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

Bcr-Abl expression in leukemic cells is known to exert a potent effect against apoptosis due to antileukemic drugs, but its mechanism has not been elucidated. Recent reports have indicated that a variety of apoptotic stimuli cause the preapoptotic mitochondrial release of cytochrome c (cyt c) into cytosol, which mediates the cleavage and activity of caspase-3 involved in the execution of apoptosis. Whether Bcr-Abl exerts its antiapoptotic effect upstream to the cleavage and activation of caspase-3 or acts downstream by blocking the ensuing degradation of substrates resulting in apoptosis, has been the focus of the present studies. In these, we used (1) the human acute myelogenous leukemia (AML) HL-60 cells that are stably transfected with the bcr-abl gene (HL-60/Bcr-Abl) and express p185 Bcr-Abl; and (2) the chronic myelogenous leukemia (CML)-blast crisis K562 cells, which have endogenous expression of p210 Bcr-Abl. Exposure of the control AML HL-60 cells to high-dose Ara-C (HIDAC), etoposide, or sphingoid bases (including C2 ceramide, sphingosine, or sphinganine) caused the accumulation of cyt c in the cytosol, loss of mitochondrial membrane potential (MMP), and increase in the reactive oxygen species (ROS). These preapoptotic events were associated with the cleavage and activity of caspase-3, resulting in the degradation of poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) and DNA fragmentation factor (DFF), internucleosomal DNA fragmentation, and morphologic features of apoptosis. In contrast, in HL-60/Bcr-Abl and K562 cells, these apoptotic stimuli failed to cause the cytosolic accumulation of cyt c and other associated mitochondrial perturbations, as well as the failure to induce the activation of caspase-3 and apoptosis. While the control HL-60 cells showed high levels of Bcl-2 and barely detectable Bcl-xL, HL-60/Bcr-Abl cells expressed high levels of Bcl-xL and undetectable levels of Bcl-2, a pattern of expression similar to the one in K562 cells. Bax and caspase-3 expressions were not significantly different between HL-60/Bcr-Abl or K562 versus HL-60 cells. These findings indicate that Bcr-Abl expression blocks apoptosis due to diverse apoptotic stimuli upstream by preventing the cytosolic accumulation of cyt c and other preapoptotic mitochondrial perturbations, thereby inhibiting the activation of caspase-3 and execution of apoptosis.
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PMID:Bcr-Abl exerts its antiapoptotic effect against diverse apoptotic stimuli through blockage of mitochondrial release of cytochrome C and activation of caspase-3. 947 36

Between February 1993 and November 1997, 62 patients with severe aplastic anaemia (SAA), acute myeloid (AML), acute lymphoid (ALL), or chronic myeloid leukaemia (CML) as well as two patients with NHL underwent allogeneic marrow transplantation (BMT) from HLA-identical or one-antigen mismatched sibling or unrelated donors. Patients received preparative regimens according to the baseline disease. Patients with SAA were conditioned with ATG/Cy (2 cases) and TAI/Cy (3 cases), AML, ALL and NHL with TBI/Cy (21 cases including two retransplantations) and CML with Mitobronitol/Ara-C/Cy except two patients conditioned traditionally with Bu/Cy. For GVHD prevention, patients received cyclosporin-A (CsA) with short course methotheraxe according to the Seattle protocol. Significantly better overall survival rates were associated with the Mitobronitol (DBM)/Ara-C/Cy conditioning regarded the patients as a whole. Autologous stem cell transplantation (bone marrow and/or peripheral blood) were performed in ten cases including 2 AML, 4 non-Hodgkin's lymphoma (NHL), 3 Hodgkin's disease (HD) and 1 patient with multiple myeloma (MM). Patients with AML and two patients with NHL were conditioned with TBI/Cy and the others with BEAM combined chemotherapy. Eight out of ten patients are leukaemia- or lymphoma-free survivors. One patient relapsed having conventional chemotherapy and interferon maintenance therapy. One patient died in a rapid relapse five months post-BMT.
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PMID:Haemopoietic cell transplantation activity and results: a single institution experience. 991 38

Thirty-one patients (20 male and 11 female; median age 51 years (16-79)) with high-risk acute myeloblastic leukemia (AML) (20 refractory AML and 11 secondary AML (s-AML) (four to myelodysplastic syndrome, five to chemo/radiotherapy, one to aplastic anemia and one blastic chronic myelogenous leukemia (B-CML)) were treated with CBDCA (300 mg/m2/day x 5 days in continuous i.v. infusion) plus intermediate-dose Ara-C (500 mg/m2/day x 3 days in rapid i.v. infusion). Nine patients (29%) achieved CR (five s-AML (three myelodysplastic syndromes, one CML and one ALL) and four refractory AML) and 11 patients had resistant disease. There were 11 early deaths (35%). Median disease-free survival of the nine responders was 4 months. The main toxicity was hematological, febrile episodes took place in nearly all the patients (96%). The CBDCA plus Ara-C regimen showed an evident antileukemic activity in high-risk leukemia. However, the lack of long-term disease-free survivors shows the need for innovative postremission strategies. The high initial response rate seen in AML secondary to myelodysplastic syndromes (MDS) warrants further investigation of CBDCA in combination regimens for MDS patients.
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PMID:Carboplatin plus cytarabine in the treatment of high-risk acute myeloblastic leukemia. 1002 88

Three patients with chronic myeloid leukemia (CML) in blastic transformation were treated with G-CSF plus middle dose cytosine arabinoside (Ara-C). G-CSF was administered (150 mg, s.c. or 300 mg, d.i.v./day) 24 hr prior to Ara-C (2-3 g/body, 6 hour d.i.v. for 2-5 days) and continued until the peripheral neutrophil count rose above 1,000/microlitre. As a supplement, VP-16 (80 mg/m2, for 2 days) was administered as warranted to control the growth of blastic cells. All 3 patients survived for more than 12 months with a favorable performance status. Normal karyotypes were detected in 2 of the patients after chemotherapy. One of those patients in paticular demonstrated normal bone marrow findings with the almost complete disappearance of the Ph-positive clone. In vitro cultures of peroxidase-negative CML blastic cells revealed that G-CSF stimulated the induction of blastic cells into the cell cycle and that blastic cell apoptosis was more pronounced in cells cultured with G-CSF plus Ara-C than with G-CSF or Ara-C alone. G-CSF plus middle dose Ara-C therapy appears to be a strong candidate for the treatment of CML in blastic transformation with a poor prognosis.
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PMID:[Induction of Ph-negative normal clone and long-term survival by combined treatment with G-CSF plus middle dose cytosine arabinoside for patients with chronic myeloid leukemia in blastic transformation]. 1002 46

The oral antitumor drugs against hematological malignancies are summarized. Sobuzoxane, a topoisomerase II inhibitor, is useful for the treatment of lymphoma, especially adult T cell leukemia/lymphoma. Sobuzoxane has an effect to protect against doxorubicin cardiotoxicity. Cytarabine ocfosfate, a derivative of cytosine arabinoside, is a useful agent against acute leukemia and MDS, especially RAEB, RAEB in T, CMMoL. The JALSG AML 92 study for APL with all-trans retinoic acid resulted in a 89% CR rate in 196 and 64% 4-year DFS in CR cases. Hydroxycarbamide is can control the WBC in CML. This agent is also effective for other myeloproliferative disorders, such as acute leukemia and MDS. Oral administration of 50 mg etoposide daily showed a good outcome in old patients with malignant lymphoma. For old patients and those with refractory hematological malignancies, oral administration of these agents can offer a new form of palliative therapy to allow them to remain at home while maintaining a high quality of life.
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PMID:[Oral antitumor drugs for hematological malignancies]. 1006 91

Neurological side effects and complications of cryoglobulinemia were observed during interferon-alpha (IFN-alpha) therapy in a patient with chronic myeloid leukemia (CML). A 50-year-old man was hospitalized because of leukocytosis and extramedullary tumors in the lumbar spine. In addition, the patient complained of dysesthesia in his feet. A diagnosis of accelerated phase CML was made. Administration of prednisolone, vincristine, hydroxyurea, and Ara-C and irradiation of the lumbar spine were started. Two months later, the patients achieved hematologic response and the size of his tumors decreased. Thereafter, we started IFN-alpha treatment (3-6 x 10(6) units daily) by intramuscular injection. After 8 weeks of this treatment, the patient complained of worsening dysesthesia in his feet. An axonal form of peripheral neuropathy was diagnosed by electrophysiological examination. Immunological studies revealed decreased complement levels and type III mixed cryoglobulinemia. Methylprednisolone pulse therapy alleviated the neurological symptoms and lowered the cryoglobulin levels. The clinical course suggested that mixed cryoglobulinemia was associated with CML and that the increase in cryoglobulin levels was caused by IFN-alpha and played a causative role in the worsening peripheral neuropathy. Therefore, to prevent these side effects, careful clinical assessment is necessary before starting IFN-alpha therapy.
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PMID:[Development of cyroglobulinemia and polyneuropathy in a chronic myeloid leukemia patient during interferon-alpha treatment]. 1035 42

OVERVIEW: Clinical indications for the use of interferons (IFNs) for cancer continue to expand and will likely continue to do so. IFNs have been approved for clinical use by the United States Food and Drug Administration for chronic myelogenous leukemia (CML), hairy cell leukemia, follicular lymphomas, Kaposi's sarcoma in the setting of AIDS, and melanoma for patients at high risk for recurrence after surgery. In addition, as a result of their antiviral activity, IFNs result in control of chronic active hepatitis and recurring papillomas that may reduce cancer development resulting from these processes and their underlying viruses. For almost all of these indications, therapeutic activity has been established from well-conducted, international phase III clinical trials. IFNs were the first successful biological therapy for human malignancy; they can synergize to produce tumor regression with surgery and chemotherapy and can potentiate other cytokines and monoclonal antibodies. IFNs and cytokines can modulate gene expression, resulting in enhanced immune effector-cell number, cytotoxicity, antigen expression, and production of other cytokines. IFNs have pleiotropic effects on cellular function, including influences on growth, differentiation, and immunologic function. For greatest effects, IFNs are used in combination with other modalities of therapy. This increases the effect of IFNs or allows IFNs to increase the effects of other therapies. Cytosine arabinoside improves the therapeutic effectiveness of IFNs in CML, and IFN-&agr;2b improves the prognosis, survival, and quality of life after surgery for high-risk patients with melanoma. Gene modulation by IFN-&agr; or IFN-&bgr; of thymidine phosphorylase, an enzyme important in DNA synthesis, has been suggested to be the basis for enhancing 5-fluorouracil (5-FU) effectiveness in preclinical models and may augment effectiveness in adenocarcinomas. IFNs increase the expression of some tumor-associated antigens that could be of benefit for combination use with monoclonal antibodies for imaging or therapy.
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PMID:Gene Regulation and Clinical Roles for Interferons in Neoplastic Diseases. 1038 4

The clonogenic cells of chronic myeloid leukaemia (CML), unlike normal haemopoietic colony forming cells (CFC), are resistant to the growth inhibitory effects of the chemokine, macrophage inflammatory protein-1alpha (MIP-1alpha). Here, we tested the hypothesis that MIP-1alpha protects normal, but not CML, CFC from the cytotoxic effects of the cell-cycle active drug cytosine arabinoside (Ara-C). Using a 24-h Ara-C protection assay we showed that MIP-1alpha confers protection to normal CFC but also sensitizes CML CFC to Ara-C. The differential MIP-1alpha responsiveness was not due to a down-regulation of MIP-1alpha receptors on CML CD34+ cells as flow cytometric analysis showed similar binding of a biotinylated MIP-1alpha molecule to normal and CML CD34+ cells. Flow cytometric analysis of the MIP-1alpha receptor subtype CCR-5 revealed comparable CCR-5 expression levels on normal and CML CD34+ cells. Furthermore, culture of CD34+ cells for 10 h in the presence of TNF-alpha resulted in an increased MIP-1alpha receptor expression on both normal and CML CD34+ cells. Our data suggest that the unresponsiveness of CML CFC to the growth inhibitory effect of MIP-1alpha is not caused by a lack of MIP-1alpha receptor or total uncoupling of the MIP-1alpha responsiveness but may be due to an intracellular signalling defect downstream of the receptors.
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PMID:Characterisation of the differential response of normal and CML haemopoietic progenitor cells to macrophage inflammatory protein-1alpha. 1060 23

The interferons are cytokines with a wide array of biological properties. In hematological malignancies the most used IFN class is -alpha; it has been used for thirty years but the mode of action is still not absolutely clear. Nevertheless, the benefits of IFN-alpha for the treatment of CMD have been described in particular for CML and less for PV, ET and MMM. IFN-alpha is presently considered the golden standard of therapy for CML patients not eligible for SCT; the antileukemic effect has been well documented by hematological and cytogenetic response. The survival advantage for IFN treated patients is remarkable in comparison with patients treated with conventional chemotherapy. Recently, the combination IFN-alpha plus Ara-C has demonstrated to increase the rate of major cytogenetic response and to prolong survival. To date, there is not a generally accepted treatment for ET, PV and MMM, which can reduce the risk of thromboembolism and/or hemorragic events. In several subsets of ET and PV patients, IFN-alpha can be considered as first line therapy. IFN-alpha is usually associated with the development of early and later side effects, that reduce the enthusiasm for its use. In the future PEG-IFN-alpha would improve the quality of life of IFN-treated CMD patients.
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PMID:The role of interferon-alpha in the treatment of myeloproliferative disorders. 1060 58

We describe a 5-year-old girl with Ph(+) CML who received a cord blood transplant in a second accelerated phase after a very early lymphoid blast crisis. She was induced into CR by ALL-directed chemotherapy and then maintained with IFN-alpha2b together with weekly rotational chemotherapy. Nineteen months after diagnosis, her mother gave birth to an HLA-compatible sibling, whose cord blood was cryopreserved. The patient's second acceleration occurred 22 months after the CML diagnosis. The subsequent conditioning regimen included busulfan 16 mg/kg, Ara-C 12 g/m2 and melphalan 140 mg/m2. In order to prevent GVHD, CsA alone was administered, 3 mg/kg i.v. per day for a total of 40 days. The total number of nucleated cells infused was 0.8 x 108/kg, with CD34+ cells 1.8 x 106/kg and CFU-GM 1 x 104/kg. Engraftment occurred on day +35. Respiratory distress, severe VOD and grade II acute gastrointestinal GVHD complicated the post-transplant period. No chronic GVHD occurred. The girl is alive 23 months after transplantation with complete donor chimerism; both Ph chromosome and bcr/abl RNA are negative. Bone Marrow Transplantation (2000) 25, 213-215.
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PMID:A successful cord blood transplant in a child with second accelerated phase chronic myeloid leukemia following lymphoid blast crisis. 1067 84


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