lymphocytic leukemia (B-CLL) cells has
been the focus of several recent studies. The aim of this study was to
evaluate the prognostic impact of CD38 expression by peripheral blood
lymphocytes on progression-free survival after first-line therapy with
high-dose chlorambucil in 53 previously untreated patients affected by
typical CD5+ CD23+ B-CLL.
16
UI - 11128117
AU - Basu S; Mitra Basu R
TI -
Theophylline as a therapy for chronic lymphocytic leukemia: a case
report and review of literature.
SO - Haematologia (Budap) 2000;30(3):225-7
AD - Department of Medical Oncology, Chittaranjan National Cancer Institute,
Calcutta, India. cncinst@giasc101.vsnl.net.in
We herein, report that theophylline which can induce apoptosis in
chronic lymphocytic leukemia (CLL) cells both in vitro and in vivo, also
appears to be effective when used clinically to treat an advanced CLL
patient.
17
UI - 11345411
AU - Ural AU
TI -
Combination chemotherapy with theophylline in chronic lymphocytic
leukemia.
SO - Haematologia (Budap) 2001;31(1):85-6
18
UI - 1421405
AU - Kreitman RJ; Chaudhary VK; Kozak RW; FitzGerald DJ; Waldman TA; Pastan I
TI -
Recombinant toxins containing the variable domains of the anti-Tac
monoclonal antibody to the interleukin-2 receptor kill malignant cells
from patients with chronic lymphocytic leukemia.
SO - Blood 1992 Nov 1;80(9):2344-52
AD - Laboratory of Molecular Biology, National Cancer Institute, National
Institutes of Health, Bethesda, MD 20892.
We have previously shown that the variable domains of the monoclonal
antibody anti-Tac [anti-Tac(Fv)] can be fused to derivatives of
Pseudomonas exotoxin (PE) or diphtheria toxin (DT) to produce
recombinant immunotoxins that kill interleukin-2 (IL-2) receptor-bearing
cells. We now report that two of these single-chain recombinant
immunotoxins, anti-Tac(Fv)-PE40KDEL and DT388-anti-Tac(Fv), are
cytotoxic toward peripheral blood mononuclear cells (PBMCs) from
patients with chronic lymphocytic leukemia (CLL). In
anti-Tac(Fv)-PE40KDEL, anti-Tac(Fv) is genetically fused to the amino
terminus of PE40KDEL, a recombinant form of PE which contains amino
acids 253-608 of PE and the -KDEL mutation at the carboxyl terminus. In
DT388-anti-Tac(Fv), anti-Tac(Fv) is fused to the carboxyl terminus of
the first 388 amino acids of DT. PBMCs from 14 patients were incubated
with the recombinant toxins for 60 hours, and [3H]-leucine incorporation
was measured. Anti-Tac(Fv)-PE40KDEL was cytotoxic to 7 of the 14 patient
samples, with half-maximal inhibition of protein synthesis (IC50)
achieved at 1.2 to 9 ng/mL (1.8 to 13 x 10(-11) mol/L).
DT388-anti-Tac(Fv) was cytotoxic to 11 of the 14 samples, with IC50s
ranging from less than 1 to 250 ng/mL. DT388-IL-2, in which the first
388 amino acids of DT are attached to IL-2, was marginally cytotoxic
toward only 4 of 13 CLL samples tested with IC50s ranging from 100 to
550 ng/mL. Trypan blue staining of cells from several patients indicated
that inhibition of protein synthesis correlated with cell death. Binding
assays using [3H]-anti-Tac indicated that the CLL cells from nine of the
patients contained between 400 and 2,500 sites per cell. Cells from
another patient, which were resistant to both anti-Tac(Fv)-PE40KDEL and
DT388-anti-Tac(Fv), had less than 100 sites per cell. We conclude that
anti-Tac(Fv)-PE40KDEL and DT388-anti-Tac(Fv) can kill CLL cells which
have low numbers of IL-2 receptors, and should be investigated further
for therapy of this disease.
19
UI - 9393878
AU - Muller C; Salles B
TI -
Regulation of DNA-dependent protein kinase activity in leukemic cells.
SO - Oncogene 1997 Nov 6;15(19):2343-8
AD - Service d'hematologie, CHU Purpan, Toulouse, France.
The DNA-dependent protein kinase (DNA-PK) complex is composed of a
catalytic (DNA-PKcs), and a regulatory subunit (Ku70/Ku86 heterodimer).
The expression and function of DNA-PK subunits was investigated in
purified blood lymphocytes obtained from patients with chronic
lymphocytic leukemia (CLL) either refractory to chemotherapy or
untreated. Variations in DNA-PK activity were found amongst CLL samples
by comparison to human cell lines. It was noticeable that the low DNA-PK
activity was associated with samples from untreated patients that
exhibited a sensitivity phenotype, determined in vitro, to the
radiomimetic agent neocarcinostatin by comparison to samples from
refractory patients. The regulation in DNA-PK activity was associated
with Ku heterodimer expression while DNA-PKcs was unaffected. Moreover,
the presence of an altered form of the Ku86 subunit was identified in
samples with low DNA-PK activity. These results suggest a regulation
process of the DNA-PK activity in fresh human cells.
20
UI - 9581813
AU - Christodoulopoulos G; Muller C; Salles B; Kazmi R; Panasci L
TI -
Potentiation of chlorambucil cytotoxicity in B-cell chronic lymphocytic
leukemia by inhibition of DNA-dependent protein kinase activity using
wortmannin.
SO - Cancer Res 1998 May 1;58(9):1789-92
AD - Lady Davis Institute for Medical Research, The Sir Mortimer B. Davis
Jewish General Hospital, Montreal, Quebec, Canada.
gchris1@po-box.mcgill.ca
In this study, we examined the ability of wortmannin to modulate
chlorambucil (CLB) cytotoxicity in lymphocyte samples from patients with
B-cell chronic lymphocytic leukemia (B-CLL). It has been suggested
previously that enhanced cross-link repair is a primary mechanism of
resistance to nitrogen mustards (NMs) in B-CLL. DNA-dependent protein
kinase (DNA-PK) is involved in the repair of double-strand breaks and in
rejoining steps in recombination mechanisms. Mutants defective in this
process are hypersensitive to alkylating agents. We have recently
demonstrated that the activity of DNA-PK is a determinant in the
cellular response of B-CLL to CLB. The DNA-PK gene has homology to the
P110 phosphatidylinositol 3-kinase (PI 3-K). Wortmannin, an inhibitor of
P110 PI 3-K, also inhibits DNA-PK activity in vitro. We investigated the
effect of wortmannin on DNA-PK activity and CLB toxicity in the
lymphocytes from 11 patients with B-CLL. Our results demonstrate that
DNA-PK activity is decreased after exposure to wortmannin in a
dose-dependent manner. Wortmannin, at nontoxic concentrations,
synergistically sensitized B-CLL lymphocytes to the effects of CLB.
Moreover, we observed a significant correlation when we compared the
fold decrease in DNA-PK activity and the synergistic value (I), obtained
when wortmannin was used at 0.1 microM. In the resistant B-CLL
lymphocyte samples, there was a highly significant correlation between
the ability of wortmannin at 0.1 and 0.25 microM to decrease the level
of DNA-PK activity and to increase CLB sensitivity. In a model of
primary human tumor cells, our findings suggest that the inhibition of
DNA-PK activity may be a powerful way to overcome resistance to NMs such
as CLB and point to new possibilities to improve the effectiveness of NM
therapy.
21
UI - 9746757
AU - Muller C; Christodoulopoulos G; Salles B; Panasci L
TI -
DNA-Dependent protein kinase activity correlates with clinical and in
vitro sensitivity of chronic lymphocytic leukemia lymphocytes to
nitrogen mustards.
SO - Blood 1998 Oct 1;92(7):2213-9
AD - Institut de Pharmacologie et de Biologie Structurale (CNRS UPR 9062),
Toulouse, France.
The objective of this study is to investigate the role of DNA-dependent
protein kinase (DNA-PK) in the chronic lymphocytic leukemia (CLL)
lymphocyte response to nitrogen mustard therapy. DNA-PK is a nuclear
serine/threonine kinase that functions in DNA double-strand break repair
and in the joining process in recombination mechanisms. In a series of
34 patients with B-CLL, either untreated (n = 16) or resistant to
chlorambucil (n = 18), the kinase activity of the complex, as determined
by its capacity to phosphorylate a peptide substrate in vitro, is
increased in the resistant samples as compared with the untreated ones
(24.4 +/- 2.6 arbitrary units [a.u.] [range, 12.7 to 55.8 a.u.] versus
8.1 +/- 2.8 a.u. [range, 0.9 to 44.5 a.u.], respectively (P < .0001]),
independent of other clinical and biological factors. Linear regression
analysis shows an excellent correlation between the level of DNA-PK
activity and the inherent in vitro sensitivity of CLL lymphocytes to
chlorambucil (r = .875, P =.0001). The regulation of DNA-PK activity was
associated with increased DNA-binding activity of its regulatory
subunit, the Ku heterodimer, in resistant samples. These results suggest
that this activity is a determinant in the cellular response to
chlorambucil and participates in the development of nitrogen
mustard-resistant disease. The increase in DNA-PK activity might
contribute to the enhanced cross-link repair that we previously
postulated to be a primary mechanism of resistance to nitrogen mustards
in CLL.
22
UI - 11187908
AU - Ali AS; Chopra R; Robertson J; Testa NG
TI -
Detection of hTERT protein by flow cytometry.
SO - Leukemia 2000 Dec;14(12):2176-81
AD - Department of Experimental Haematology, Paterson Institute for Cancer
Research, Manchester, UK.
Telomerase is a telomere-specific DNA polymerase consisting of protein
and RNA components, which is activated in germline cells and the
majority of cancers and serves to counter the consequences of telomere
shortening. The protein component, hTERT, is believed to be the
catalytic subunit of human telomerase and its expression at the mRNA
level correlates well with telomerase activity in vitro. Current
techniques for assaying telomerase activity detect only the mean
activity in a sample and are unable to isolate specific cell
sub-populations. This report describes the development and validation of
a cellular, immunofluorescence-based flow cytometry assay that allows
detection of intranuclear hTERT while maintaining identifiable cell
population characteristics. The assay was shown to be both sensitive to
changes in telomerase expression and was semi-quantitative. In both cell
line differentiation experiments and in primary cells, a good
correlation existed between hTERT expression measured by flow cytometry
and telomerase activity detected by the telomeric repeat amplification
protocol (TRAP). The method developed offers a quick, simple and
reproducible cellular-based assay for hTERT expression. This assay will
provide a useful, new tool for future investigations, facilitating the
analysis of hTERT expression in mixed cell populations.
23
UI - 11552986
AU - Wickremasinghe RG; Ganeshaguru K; Jones DT; Lindsay C; Spanswick VJ;
TI -
Hartley JA; Wadhwa M; Thorpe R; Hoffbrand AV; Prentice HG; Mehta AB
Autologous plasma activates Akt/protein kinase B and enhances basal
survival and resistance to DNA damage-induced apoptosis in B-chronic
lymphocytic leukaemia cells.
SO - Br J Haematol 2001 Sep;114(3):608-15
AD - Department of Haematology, Royal Free and University College School of
Medicine, London, UK. r.wickremasinghe@rfc.ucl.ac.uk
We have studied the actions of autologous plasma on both basal and DNA
damage-induced apoptosis in B-chronic lymphocytic leukaemia (B-CLL)
cells. Apoptosis was quantified using morphological criteria and Western
blot analysis for the apoptosis-specific p85 fragment of poly(ADP
ribose) polymerase. Cell viability was estimated using the methyl
thiazol tetrazolium bromide dye reduction assay. Plasma cultures showed
lower rates of basal apoptosis as well as a decreased cytotoxic response
to chlorambucil and gamma-radiation compared with cultures in fetal calf
serum. Experiments using neutralizing antibodies suggested that the
protective actions of plasma could not be accounted for by interleukin
4, the interferons alpha or gamma or stromal cell-derived factor 1, each
of which have been shown to protect B-CLL cells from apoptosis in vitro.
Plasma addition to B-CLL cells resulted in rapid activation of the Akt
protein kinase, a key signalling enzyme that has been implicated in
anti-apoptotic signalling. LY294002, an inhibitor of
phosphatidylinositol 3'-kinase, blocked Akt activation by plasma. To the
best of our knowledge, this is the first report to show that factors
present in plasma promote basal survival of B-CLL cells and resistance
to cytotoxic drugs via stimulation of the Akt cytoprotective-signalling
pathway. Pharmacological blockade of this pathway may have potential in
the development of novel therapeutic strategies for B-CLL treatment.
24
UI - 11891815
AU - Chemnitz J; Draube A; Diehl V; Wolf J
TI -
Successful treatment of steroid and cyclophosphamide-resistant hemolysis
in chronic lymphocytic leukemia with rituximab.
SO - Am J Hematol 2002 Mar;69(3):232-3
25
UI - 11910823
AU - Harsch IA
TI -
[The basic disease had already been diagnosed. Abdominal pain increased]
SO - MMW Fortschr Med 2002 Feb 21;144(8):42-4
AD - Medizinische Klinik I mit Poliklinik der Universitat Erlangen-Nurnberg,
Krankenhausstrasse 12, D-91054 Erlangen.
26
UI - 11886380
AU - Consoli U; Santonocito A; Stagno F; Fiumara P; Privitera A; Parisi G;
TI -
Giustolisi GM; Pavone B; Palumbo GA; Di Raimondo F; Milone G; Guglielmo
P; Giustolisi R
Multidrug resistance mechanisms in chronic lymphocytic leukaemia.
SO - Br J Haematol 2002 Mar;116(4):774-80
AD - Division of Haematology with Bone Marrow Transplantation, University of
Catania, Italy. ugo.consoli@tin.it
We evaluated the presence of P-glycoprotein (P-gp)-170, multidrug
resistance protein (MRP), lung resistance protein (LRP)-56 and Bcl-2 in
CD19-positive cells from 100 cases of chronic lymphocytic leukaemia
(CLL). P-gp-170 was found in 73% of the CLL cases with no significant
difference regarding stage or previous treatment. LRP-56 protein was
homogeneously distributed with no differences for stage or treatment.
MRP protein was detected at a low level of expression in 49.4% of CLL
patients with no differences for stage or treatment. Bcl-2 protein was
expressed at a high level in all CLL patients and higher levels were
found in the advanced stage. This leads us to conclude that P-gp, MRP,
LRP-56 and Bcl-2 are frequently expressed in CLL. P-gp, MRP and LRP are
not correlated to stage or previous treatment. Bcl-2 is higher in
advanced-stage patients. The clinical and biological significance of
these zMDR mechanisms in CLL remains to be fully explained.
27
UI - 11886381
AU - Summerfield GP; Taylor PR; Mounter PJ; Proctor SJ
TI -
High-dose chlorambucil for the treatment of chronic lymphocytic
leukaemia and low-grade non-Hodgkin's lymphoma.
SO - Br J Haematol 2002 Mar;116(4):781-6
AD - Queen Elizabeth Hospital, Gateshead, University of Newcastle upon Tyne,
Newcastle upon Tyne, UK.
geoffrey.summerfield@exchange.gatesh-tr.northy.nhs.uk
Chlorambucil has been used for many years for the treatment of low-grade
B-cell lymphoproliferative disorders, including chronic lymphocytic
leukaemia and low-grade non-Hodgkin's lymphoma. There is evidence in the
literature that increasing the dose of chlorambucil produces better
results than 'standard' doses in terms of response rates and overall
survival. There is also evidence that this approach may be at least as
effective as the use of fludarabine, as well as being very much less
expensive. We describe a high-dose chlorambucil (HDC) regimen, which
involves a sustained but intermittent dose of chlorambucil, i.e. 30 mg/d
for 4 d per week for 4 weeks, followed by a further four courses at
fortnightly intervals for 8 weeks (a total of eight 4-d courses) given
as a single drug over an initial 12-week period. The outcome of
treatment in previously treated and untreated patients was excellent,
with a median time to treatment failure of 33 months for the patient
cohort overall and for previously treated and chemotherapy-naive
patients of 13 and 104 months respectively. In patients previously
treated with fludarabine, 78% had a response. Autoimmune haemolytic
anaemia was reversed in one patient. Toxicity, both haematological and
other, was minimal. We propose that escalated-dose chlorambucil regimens
should be compared with fludarabine in randomized controlled trials,
rather than 'standard' lower dose protocols.
28
UI - 11830481
AU - Pedersen IM; Buhl AM; Klausen P; Geisler CH; Jurlander J
TI -
The chimeric anti-CD20 antibody rituximab induces apoptosis in B-cell
chronic lymphocytic leukemia cells through a p38 mitogen activated
protein-kinase-dependent mechanism.
SO - Blood 2002 Feb 15;99(4):1314-9
AD - Leukemia Laboratory, Department of Hematology, The Finsen Centre,
Rigshospitalet, Copenhagen, Denmark.
Antibodies against CD20 can activate complement and induce
antibody-dependent cellular cytotoxicity (ADCC) in B lymphocytes. In
B-cell lines, such antibodies also induce apoptosis. In this study, the
expression and function of CD20 on B-cell chronic lymphocytic leukemia
(B-CLL) cells were analyzed. Flow cytometric analysis demonstrated that
B-CLL cells express CD20 with a fluorescence intensity that is
significantly weaker than that of normal CD5(+) and CD5(-) B cells and
that of malignant CD5(-) low-grade non-Hodgkin lymphoma cells. A small
population of cells from healthy donors that have an expression pattern
of CD5 and CD20 identical to that of B-CLL cells were identified, and
this population was confirmed to be of T lineage, not B lineage. Culture
of freshly isolated B-CLL cells in the presence of the chimeric
anti-CD20 antibody rituximab and a cross-linking F(ab)(2) fragment,
resulted in dose- and time-dependent induction of apoptosis. The
induction of apoptosis occurred under conditions in which the influence
of complement activation and ADCC was negligible. Cross-linking of
rituximab induced strong and sustained phosphorylation of the 3 mitogen
activated protein (MAP) kinases c-Jun NH2-terminal protein kinase,
extracellular signal-regulated kinase, and p38. Introduction of the p38
inhibitor SB203580 into the system completely blocked signaling
downstream of p38, as evidenced by the absence of MAPKAP K2 activity,
and significantly reduced the degree of anti-CD20-induced apoptosis.
These results demonstrate that cross-linking of rituximab bound to CD20
on freshly isolated B-CLL cells induces apoptosis through a signaling
pathway that is dependent on p38 MAP-kinase activation.
29
UI - 11830482
AU - Decker T; Hipp S; Kreitman RJ; Pastan I; Peschel C; Licht T
TI -
Sensitization of B-cell chronic lymphocytic leukemia cells to
recombinant immunotoxin by immunostimulatory phosphorothioate
oligodeoxynucleotides.
SO - Blood 2002 Feb 15;99(4):1320-6
AD - 3rd Department of Medicine, Technical University of Munich, Munich,
Germany. t.decker@lrz.tum.de
A recombinant anti-CD25 immunotoxin, LMB-2, has shown clinical efficacy
in hairy cell leukemia and T-cell neoplasms. Its activity in B-cell
chronic lymphocytic leukemia (B-CLL) is inferior but might be improved
if B-CLL cells expressed higher numbers of CD25 binding sites. It was
recently reported that DSP30, a phosphorothioate
CpG-oligodeoxynucleotide (CpG-ODN) induces immunogenicity of B-CLL cells
by up-regulation of CD25 and other antigens. The present study
investigated the antitumor activity of LMB-2 in the presence of DSP30.
To this end, B-CLL cells from peripheral blood of patients were isolated
immunomagnetically to more than 98% purity. Incubation with DSP30 for 48
hours augmented CD25 expression in 14 of 15 B-CLL samples, as assessed
by flow cytometry. DSP30 increased LMB-2 cytotoxicity dose dependently
whereas a control ODN with no CpG motif did not. LMB-2 displayed no
antitumor cell activity in the absence of CpG-ODN as determined
colorimetrically with an
(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfopheny
l)-2H-tetrazolium, inner salt (MTS) assay. In contrast, B-CLL growth was
inhibited in 12 of 13 samples with 50% inhibition concentrations
(IC(50)) in the range of LMB-2 plasma levels achieved in clinical
studies. Two samples were not evaluable because of spontaneous B-CLL
cell death in the presence of DSP30. Control experiments with an
immunotoxin that does not recognize hematopoietic cells, and an
anti-CD22 immunotoxin, confirmed that sensitization to LMB-2 was
specifically due to up-regulation of CD25. LMB-2 was much less toxic to
normal B and T lymphocytes compared with B-CLL cells. In summary,
immunostimulatory CpG-ODNs efficiently sensitize B-CLL cells to a
recombinant immunotoxin by modulation of its target. This new treatment
strategy deserves further attention.
30
UI - 11111455
AU - Goldman D
TI -
Chronic lymphocytic leukemia and its impact on the immune system.
SO - Clin J Oncol Nurs 2000 Sep-Oct;4(5):233-4, 236
AD - Cancer Institute of New Jersey, New Brunswick, USA.
Myelosuppression and immunosuppression are terms that often are used
interchangeably, yet they have very different meanings.
Myelosuppression, which is caused by many types of cancer treatments
(e.g., chemotherapy, radiation therapy), occurs when the body's
population of blood cells is lowered. In contrast, immunosuppression
occurs when the body's immune function is compromised. Diseases of
either the B or T lymphocytes (e.g., lymphoma, multiple myeloma, CLL)
alter the normal functioning of the lymphocytes, rendering them unable
to mount an immune response. With CLL, B lymphocytes are unable to
mature into immunoglobulin-producing plasma cells (delGiglio et al.,
1993). Multiple myeloma occurs when the plasma cells become malignant
(Mansen et al., 1997). Knowledge of the basic principles of immunology
assists nurses in understanding the complexities of the immune system
and the effects of common cancer treatments. Patients with CLL require
astute assessment of infectious symptoms, comprehensive nursing care and
symptom management, and education about the disease and its effects.
Hays and McCartney (1998) also noted that the challenges of caring for
patients with CLL include patient management in the outpatient setting,
quality-of-life issues, and ongoing support because of the chronicity of
the disease.
31
UI - 11943260
AU - Wiley JS; Dao-Ung LP; Gu BJ; Sluyter R; Shemon AN; Li C; Taper J; Gallo
TI -
J; Manoharan A
A loss-of-function polymorphic mutation in the cytolytic P2X7 receptor
gene and chronic lymphocytic leukaemia: a molecular study.
SO - Lancet 2002 Mar 30;359(9312):1114-9
AD - Sydney University Department of Medicine, Nepean Hospital, PO Box 63,
New South Wales, 2751, Penrith, Australia. wileyj@medicine.usyd.edu.au
BACKGROUND: Chronic lymphocytic leukaemia (CLL) has a familial incidence
nearly three times higher than expected for the general population and
one predisposing factor might be an inherited failure of mechanisms
involved in apoptosis of lymphocytes. Our aim was to ascertain whether
or not a defect in a proapoptotic pathway, caused by a single nucleotide
polymorphism that results in loss-of-function of P2X7 in healthy
individuals, was present in leukaemic B lymphocytes of patients with
CLL. METHODS: We extracted genomic DNA from the peripheral blood
leucocytes of 36 unrelated individuals with CLL, four individuals with
familial CLL, and 46 age-matched controls. We sequenced a PCR product to
detect mutations in exon 13 of P2X7. In most patients with CLL, we
measured expression and function of the P2X7 receptor by flow cytometry
in B lymphocytes and T lymphocytes. FINDINGS: The prevalence of the
polymorphic mutation and the frequency of the mutant allele were
three-fold greater in individuals with CLL than in white, elderly
controls. Individuals homozygous for the polymorphic allele had no P2X7
receptor function and heterozygotes had half the mean function of that
seen in individuals homozygous for the wildtype allele; amounts of
ATP-induced apoptosis varied accordingly. In two families, in which we
studied a father-son pair and a sister-sister pair with CLL, loss of
P2X7 function arose because of inheritance of one or two 1513A-->C
alleles for P2X7. INTERPRETATION: Activation of the P2X7 receptor leads
to apoptosis of lymphocytes in individuals with CLL, and reduced
function of this receptor has an anti-apoptotic effect, resulting in an
increase in B-cell numbers. Thus, inheritance of a loss-of-function
polymorphic mutation at position 1513 in the P2X7 gene could contribute
to the pathogenesis of CLL.
32
UI - 11932906
AU - Perkins JG; Flynn JM; Howard RS; Byrd JC
TI -
Frequency and type of serious infections in fludarabine-refractory
B-cell chronic l
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