Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prognostic models for acute myeloid and lymphoid leukemias are presented that demonstrate that cell kinetic quiescence in acute leukemia is associated with poor response to chemotherapy, short remission duration, and survival. Recruitment of cells into the cell cycle should therefore enhance cytotoxic effects of cell cycle - specific chemotherapeutic agents. We previously demonstrated recruitment of myeloid leukemic cells by cytokines. We have now investigated whether recruitment can be used to increase cell killing by cytosine arabinoside (Ara-C). Blast cells from 16 acute leukemias were stimulated with cytokines as follows: 13 acute myeloid leukemias (AML) and 3 chronic myeloid leukemia (CML) in blastic phase (1 lymphoid, 2 myeloid) were treated with recombinant human granulocyte colony stimulating factor (rhG-CSF), recombinant human granulocyte-macrophage colony stimulating factor (rhG-CSF, AMGEN, 500 U/ml each), and recombinant human interleukin-3 (rhIL-3, IMMUNEX, 20 ng/ml), alone and in combination. After 48 h, at the time of maximal DNA synthesis, Ara-C (10(-3) M) was added and cell counts, cytokinetics (DNA/RNA, DNA/bromodeoxyuridine and DNA/Ki67 flow cytometry), and cell viability/clonogenicity (fluorescein diacetate/propidium iodide exclusion flow cytometry) were investigated. In all 13 cases of AML recruitment was found; in 6 of these cases over a three fold increase in S phase (P = 0.008) and a significant (P = 0.004) depletion of G0 was demonstrated. In 9 of 13 patients with AML, the effect of Ara-C was investigated, and in 3 of 5 patients with over three fold increase in S phase, Ara-C toxicity was enhanced. None of the patients with less than a three fold increase in S phase and no demonstrable recruitment from G0 had increased Ara-C cytotoxicity. Ara-C cytoreduction was paralled by reduction in clonogenicity as demonstrated by fluorescein diacetate/propidium iodide (FDA/PI) flow cytometry. Four samples of acute lymphoblastic leukemia (ALL) were treated with low molecular weight B-cell growth factor (15 kDa) and recruitment of aneuploid cells from G0 to G1 was found in all patients (from 19.3% to 84.9%). These results indicate that recruitment of leukemic cells is inducible by cytokines and that the cytotoxicity of cell cycle-specific drugs such as Ara-C can be increased. This concept is presently being tested in vivo.
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PMID:Colony-stimulating factors (rhG-CSF, rhGM-CSF, rhIL-3, and BCGF) recruit myeloblastic and lymphoblastic leukemic cells and enhance the cytotoxic effects of cytosine-arabinoside. 232 74

We analyzed active oxygen (hydroperoxide; H2O2) production by peripheral neutrophils in various hematological diseases by flow cytometry. One hundred microliters of heparinized fresh blood was sequentially incubated at 37 degrees C with 2',7'-dichlorofluorescein diacetate and with or without phorbol myristate acetate (PMA). After hemolysis, the pelleted white blood cells were subjected to flow cytometry, and the neutrophil fraction was gated on the cytogram. Production of H2O2 by the fraction was estimated by determining the increase in the relative intensity of fluorescence emitted from the fraction in response to stimulation by PMA. In controlled chronic myelogenous leukemia (CML) (WBC < 1 x 10(10)/1), H2O2 production was normal, while in uncontrolled CML (WBC > or = 1 x 10(10)/1), it was reduced. In myelodysplastic syndrome (MDS), H2O2 production was also reduced, but no significant difference was observed among FAB classification disease types in MDS patients. In untreated acute non-lymphocytic leukemia (ANLL), H2O2 production was reduced, while in the complete remission stage of ANLL, its level was normal, suggesting recovery from normal clones. In aplastic anemia, the H2O2 production level was normal. Steroid therapy might be responsible for the reduction of H2O2 production in non-Hodgkin's lymphoma and multiple myeloma. The production of H2O2 is closely related to the oxygen-dependent bactericidal activity of neutrophils, and, hence, can be utilized as an index to indicate susceptibility to infection. This neutrophil function can be determined easily in ordinary clinical facilities by using flow cytometry, and care should be taken to prevent infection when H2O2 production is reduced.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Flow cytometric determination of active oxygen (hydroperoxide) produced by peripheral blood neutrophils in patients with hematological disorders. 836 85

Chronic myeloid leukemia (CML) is characterized by an increased proliferative activity of the leukemic progenitors that produce an elevated number of mature granulocytes. Nevertheless, cell cycle-active agents, even in very high doses, are alone unable to eradicate the leukemic clone, suggesting the presence of a rare subset of quiescent leukemic stem cells. To isolate such cells, we first used Hoechst 33342 and Pyronin Y staining to obtain viable G(0) and G(1)/S/G(2)/M fractions of CD34(+) cells by fluorescence-activated cell sorting (FACS) from 6 chronic-phase CML patients' samples and confirmed the quiescent and cycling status of the 2 fractions by demonstration of expected patterns of Ki-67 and D cyclin expression. Leukemic (Ph(+)/BCR-ABL(+)) cells with in vitro progenitor activity and capable of engrafting immunodeficient mice were identified in the directly isolated G(0) cells. Single-cell reverse transcriptase-polymerase chain reaction (RT-PCR) analysis showed that many leukemic CD34(+) G(0) cells also expressed BCR-ABL mRNA. CD34(+) from 8 CML patients were also labeled with carboxyfluorescein diacetate succinimidyl diester (CFSE) before being cultured (with and without added growth factors) to allow viable cells that had remained quiescent (ie, CFSE(+)) after 4 days to be retrieved by FACS. Leukemic progenitors were again detected in all quiescent populations isolated by this second strategy, including those exposed to a combination of flt3-ligand, Steel factor, interleukin-3, interleukin-6, and granulocyte colony-stimulating factor. These findings provide the first direct and definitive evidence of a deeply but reversibly quiescent subpopulation of leukemic cells in patients with CML with both in vitro and in vivo stem cell properties.
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PMID:Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. 1047 35

In clinical trials, the tyrosine kinase inhibitor STI571 has proven highly effective in reducing leukemic cell burden in chronic myeloid leukemia (CML). The overall sensitivity of CML CD34(+) progenitor cells to STI571 and the degree to which cell death was dependent on cell cycle status were determined. Stem cells (Lin(-)CD34(+)) from the peripheral blood of patients with CML in chronic phase and from granulocyte-colony-stimulating factor-mobilized healthy donors were labeled with carboxy-fluorescein diacetate succinimidyl diester dye to enable high-resolution tracking of cell division. Then they were cultured for 3 days with and without growth factors +/- STI571. After culture, the cells were separated by fluorescence-activated cell sorting into populations of viable quiescent versus cycling cells for genotyping. For healthy controls, in the presence of growth factors, STI571 affected neither cell cycle kinetics nor recovery of viable cells. In the absence of growth factors, normal cells were unable to divide. For CML samples, in the presence or absence of growth factors, the response to STI571 was variable. In the most sensitive cases, STI571 killed almost all dividing cells; however, a significant population of viable CD34(+) cells was recovered in the undivided peak and confirmed to be part of the leukemic clone. STI571 also appeared to exhibit antiproliferative activity on the quiescent population. These studies confirm that CML stem cells remain viable in a quiescent state even in the presence of growth factors and STI571. Despite dramatic short-term responses in vivo, such in vitro insensitivity to STI571, in combination with its demonstrated antiproliferative activity, could translate into disease relapse after prolonged therapy.
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PMID:Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. 1175 87

Imatinib mesylate (STI571) is a promising new treatment for chronic myelogenous leukemia (CML). The effect of imatinib mesylate on primitive malignant progenitors in CML has not been evaluated, and it is not clear whether suppression of progenitor growth represents inhibition of increased proliferation, induction of apoptosis, or both. We demonstrated here that in vitro exposure to concentrations of imatinib mesylate usually achieved in patients (1-2 microM) for 96 hours inhibited BCR/ABL-positive primitive progenitors (6-week long-term culture-initiating cells [LTCICs]) as well as committed progenitors (colony-forming cells [CFCs]). No suppression of normal LTCICs and significantly less suppression of normal CFCs were observed. A higher concentration of imatinib mesylate (5 microM) did not significantly increase suppression of CML or normal LTCICs but did increase suppression of CML CFCs, and to a lesser extent, normal CFCs. Analysis of cell division using the fluorescent dye carboxyfluorescein diacetate succinimidyl ester indicated that imatinib mesylate (1-2 microM) inhibits cycling of CML primitive (CD34(+)CD38(-)) and committed (CD34(+)CD38(+)) progenitors to a much greater extent than normal cells. Conversely, treatment with 1 to 2 microM imatinib mesylate did not significantly increase the percentage of cells undergoing apoptosis. Although a higher concentration of imatinib mesylate (5 microM) led to an increase in apoptosis of CML cells, apoptosis also increased in normal samples. In summary, at clinically relevant concentrations, imatinib mesylate selectively suppresses CML primitive progenitors by reversing abnormally increased proliferation but does not significantly increase apoptosis. These results suggest that inhibition of Bcr-Abl tyrosine kinase by imatinib mesylate restores normal hematopoiesis by removing the proliferative advantage of CML progenitors but that elimination of all CML progenitors may not occur.
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PMID:Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation. 1198 38

The BCR/ABL tyrosine kinase inhibitor imatinib mesylate is highly effective in the treatment of chronic myelogenous leukemia (CML) but fails to eliminate all leukemia cells. Residual leukemia stem and progenitor cells persist in imatinib-responsive patients and may be a potential source of relapse. Previous studies indicate that imatinib preferentially targets dividing cells, and nondividing progenitor cells are resistant to imatinib-mediated apoptosis. We investigated whether growth factor stimulation of progenitor proliferation could reduce the number of residual nondividing cells remaining after imatinib treatment. CML and normal CD34(+) cells were labeled with 5-(and 6-)-carboxyfluorescein diacetate succinimidyl ester (CFSE) to track cell division and cultured in low or high concentrations of growth factor to determine effects of growth factor stimulation on nondividing cells. High growth factor concentrations significantly enhanced CML proliferation with or without imatinib treatment and significantly reduced the number of viable, nondividing CFSE bright cells remaining after imatinib exposure. Stimulation with high growth factor before imatinib treatment further reduced the number of residual nondividing CML CD34(+) cells. Importantly, clinically achievable concentrations of granulocyte macrophage colony-stimulating factor alone or in combination with granulocyte colony-stimulating factor also significantly reduced nondividing CML CD34(+) cells. These results support the potential efficacy of growth factor stimulation in reducing the residual leukemia progenitor population in imatinib-treated patients.
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PMID:Growth factor stimulation reduces residual quiescent chronic myelogenous leukemia progenitors remaining after imatinib treatment. 1728 45

In order to establish the method of generating powerful gammadelta T cells for anti-tumor immunotherapy, we investigated the effects of monocyte-derived dendritic cells (mo-DCs) on anti-tumor cytotoxicity of expanded gammadelta T cells. Activation of gammadelta T cells co-cultured for 2-3 days with immature or mature mo-DCs was evaluated by CD69 expression and anti-tumor cytotoxicity using two assays : the 5- (and 6-) carboxyfluorescein diacetate, succinimidyl ester-based cytotoxicity assay and the calcein-AM-based Terascan assay. gammadelta T cells were used as effector cells and myeloma cell line (RPMI8226) or chronic myelogenous leukemia blastic crisis cell line (C2F8) were used as target cells. CD69 expression on gammadelta T cells was enhanced by co-culture with both immature and mature mo-DCs in a cell-number-dependent fashion. CD69 expression was enhanced after addition of mo-DCs of either autologous or allogeneic origin. Activation of gammadelta T cells with mo-DCs enhanced anti-tumor cytotoxicity of gammadelta T cells against RPMI8226 and C2F8 in an effector-to-target ratio-dependent manner. Activation of gammadelta T cells by mo-DCs was associated with the enhancement of anti-tumor cytotoxicity of gammadelta T cells. Potent gammadelta T cells activated by mo-DCs were considered to be applicable to an efficient gammadelta T cell-mediated immunotherapy for tumors.
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PMID:Enhancement of anti-tumor cytotoxicity of expanded gammadelta T Cells by stimulation with monocyte-derived dendritic cells. 1804 Jan 45

This study was aimed to investigate the effect of artificial antigen-presenting cells (aAPCs) on inducing activation and proliferation of specific T-lymphocytes through stimulating biological function of dendritic cells with aAPCs in vitro. The specific antigen of chronic myeloid leukemia CML-28 was screened as objective antigen peptide by using magnetic microbeads as vector; the CML-28 epitope sequence (Vltfaldsv) was obtained by antigen epitope prediction software; this epitope was coupled with MHC molecule and used as first signal molecule, the B7-1 molecule was used as second signal molecule; these 2 molecules simultaneously were loaded onto surface of magnetic microbeads so as to contract aAPC complex. The bone marrow mononuclear cells were derived from HLA-A2(+) healthy bone marrow donors, CD8(+) T lymphocytes were screened and co-cultured with aAPC complex. During culture the 5, 6-carboxyfluorescein diacetate succinimidyl ester (CFSE) was added and proliferation of T-lymphocytes was detected by CPSE and proliferation level of specific T lymphocytes was detected by flow cytometry. The results showed that the proliferation level of CML-28 specific T lymphocytes obviously increased in experimental group, average level was 17.34 +/- 0.65%, while average level in control was 2.25 +/- 0.43%, there was significant difference between them (p < 0.01). It is concluded that the aAPC complex can mimic human APCs in vitro, and stimulate activation and proliferation of CD8(+) specific T lymphocytes.
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PMID:[Activation of specific T lymphocyte induced by artificial antigen presenting cell complex in vitro]. 1854 48

CD34 is the most frequently used marker for the selection of cells for bone marrow (BM) transplantation. The use of CD133 as an alternative marker is an open research topic. The goal of this study was to evaluate the proliferation and differentiation potential for hematopoiesis (short and long term) of CD133+ and CD34+ populations from bone marrow and mobilized peripheral blood. Eight cell populations were compared: CD34+ and CD133+ cells from both the BM (CML Ph-, CML Ph+, and healthy volunteers) and mobilized peripheral blood cells. Multicolor flow cytometry and cultivation experiments were used to measure expression and differentiation of the individual populations. It was observed that the CD133+ BM population showed higher cell expansion. Another finding is that during a 6-day cultivation with 5(6)-carboxyfluorescein diacetate N-succinimidyl ester (CFSE), more cells remained in division D0 (non-dividing cells). There was a higher percentage of CD38- cells observed on the CD133+ BM population. It was also observed that the studied populations contained very similar but not the same pools of progenitors: erythroid, lymphoid, and myeloid. This was confirmed by CFU-GM and CFU-E experiments. The VEGFR antigen was used to monitor subpopulations of endothelial sinusoidal progenitors. The CD133+ BM population contained significantly more VEGFR+ cells. Our findings suggest that the CD133+ population from the BM shows better proliferation activity and a higher distribution of primitive progenitors than any other studied population.
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PMID:Proliferation and differentiation potential of CD133+ and CD34+ populations from the bone marrow and mobilized peripheral blood. 2082 Oct 12

Development of small molecule tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia has been astonishingly successful; however, their off-target effects have generated both challenges and opportunities for extending their clinical application. Dasatinib and imatinib are two of the most commonly used tyrosine kinase inhibitors and both have been shown to impact T-cell function. Due to this activity, their use as potential immune suppressants has been proposed. In this report, we investigated drug interactions with cyclosporine A in suppressing T-cell proliferation. Dasatinib and imatinib were titrated against varying concentrations of cyclosporine in the cultures and T-cell proliferation assessed by 5-6-carboxyfluorescein diacetate, succinimidyl ester dye dilution. These proliferation data were then used to determine the combination index to evaluate additive, synergistic, or antagonistic interactions between the drugs. This analysis uncovered a number of different drug interactions affecting T-cell proliferation. Cyclosporine had an additive or synergistic effect on T-cell proliferation when combined with dasatinib and imatinib for 3 of the 4 methods of stimulating T-cell proliferation. However, when T cells were stimulated with anti-CD3 and anti-CD28 antibodies, this interaction was found to be strongly antagonistic at low dasatinib concentrations. In contrast, this strong antagonism was not observed when imatinib was used in combination with cyclosporine A. This study suggests drug interactions affecting T cells may need to be carefully taken into account when using tyrosine kinase inhibitors. Furthermore, the technique to evaluate drug interactions is novel, and applicable to study any interaction affecting proliferation.
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PMID:Drug-interaction studies evaluating T-cell proliferation reveal distinct activity of dasatinib and imatinib in combination with cyclosporine A. 2252 68


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