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)

Juvenile chronic myelogenous leukemia (JCML) is a rare pediatric malignancy characterized by marked hepatosplenomegaly, leukocytosis with prominent monocytosis, elevated fetal hemoglobin, no Philadelphia chromosome, and generally a poor prognosis. In vitro, JCML peripheral blood granulocyte-macrophage progenitors (granulocyte-macrophage colony-forming units, CFU-GM) demonstrate the unique characteristic of "spontaneous" proliferation at very low cell densities in the absence of exogenous growth factors. The "spontaneous" CFU-GM proliferation can be abolished by prior adherent cell (monocyte) depletion, suggesting a paracrine mode of cellular proliferation. Although previous studies using a [3H]thymidine ([3H]TdR) incorporation assay suggested an important role for granulocyte-macrophage colony-stimulating factor (GM-CSF) in JCML, many non-growth factor-related reasons for [3H]TdR incorporation and the relatively low level of inhibition of [3H]TdR uptake left those conclusions open to question. Therefore, we performed clonal CFU-GM assays, which more specifically reflect cytokine effects on CFU-GM, using JCML peripheral blood mononuclear cells (PBMNC) and neutralizing antibodies against GM-CSF, granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating (M-CSF), interleukin 3 (IL-3), interleukin 1 alpha (IL-1 alpha), interleukin 1 beta (IL-1 beta), interleukin 4 (IL-4), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF alpha), and interferon gamma (IFN gamma). Cultures containing anti-GM-CSF alone inhibited "spontaneous" JCML CFU-GM by 87% +/- 9% (mean +/- standard error of the mean [SEM]). No other anti-cytokine antibody produced a significant inhibition of CFU-GM growth. Various combinations of antibodies, excluding anti-GM-CSF, failed to demonstrate any synergistic inhibitory effects upon CFU-GM. Because this apparent paracrine cellular stimulation could be due to excessive cytokine production, by monocytes or other accessory cells, we examined cytokine levels in conditioned media from various JCML cell populations using enzyme-linked immunosorbent assays (ELISAs). Monocytes from only a minority of JCML patients produced higher than normal quantities of GM-CSF, G-CSF, IL-1 beta, IL-6, and/or TNF alpha, but no obvious pattern could be discerned. Further, only 7 of 15 JCML monocyte-conditioned media (MCM) had elevated GM-CSF, and 6 of 15 JCML patients had normal levels of all nine cytokines tested. The monocyte depletion experiments and the inhibition experiments with anti-cytokine antibodies taken together demonstrate clearly that the "spontaneous" growth of JCML CFU-GM in vitro critically depends on at least one monocyte-derived growth factor, GM-CSF.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The role of monocyte-derived hemopoietic growth factors in the regulation of myeloproliferation in juvenile chronic myelogenous leukemia. 191 2

A fifty-one-year-old male patient visited the Department of Dermatology of Toho University Ohashi Hospital with a complaint of generalized exanthema, which was diagnosed assyringoma; at that time his leukocytosis was recognized. He was admitted to our department on August 8, 1988. Physical examination on admission revealed slight hepatosplenomegaly. WBC count was elevated (50,700/microliters). He was diagnosed as having Ph1-positive CML in the chronic phase and was treated with IFN-alpha (HLBI, Sumitomo, 3 x 10(6) units/day, daily, I. M.) from August 12, but an elevated lesion was detected at the lower part of his esophagus by endoscopy, and it was diagnosed by biopsy as squamous cell carcinoma. Radical operation for esophageal cancer was performed on September 26; at that time his WBC count was 17,400/microliters. After discharge, his WBC level was maintained within normal range by IFN-alpha. On August 2, 1989, he was readmitted to our hospital because of lymphoblastic crisis. Although he attained transient complete remission, he died of pneumonia after the relapse on January 10, 1990. IFN-alpha therapy is suggested to be useful for the treatment of CML associated with gastrointestinal cancer because of its possible parenteral administration and mild toxicity.
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PMID:[Chronic myelocytic leukemia induced into remission by interferon-alpha associated with early esophageal cancer]. 192 Aug 43

Since the introduction of interferon alpha-2b (IFN alpha-2b) into clinical oncology there have been several reports dealing with acute renal failure during therapy with this new type of anticancer drug. We investigated 58 patients (pts) with myeloproliferative syndromes (56 pts with chronic myelogenous leukemia, 2 pts with essential thrombocythemia) who were treated with 4 x 10(6) IU IFN alpha-2b each day subcutaneously. In order to assess the nephrotoxic potential we used the following noninvasive methods: 1. Analysis of the excretion of 4 urinary enzymes (LDH, LAP, GGT, NAG), 2. Determination of the excretion of protein, albumin, alpha-1-microglobulin immunoglobulin G (Ig G), 3. serum creatinine. The investigations were done every 2 weeks and took 70 weeks. We found an increase in the excretion of all 4 enzymes which remained stable during the whole observation period, protein excretion was pathological in about 20% of all pts and reached values of up to 9.07 g/L alpha-1-microglobulin was excreted in pathological amounts in about 20% of all pts during the whole observation period, albumin was found in pathological quantities in about 15% of all pts and Ig G was pathologically increased in the urine in about 10% of the pts. Serum creatinine rose in 5-10% of the pts up to 1.5 mg/dL. In conclusion, IFN alpha-2b is capable of inducing combined glomerular and tubular damage. Therefore, avoiding additional nephrotoxic insults is desirable.
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PMID:Investigations on the subclinical and clinical nephrotoxicity of interferon alpha-2B in patients with myeloproliferative syndromes. 195 45

Eighteen patients with myeloproliferative syndrome (14 with chronic myeloid leukemia, four with essential thrombocytosis) were investigated for modulation of HLA antigens on peripheral blood lymphocytes, monocytes, and hematopoietic precursors during IFN alpha therapy as a sign of potentially increased immune recognition of malignant cells. After 1 month of IFN alpha therapy, an increased number of monocytes and hematopoietic precursor cells, but not of lymphocytes, expressed HLA-DQ antigens. In addition, a strong induction of HLA class-I antigens was found on both hematopoietic progenitors and normal peripheral blood mononuclear cells. With daily injections of IFN in the first month of therapy stimulation continuously increased, suggested a major effect of IFN alpha on hematopoietic progenitors with sustained enhanced expression of HLA class-I antigens during differentiation of myelomonocytic cells. HLA class-I antigen expression was consistently augmented by IFN alpha in all patients, irrespective of their hematological response.
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PMID:In vivo induction of HLA molecules in patients with myeloproliferative syndrome during IFN alpha treatment. 195 50

Human interferon-alpha (IFN-alpha) has been shown to be effective in the treatment of Philadelphia chromosome (Ph1)-positive chronic myelogenous leukemia (CML) in the benign stable phase. The present study indicates that IFN-alpha may have a suppressive effect on Ph1-positive clones not only in the early stable phase but also in the accelerated phase with additional chromosomal abnormalities in some patients. In this study, in addition to 5 benign-phase patients, 3 patients with CML in the accelerated phase who had additional chromosomal abnormalities were treated with IFN-alpha. The presence of the Ph1-positive clone was estimated by chromosomal analysis and by Southern analysis at the DNA level using a 3' breakpoint cluster region (bcr) probe. Hematological remission and the suppression of proliferation of Ph1-positive clone to various extents were achieved by IFN-alpha treatment in 2 benign-phase patients and 3 patients with additional chromosomal abnormalities. Interestingly, in one of the latter three patients, Ph1-positive clones with or without additional chromosomal abnormalities were completely suppressed judging from chromosomal analysis and from the disappearance of bcr gene rearrangements.
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PMID:Effect of interferon-alpha in patients with chronic myelogenous leukemia in the accelerated phase: cytogenetic and molecular studies. 197 21

alpha-Interferon (IFN-alpha) is important in the management of chronic myelogenous leukemia (CML). The P210bcr/abl fusion protein, with enhanced tyrosine kinase activity, is implicated in the pathogenesis and progression of the disease. To elucidate the inhibitory mechanism of IFN-alpha on CML cell proliferation, we studied the effect of IFN-alpha on P210bcr/abl in K-562 cells. The phosphorylated level of P210bcr/abl was not altered by treatment with IFN-alpha alone despite its inhibiting cell proliferation. However, when K-562 cells were treated with either a low (5 x 10(2) U/ml) or high (10(4) U/ml) concentration of IFN-alpha in the presence of hemin, P210bcr/abl protein activity decreased through reduction of in vivo phosphorylation, but not through inhibition of de novo protein synthesis. Furthermore, hemoglobin content was increased by IFN-alpha at both low and high concentrations in tandem with hemin-induced erythroid differentiation and the change in P210bcr/abl. These results demonstrate that IFN-alpha synergises hemin-mediated erythroid differentiation as it reduces the in vivo tyrosine phosphorylation of P210bcr/abl in K-562 cells.
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PMID:Alpha-interferon reduces in vivo phosphorylation of P210bcr/abl protein during hemin-induced erythroid differentiation of K-562 cells. 199 6

Treatment of Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) with recombinant interferon-alpha (IFN-A) results in complete disappearance of the Ph chromosome in about 10% to 15% of patients in early chronic phase. This group has a long survival and very low incidence of blast crisis. The first known case is reported of extramedullary blastic transformation in a patient with medullary complete cytogenetic response (0% Ph-positive metaphases) to IFN-A. Four episodes of extramedullary blast crisis have occurred in this patient. The first three episodes were lymphoid by morphology and cytochemical stains. Molecular analysis confirmed breakpoint cluster region rearrangement. The most recent transformation was myeloid in nature and involved bone and pulmonary parenchyma. The patient is currently undergoing a second autologous transplantation with stored bone marrow that is Ph negative. The patient has survived more than 18 months since the first episode of blast crisis, and the bone marrow is normal.
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PMID:Extramedullary blast crisis in a patient with Philadelphia chromosome-positive chronic myelogenous leukemia in complete cytogenetic remission. 200 8

The possible synergistic interaction between azidothymidine (AZT) and interferon alpha (rIFN-alpha 2a) in the treatment of chronic myelogenous leukemia (CML) was studied in vitro using marrow or peripheral blood hematopoietic progenitors from 10 patients with CML in the mixed (CFU-GEMM) colony culture assay. Used singly, either agent inhibited erythroid (BFU-E) and granulocyte-macrophage (CFU-GM) CML hematopoietic progenitor proliferation in a dose-dependent fashion, with the inhibitory effect being more pronounced on BFU-E than on CFU-GM colony-forming cells. The combination of both drugs in therapeutic concentrations exerted a significant synergistic inhibition on CML stem cells as assessed by the median-effect principle and isobologram equation analysis. A suboptimal dose of AZT (0.5 mumol/l) synergistically augmented the effect of rIFN-alpha 2a whereas an inactive dose of 10 U/ml rIFN-alpha 2a similarly enhanced the CML stem cell growth inhibition exerted by AZT. Our data indicate that AZT may augment the already established therapeutic benefits of IFN-alpha in CML.
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PMID:Synergistic antiproliferative effect of interferon alpha and azidothymidine in chronic myelogenous leukemia. 202 Jan 93

We studied the effect of recombinant interferon-alpha 2a (IFN alpha) on the interaction between stromal cells and granulocyte-macrophage colony-forming units (CFU-GM) from the marrow of normal individuals and chronic myeloid leukemia (CML) patients in chronic phase in long-term bone marrow cultures using preformed stromal layers. These stromal layers were established with marrow cells from normal allogeneic donors and grown to confluence in the presence or absence of IFN alpha at low concentration (100 U/ml). The number of CML CFU-GM localized within IFN alpha-treated stromal layers was significantly greater than the corresponding number localized within control stromal layers. Conversely, the distribution of normal CFU-GM between the adherent and nonadherent compartments was unaffected by IFN alpha treatment of the stromal layer. Preincubation of CML marrow cells with IFN alpha did not alter this distribution, so the observed effect of IFN alpha must be due to a primary action on stromal layers. Thus, in addition to its well known antiproliferative effect, IFN alpha enhances the capacity of marrow stromal cells to bind and/or retain CML progenitor cells, and the resulting restoration of normal regulatory control may be the basis for the selectivity of IFN alpha in CML.
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PMID:Interferon-alpha alters the distribution of CFU-GM between the adherent and nonadherent compartments in long-term cultures of chronic myeloid leukemia marrow. 202 84

After years of stagnation in the treatment of chronic haematological malignancies, some interesting agents have emerged which might improve the prognosis of these diseases. For chronic leukaemias of lymphoid lineage, three new chemical agents, all purine analogues, seem to be of particular interest. Pentostatin is a specific inhibitor of ADA and has been shown to be highly efficient in producing CR in patients with HCL. Its relative merit compared with IFN-alpha for the treatment of HCL is being studied in ongoing randomized trials. Pentostatin is also active in B-CLL and promising activities have been demonstrated in T- or B-PLL and ATCL. Fludarabine is an analogue of adenine which is resistant to the deamination of ADA. It has been reported to be highly active for patients with both pretreated or non-treated B-CLL. CR rates of 13% with overall response rates of 57% can be achieved, even in heavily pretreated patients. Its activity in the other lymphoid malignancies is not yet known. CdA, a substrate analogue of ADA, has also produced encouraging results in B-CLL, HCL and T cell malignancies, and in some patients with just one single course. Thus far, experience with this drug comes from one institution and requires further confirmation. For chronic myeloproliferative diseases, little progress has yet been made. Although IFN-alpha seems to be active in CML and to result in cytogenetic remissions in bone marrow, a definite advantage of this biological agent over conventional chemotherapy as regards survival and life quality has not yet been proven. Allogeneic bone marrow transplantation is beneficial for those patients who are eligible. No remarkable advances have been made in the treatment of myeloproliferative disorders except for the development of an antiplatelet drug, anagrelide. This agent seems to be highly effective in controlling thrombocytosis. The relative merit of this agent as compared with IFN-alpha, as well as the impact of this agent on the survival and on life-quality of patients with myeloproliferative disorders, have yet to be defined.
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PMID:Chemotherapy of chronic haematological malignancies. 203 59


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