Differentiating effect of thalidomide and GM-CSF combination on HL-60 acute promyelocytic leukemia cells
Aim: To investigate whether granulocyte-macrophage colony-stimulating factor (GM-CSF) with or without thalidomide can induce apoptosis and differentiation of HL-60 acute promyelocytic leukemia cell line in vitro. Methods: Effect of GM-CSF and thalidomide on proliferation of HL-60 cells was evaluated...
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| Date: | 2006 |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
2006
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| Cite this: | Differentiating effect of thalidomide and GM-CSF combination on HL-60 acute promyelocytic leukemia cells / A.U. Ural, F. Avcu, M. Zerman, M.I. Yilmaz, A. Pekel, M. Beyzadeoglu // Experimental Oncology. — 2006. — Т. 28, № 3. — С. 216-219. — Бібліогр.: 16 назв. — англ. |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine| _version_ | 1859797475949281280 |
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| author | Ural, A.U. Avcu, F. Zerman, M. Yilmaz, M.I. Pekel, A. Beyzadeoglu, M. |
| author_facet | Ural, A.U. Avcu, F. Zerman, M. Yilmaz, M.I. Pekel, A. Beyzadeoglu, M. |
| citation_txt | Differentiating effect of thalidomide and GM-CSF combination on HL-60 acute promyelocytic leukemia cells / A.U. Ural, F. Avcu, M. Zerman, M.I. Yilmaz, A. Pekel, M. Beyzadeoglu // Experimental Oncology. — 2006. — Т. 28, № 3. — С. 216-219. — Бібліогр.: 16 назв. — англ. |
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| container_title | Experimental Oncology |
| description | Aim: To investigate whether granulocyte-macrophage colony-stimulating factor (GM-CSF) with or without thalidomide can induce apoptosis and differentiation of HL-60 acute promyelocytic leukemia cell line in vitro. Methods: Effect of GM-CSF and thalidomide on proliferation of HL-60 cells was evaluated by MTT assay, cell cycle analysis was performed by propidium iodide staining approach and flow cytometry, and apoptosis rate was analyzed using FITC-conjugated annexin-V and FACScan flow cytometry. Results: The study revealed that thalidomide alone at high concentrations inhibited HL-60 cell growth and induced apoptosis. Three days treatment of low-dose thalidomide in combination with GM-CSF induced marked terminal differentiation of HL-60 cells, as it was assessed by increased expression of differentiation antigens on cell surface. Conclusion: Treatment of HL-60 cells by low concentration of thalidomide combined with GM-CSF induced terminal differentiation of HL60 cells in vitro, which may be advantageous for the elaboration of novel therapeutic regimens in patients with differentiation-inducible leukemias.
Цель: изучить эффект гранулоцитарно-макрофагального колониестимулирующего фактора (ГМ-КСФ) в сочетании
с талидомидом на индукцию апоптоза и дифференцировку клеток острого промиелоцитарного лейкоза линии HL-60
in vitro. Методы: для оценки пролиферации и жизнеспособности клеток HL-60 применяли MTT анализ, для изучения
клеточного цикла — окраску пропидиум бромидом и проточную цитометрию. Для оценки апоптоза клетки линии HL-60
обрабатывали талидомидом, ГМ-КСФ, и совместно талидомидом и ГМ-КСФ в течении 48 ч, и затем метили анексином,
конъюгированным с FITC, и анализировали с помощью проточной цитометрии. Результаты: талидомид в высоких
концентрациях ингибирует пролиферацию клеток HL-60 и вызывает апоптоз. В сочетании с ГМ-КСФ в течение 3 дней
талидомид в низкой концентрации индуцировал терминальную дифференцировку клеток HL-60, о чем свидетельствовало
появление экспрессии дифференцировочных антигенов на поверхности клеток. Выводы: применение талидомида в низкой
концентрации в сочетании с ГМ-КСФ вызывает терминальную дифференцировку клеток HL-60.
|
| first_indexed | 2025-12-02T14:18:31Z |
| format | Article |
| fulltext |
216 Experimental Oncology 28, 216–219, 2006 (September)
Induction chemotherapy with standard cytotoxic
chemotherapeutic agents produces complete remis‑
sion in the majority of the patients with acute myelo‑
geneous leukemia (AML). Unfortunately, most of these
patients relapse and eventually die from the disease.
Efforts to increase the overall and disease‑free sur‑
vival rates in AML are focused on improving the effi‑
cacy of post remission consolidation by administering
dose‑intensified cytotoxic chemotherapeutic agents
alone or combined with autologous or allogeneic stem
cell support [6].
Besides the antiangiogenic and immunomodula‑
tory effects of thalidomide, it acts directly by inducing
apoptosis or cell cycle block at G1 phase, in multiple
myeloma (MM) cell lines and in MM cells that are re‑
sistant to melphalan, doxorubicin, and dexamethasone
[5]. Furthermore, thalidomide has been reported to
have antitumor activity via induction of apoptosis in
AML cells [12], whereas single agent thalidomide has
not been regarded as an optimal choice of therapy for
salvaging patients with poor prognosis or refractory
AML in clinical studies [14].
Early studies have shown that most AML blasts
express cytokine receptors for myeloid growth factors.
Moreover, granulocyte‑macrophage colony‑stimula‑
ting factor (GM‑CSF), interleukin 3, and granulocyte
colony‑stimulating factor (G‑CSF) increase colony
formation and induce proliferation in up to 80% of
primary AML blasts. In addition, signals that stimulate
cell cycle progression (e. g. c‑myc) inhibit differentia‑
tion, while many agents with differentiating activity are
cytostatic [10]. Thus, inhibition of cell cycling may be a
permissive or inductive requirement for differentiation.
Matsui et al. [8] have demonstrated that combination
of clinical applicable cell cycle inhibitors (e. g. phenyl‑
butyrate, hydroxyurea and bryostatin‑1) with growth
factors induces terminal favorable differentiation of
treatment‑resistant myeloid leukemias.
To further investigate the antileukemic and dif‑
ferentiation potential of thalidomide, we studied its
differentiating and proapoptotic effects in vitro toward
HL‑60 cells alone or in combination with GM‑CSF.
materials and methods
Cell line. The human acute myelogeneous leukemia
HL‑60 cell line was kindly provided by the Department
of Molecular Pharmacology and Therapeutics (Memo‑
differentiatinG effect of thalidomide
and Gm-csf combination on hl-60 acute
promyelocytic leukemia cells
A.U. Ural1, 2, *, F. Avcu1, 2, M. Zerman3, M.I. Yilmaz3, A. Pekel4, M. Beyzadeoglu5
1Department of Hematology, Gulhane Military Medical Academy,
Ankara, Turkey
2Medical Research Center, Gulhane Military Medical Academy,
Ankara, Turkey
3Department of Internal Medicine, Gulhane Military Medical Academy,
Ankara, Turkey
4Department of Immunology, Gulhane Military Medical Academy,
Ankara, Turkey
5Department of Radiation Oncology, Gulhane Military Medical Academy,
Ankara, Turkey
Aim: To investigate whether granulocyte-macrophage colony-stimulating factor (GM-CSF) with or without thalidomide can induce
apoptosis and differentiation of HL-60 acute promyelocytic leukemia cell line in vitro. Methods: Effect of GM-CSF and thalido-
mide on proliferation of HL-60 cells was evaluated by MTT assay, cell cycle analysis was performed by propidium iodide staining
approach and flow cytometry, and apoptosis rate was analyzed using FITC-conjugated annexin-V and FACScan flow cytometry.
Results: The study revealed that thalidomide alone at high concentrations inhibited HL-60 cell growth and induced apoptosis.
Three days treatment of low-dose thalidomide in combination with GM-CSF induced marked terminal differentiation of HL-60
cells, as it was assessed by increased expression of differentiation antigens on cell surface. Conclusion: Treatment of HL-60 cells
by low concentration of thalidomide combined with GM-CSF induced terminal differentiation of HL60 cells in vitro, which may be
advantageous for the elaboration of novel therapeutic regimens in patients with differentiation-inducible leukemias.
Key Words: thalidomide, GM-CSF, HL-60, differentiation, apoptosis.
Received: August 30, 2006.
*Correspondence: Fax: 90-312-304-4150
E-mail: aural@gata.edu.tr;
aliugurum@yahoo.com
Abbreviations used: AML — acute myelogeneous leukemia;
ATRA — all-trans-retinoic-acid; DMSO — dimethyl sulfoxide;
FITC — fluorescein isothiocyanate; G-CSF — granulocyte colony-
stimulating factor; GM-CSF — granulocyte-macrophage colony-
stimulating factor; MM — multiple myeloma; MTT — 3-(4,5-dime-
thyl-thiazoyl)-2,5-diphenyl-SH-tetrazolium bromide; PI — propi-
dium iodide.
Exp Oncol 2006
28, 3, 216–219
Experimental Oncology 28, 216–219, 2006 (September) 217
rial Sloan‑Kettering Cancer Center, USA). HL‑60 cells
were maintained in RPMI 1640 medium (Sigma, USA)
supplemented with 10% heat‑inactivated fetal calf
serum (Sigma, USA), and 2 mM L‑glutamine (Sigma,
USA), 100 μg/mL streptomycin and 100 U/mL penicillin
(Sigma, USA) at 37 °C in a 5% CO2 atmosphere.
Reagents. Thalidomide was kindly provided by
Celgene (USA). Leucomax 400 μg (Novartis, Turkey)
was used as a source of GM‑CSF. A stock solution of
GM‑CSF was prepared in phosphate buffered saline
(PBS) (Sigma, USA), pH 7.4 and filter‑sterilized using
a 0.22 µm filter. Thalidomide was dissolved in 0.1%
DMSO (Sigma, USA) and diluted in culture medium
(0.01 to 100 µM) immediately before use.
MTT assay. The MTT (Biological Industries, Is‑
rael) cell viability assay was performed as previously
described [15], and the absorbance at 570‑nm was
recorded using a 96‑well microplate reader (Bio‑Tek
Instruments Inc., USA). Each experiment was repeated
3 times.
In some studies, target HL‑60 cells were plated at
a density of 5 x 104 per well in 24‑well plates (Costar,
USA) with media containing 200 U/ml GM‑CSF for
increasing time of incubation to determine the prolife‑
rative effect of GM‑CSF. In each separate experiment,
following incubation, cells were harvested, suspended
in PBS and cell number determined using haemocy‑
tometer (Bright‑line, Hausser Scientic, USA).
Cell cycle analysis, and determination of apop-
tosis. For cell cycle analysis, the cells were washed
once in PBS and then stained with PI using a com‑
mercial kit (Cycle Test Plus DNA Reagents Kit; Becton
Dickinson, USA) for 10 min at 4 °C in the dark, and the
cells were analyzed with a flow cytometer (FACScan;
Becton Dickinson, USA). Analysis was carried out on
three separate experiments.
To assess apoptosis, cells were seeded in a 24‑well
plate and treated with thalidomide, GM‑CSF, or their
combination for 48 h, and then the cells were labeled
with FITC‑conjugated annexin‑V (Becton Dickinson,
USA) and detected by FACScan flow cytometry.
Treated cells were dissociated and washed twice in
a binding buffer (10 mM HEPES, 140 mM NaCl and
2.5 mM CaCl2). Cells were then labeled with 5 μL
Annexin‑V‑FITC/50 μL binding buffer for 15 min in the
dark and at room temperature. Immediately prior to
analysis on the flow cytometer, the samples were also
labeled with 250 μL of a 10 mg/ml stock PI solution.
Analysis was carried out in triplicate.
Determination of differentiation markers. The
extent of monocyte differentiation induced in HL‑60
cells by thalidomide (20 μM) with or without GM‑CSF
(200 U/ml) after 48 h incubation was determined
by monitoring the CD14, CD11b and CD11c surface
markers by flow cytometry. Aliquots of 1 x 106 HL‑60
cells were harvested at various time points, centri‑
fuged, and washed twice with 1 x PBS. The cell pellet
was resuspended in 100 μL PBS; and 20 μL of mono‑
clonal antibodies specific for CD14, CD11b and CD11c
(Becton Dickinson, USA) were added, and the mixture
was incubated in the dark at 2–8 °C for 15–30 min. The
excess antibody was washed off with 1 x PBS, and the
pellet was resuspended in 500 μL of 1 x PBS. The cells
were analyzed by FACScan flow cytometer.
Statistical analysis. Student’s two‑tailed t‑test
was used to determine statistical significance of de‑
tected differences. A value of p < 0.05 was considered
statistically significant.
results and discussion
As shown in Fig. 1, a, MTT assay revealed significant
antiproliferative effect of thalidomide against HL‑60
cells after 48 and 72 h of incubation with the agent only
if its concentration is higher than 50 µM (p < 0.01).
fig. 1. Effect of thalidomide (a) and 200 U/ml GM‑CSF (b) on
proliferation of HL‑60 cells. a: HL‑60 cells were incubated with
thalidomide for 48 (‑‑) and 72 h (‑‑). Results are expressed
as control or absolute cell numbers (%). The data are presented
as Mean ± SD of three separate experiments
*Statistically significant values compared with control (p < 0.01).
Since thalidomide has been reported to have
antitumor activity [12], we studied its influence on
programmed cell death in HL‑60 cells. Apoptotic cells
were detected as a significant sub‑G1 shoulder (Mean
32.7 ± 3.5%; p < 0.001) representing hypodiploid cells
in cultures that had been treated with 50 µM thalido‑
mide, but not in untreated cells (Table 1). Thalidomide
(20 µM) inhibited the cells proliferation associated with
cell cycle arrest at G1 but without significant cytotoxicity
as assessed by MTT assay (Fig. 1, a) or flow cytometric
analysis of apoptosis (Table 1). The percentage of apop‑
totic, necrotic, and viable cells after single or combined
treatment was evaluated by Annexin‑V binding. Repre‑
sentative data are shown in Table 2. A minimal apoptotic
rate was observed with low dose thalidomide when
compared to untreated cells. In contrast, treatment of
cells with high dose thalidomide (50 µM) dramatically
augmented apoptosis concordant with cell cycle analy‑
218 Experimental Oncology 28, 216–219, 2006 (September)
sis data. Thalidomide alone has not displayed enhanced
CD14, CD11b and CD11c expression (Fig. 2).
Table 1. Analysis of cell cycle distribution of HL-60 cells incubated with
thalidomide, GM-CSF, or their combination for 48 h. Results are presented
as % cells and represent the mean ± SD of three separate experiments
Cell
cycle
phase
Control
Thalido-
mide
(20 µM)
Thalido-
mide
(50 µM)
GM-CSF
(200 U/ml)
Thalidomide
(20 µM) +
GM-CSF
(200 U/ml)
G0-G1 28.4 ± 1.4 48.2 ± 6.2 22.3 ± 1.2 29.1 ± 2.2 49.2 ± 7.1
S 65.2 ± 3.4 34.5 ± 2.3 34.8 ± 2.7 68.7 ± 4.1 38.7 ± 4.2
G2-M 6.4 ± 0.9 16.2 ± 1.3 10.2 ± 1.2 2.2 ± 0.4 12.1 ± 1.7
Sub-G1
(apop-
tosis)
1.1 ± 0.2 32.7 ± 3.5
Table 2. Flow cytometric analysis of apoptotic rate of HL-60 cells incu-
bated for 48 h with thalidomide, GM-CSF, or their combination
Staining Control
Thalido-
mide
(20 µM)
Thalido-
mide
(50 µM)
GM-CSF
(200 U/ml)
Thalidomide
(20 µM) +
GM-CSF (200
U/ml)
Annexin
V-/PI-,
viable cells (%)
88.5 70.9 9.5 88.8 91.2
Annexin
V+/PI– early
apoptotic cells
(%)
3.8 7.2 2.3 1.5 2.3
Annexin
V+/PI+,
late apoptotic
cells (%)
2.5 13.3 80.6 3.4 2.7
Annexin V–/
PI+, necrotic
cells (%)
5.2 8.6 7.6 4.5 4.5
fig. 2. Effects of thalidomide and GM‑CSF on surface antigen
expression on HL‑60 cells. Cells were incubated for 48 h in the
absence (Control) or presence of 20 μΜ thalidomide with or without
200 U/ml GM‑CSF and then assessed for the surface expression
of CD14, CD11b and CD11a by flow cytometry. Results represent
means of three separate experiments; bars, SD. P was determined
for the comparison of all treatment groups
*Statistically significant values compared with control (p < 0.01).
Enhanced terminal differentiation of leukemic
cells resulting from the combined use of growth fac‑
tors and pharmacological differentiating agents other
than thalidomide has been described [16]. A study by
Matsui et al. [8] has shown that neutralizing antibod‑
ies directed against GM‑CSF, completely inhibited the
activity of all differentiating agents tested. These data
suggest that pharmacological differentiating agents
require the additional activity of growth factors for
inducing tumor cell terminal differentiation. An ad‑
vantage of using thalidomide is its additional effect to
the neutralizing effect of some proinflammatory, pro‑
apoptotic cytokines [7], whereby thalidomide is also
known to induce apoptosis and cell cycle block at G1
phase in leukemic cells [12]. However, the stated dif‑
ferentiating effect of thalidomide by affecting cell cycle
could not specifically be considered attributable to the
drug in our study. The other clinically applicable cell
cycle inhibitors (i. e. phenylbutyrate, hydroxyurea and
bryostatin) in combination with lineage specific growth
factors may induce tumor cell differentiation.
The association between cell cycle inhibition and
cellular differentiation is well recognized; the induction of
differentiation of both normal and malignant cells is as‑
sociated with cell cycle inhibition that is mediated by the
cycle dependent kinase (cdk) activity and the induction
of cdk inhibitor p21 [13]. The inhibition of cell cycle may
play an important role in the activity of pharmacological
differentiating agents where most agents, such as ATRA,
vitamin D, share this biological property despite interact‑
ing with a diverse array of cellular targets [9].
Although HL‑60 cells express functional GM‑CSF
receptors [11], GM‑CSF alone had no significant effect
on the differentiation of cells as assessed by analysis of
CD14, CD11b and CD11c expression (Fig. 2). However,
GM‑CSF alone had a significant effect on the growth
of HL‑60 cells compared to control (Fig. 1, b). The ad‑
dition of GM‑CSF to thalidomide displayed enhance‑
ment CD14, CD11b and CD11c expression on HL‑60
cells compared to the control (p < 0.01) (Fig. 2). But
GM‑CSF and thalidomide combination has not induced
apoptosis (Table 1).
Lineage‑specific growth factors, such as G‑CSF
and GM‑CSF, have pleitropic effects on both malignant
and normal cells with enhanced proliferation, cell sur‑
vival promotion resulting in favorable differentiation and
desired functional activity of myeloid cells. The stimula‑
tory effects of myeloid growth factors on leukemic cell
growth may predominate in most settings; however it
has been shown previously that GM‑CSF preferentially
enhances the differentiation, rather than proliferation,
of malignant progenitors [4]. This could be a result of
an abnormal function or expression of G‑CSF/GM‑CSF
receptor‑associated signal transduction proteins such
as Jak kinases or STAT transcription factors [3]. In fact,
it has been reported that Jak2 kinase is necessary for
STAT activation by GM‑CSF receptor and is required
for cellular proliferation [1, 2]. Therefore, the Jak‑STAT
pathway might be critical for the anti‑apoptotic activity
of GM‑CSF in HL‑60 cells treated with a combination
of thalidomide and GM‑CSF in our study.
In conclusion, we have shown that blocking the cell
cycle by thalidomide at G1 augmented growth factor
driven differentiation of HL‑60 cells. Our current data
indicate that the full induction of terminal differentiation
requires cell cycle inhibition by any agent combined with
lineage specific growth factors, and the combination of
GM‑CSF and thalidomide may be used in the clinical
practice for the management of acute promyelocytic
or differentiation‑inducible leukemias.
Experimental Oncology 28, 216–219, 2006 (September) 219
Copyright © Experimental Oncology, 2006
acknowledGement
This study was supported by a research grant from
Gulhane Medical Faculty Research Center.
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ГМ-КСФ в Сочетании С талидоМидоМ вызывает
диФФеренцировКу КлетоК линии hl-60 СтроГо
проМиелоцитарноГо лейКоза человеКа
Цель: изучить эффект гранулоцитарно-макрофагального колониестимулирующего фактора (ГМ-КСФ) в сочетании
с талидомидом на индукцию апоптоза и дифференцировку клеток острого промиелоцитарного лейкоза линии HL-60
in vitro. Методы: для оценки пролиферации и жизнеспособности клеток HL-60 применяли MTT анализ, для изучения
клеточного цикла — окраску пропидиум бромидом и проточную цитометрию. Для оценки апоптоза клетки линии HL-60
обрабатывали талидомидом, ГМ-КСФ, и совместно талидомидом и ГМ-КСФ в течении 48 ч, и затем метили анекси-
ном, конъюгированным с FITC, и анализировали с помощью проточной цитометрии. Результаты: талидомид в высоких
концентрациях ингибирует пролиферацию клеток HL-60 и вызывает апоптоз. В сочетании с ГМ-КСФ в течение 3 дней
талидомид в низкой концентрации индуцировал терминальную дифференцировку клеток HL-60, о чем свидетельствовало
появление экспрессии дифференцировочных антигенов на поверхности клеток. Выводы: применение талидомида в низкой
концентрации в сочетании с ГМ-КСФ вызывает терминальную дифференцировку клеток HL-60.
Ключевые слова: талидомид, ГМ-КСФ, HL-60, дифференцировка, апоптоз.
|
| id | nasplib_isofts_kiev_ua-123456789-137571 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 1812-9269 |
| language | English |
| last_indexed | 2025-12-02T14:18:31Z |
| publishDate | 2006 |
| publisher | Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| record_format | dspace |
| spelling | Ural, A.U. Avcu, F. Zerman, M. Yilmaz, M.I. Pekel, A. Beyzadeoglu, M. 2018-06-17T13:03:39Z 2018-06-17T13:03:39Z 2006 Differentiating effect of thalidomide and GM-CSF combination on HL-60 acute promyelocytic leukemia cells / A.U. Ural, F. Avcu, M. Zerman, M.I. Yilmaz, A. Pekel, M. Beyzadeoglu // Experimental Oncology. — 2006. — Т. 28, № 3. — С. 216-219. — Бібліогр.: 16 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/137571 Aim: To investigate whether granulocyte-macrophage colony-stimulating factor (GM-CSF) with or without thalidomide can induce apoptosis and differentiation of HL-60 acute promyelocytic leukemia cell line in vitro. Methods: Effect of GM-CSF and thalidomide on proliferation of HL-60 cells was evaluated by MTT assay, cell cycle analysis was performed by propidium iodide staining approach and flow cytometry, and apoptosis rate was analyzed using FITC-conjugated annexin-V and FACScan flow cytometry. Results: The study revealed that thalidomide alone at high concentrations inhibited HL-60 cell growth and induced apoptosis. Three days treatment of low-dose thalidomide in combination with GM-CSF induced marked terminal differentiation of HL-60 cells, as it was assessed by increased expression of differentiation antigens on cell surface. Conclusion: Treatment of HL-60 cells by low concentration of thalidomide combined with GM-CSF induced terminal differentiation of HL60 cells in vitro, which may be advantageous for the elaboration of novel therapeutic regimens in patients with differentiation-inducible leukemias. Цель: изучить эффект гранулоцитарно-макрофагального колониестимулирующего фактора (ГМ-КСФ) в сочетании с талидомидом на индукцию апоптоза и дифференцировку клеток острого промиелоцитарного лейкоза линии HL-60 in vitro. Методы: для оценки пролиферации и жизнеспособности клеток HL-60 применяли MTT анализ, для изучения клеточного цикла — окраску пропидиум бромидом и проточную цитометрию. Для оценки апоптоза клетки линии HL-60 обрабатывали талидомидом, ГМ-КСФ, и совместно талидомидом и ГМ-КСФ в течении 48 ч, и затем метили анексином, конъюгированным с FITC, и анализировали с помощью проточной цитометрии. Результаты: талидомид в высоких концентрациях ингибирует пролиферацию клеток HL-60 и вызывает апоптоз. В сочетании с ГМ-КСФ в течение 3 дней талидомид в низкой концентрации индуцировал терминальную дифференцировку клеток HL-60, о чем свидетельствовало появление экспрессии дифференцировочных антигенов на поверхности клеток. Выводы: применение талидомида в низкой концентрации в сочетании с ГМ-КСФ вызывает терминальную дифференцировку клеток HL-60. This study was supported by a research grant from Gulhane Medical Faculty Research Center. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Original contributions Differentiating effect of thalidomide and GM-CSF combination on HL-60 acute promyelocytic leukemia cells ГМ-КСФ в сочетании с талидомидом вызывает дифференцировку клеток линии HL-60 строго промиелоцитарного лейкоза человека Article published earlier |
| spellingShingle | Differentiating effect of thalidomide and GM-CSF combination on HL-60 acute promyelocytic leukemia cells Ural, A.U. Avcu, F. Zerman, M. Yilmaz, M.I. Pekel, A. Beyzadeoglu, M. Original contributions |
| title | Differentiating effect of thalidomide and GM-CSF combination on HL-60 acute promyelocytic leukemia cells |
| title_alt | ГМ-КСФ в сочетании с талидомидом вызывает дифференцировку клеток линии HL-60 строго промиелоцитарного лейкоза человека |
| title_full | Differentiating effect of thalidomide and GM-CSF combination on HL-60 acute promyelocytic leukemia cells |
| title_fullStr | Differentiating effect of thalidomide and GM-CSF combination on HL-60 acute promyelocytic leukemia cells |
| title_full_unstemmed | Differentiating effect of thalidomide and GM-CSF combination on HL-60 acute promyelocytic leukemia cells |
| title_short | Differentiating effect of thalidomide and GM-CSF combination on HL-60 acute promyelocytic leukemia cells |
| title_sort | differentiating effect of thalidomide and gm-csf combination on hl-60 acute promyelocytic leukemia cells |
| topic | Original contributions |
| topic_facet | Original contributions |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/137571 |
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