Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied serum lipid and lipoprotein changes before and after induction treatment in 25 acute nonlymphocytic leukemia (ANLL) and in 18 acute lymphocytic leukemia (ALL) patients in order to investigate their relationship with disease activity and their prognostic relevance. ANLL at diagnosis is associated with significantly low levels of all lipid parameters, the same applies to ALL patients apart from plasma triglycerides and very-low-density-lipoprotein cholesterol (VLDL-C) which are significantly higher than in the normal population. In ANLL responders, after effective chemotherapy, a significant increase of total cholesterol, low-density-lipoprotein cholesterol (LDL-C) and apolipoprotein B levels, without changes of high-density-lipoprotein cholesterol (HDL-C) values, is observed. A further decrease of total cholesterol and LDL-C was found in nonresponders and in ANLL responders treated with granulocyte-macrophage colony-stimulating factor (GM-CSF), known for its cholesterol-lowering action; in fact after the completion of GM-CSF therapy, these parameters returned progressively toward normal values. In ALL responders an increase of total cholesterol, HDL-C and apolipoprotein A1 with a simultaneous decrease of triglycerides and VLDL-C is evident; no variation was found in the nonresponder group. These results suggest a close correlation between serum lipids and acute leukemia: total cholesterol and LDL-C in ANLL, and HDL-C and VLDL-C in ALL may be considered reliable markers of complete remission and may be useful in the follow-up of leukemic patients.
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PMID:Prognostic relevance of lipoprotein cholesterol levels in acute lymphocytic and nonlymphocytic leukemia. 867 57

Placebo-controlled and/or historically controlled trials have shown that granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor (GM-CSF) enhance neutrophil recovery rates and occasionally reduce the rate and duration of infection. Some data appear to support an advantage with GM-CSF in reducing the incidence of fungal infections. Immunomodulation with cytokines such as interferon or interleukin-2 may prove to be of benefit in the management of acute leukemia when used in combination or sequence with chemotherapy.
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PMID:Use of cytokines in the treatment of acute lymphoblastic leukemia. 917 81

We report here a naturally occurring isoform of the human beta chain common to the receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 (GMRbetaC) with a truncated intracytoplasmic tail caused by deletion of a 104-bp exon in the membrane-proximal region of the chain. This beta intracytoplasmic truncated chain (betaIT) has a predicted tail of 46 amino acids, instead of 432 for betaC, with 23 amino acids in common with betaC and then a new sequence of 23 amino acids. In primary myeloid cells, betaIT comprised approximately 20% of the total beta chain message, but was increased up to 90% of total in blast cells from a significant proportion of patients with acute leukemia. Specific anti-betaIT antibodies demonstrated its presence in primary myeloid cells and cell lines. Coexpression of betaIT converted low-affinity GMRalpha chains (KD 2.5 nmol/L) to higher-affinity alphabeta complexes (KD 200 pmol/L). These could bind JAK2 that was tyrosine-phosphorylated by stimulation with GM-CSF. betaIT did not support GM-CSF-induced proliferation when cotransfected with GMRalpha into CTLL-2 cells. Therefore, it may interfere with the signal-transducing properties of the betaC chain and play a role in the pathogenesis of leukemia.
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PMID:A truncated isoform of the human beta chain common to the receptors for granulocyte-macrophage colony-stimulating factor, interleukin-3 (IL-3), and IL-5 with increased mRNA expression in some patients with acute leukemia. 941 69

Previous studies of the hematologic effects of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have emphasized the morphologic changes induced by these growth factors, but few have reported increases in blasts. Here, we report six cases in which growth factor treatment resulted in a marked but temporary increase in peripheral and bone marrow blasts that led to diagnostic confusion with acute leukemia and high-grade myelodysplastic syndromes. Five of the six patients were receiving treatment for hematologic malignant neoplasms, and one patient had an optic nerve germinoma. Growth factor treatment included single agent therapy with G-CSF (three patients), GM-CSF (one patient), or simultaneous therapy with G-CSF and GM-CSF (two patients). In two patients, there was a dramatic increase in blasts in the peripheral blood (39% and 20%), whereas four had substantial increases in blasts on the aspirate smear (8%-41%). One patient had a medium-sized blast cluster shown on the core biopsy specimen. The blasts decreased after removal of growth factor in all patients. The findings indicate that growth factor therapy can cause a substantial transient increase in blasts in the bone marrow and peripheral blood that may be confused with relapse of acute leukemia or progression of a myelodysplastic syndrome.
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PMID:Transient increase in blasts mimicking acute leukemia and progressing myelodysplasia in patients receiving growth factor. 1023 Mar 65

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is an EGF family member expressed by numerous cell types that binds to EGF receptor 1 (HER-1) or 4 (HER-4) inducing mitogenic and/or chemotactic activities. Membrane-bound HB-EGF retains growth activity and adhesion capabilities and the unique property of being the receptor for diphtheria toxin (DT). The interest in studying HB-EGF in acute leukemia stems from these mitogenic, chemotactic, and receptor functions. We analyzed the expression of HB-EGF in L428, Raji, Jurkat, Karpas 299, L540, 2C8, HL-60, U937, THP-1, ML-3, and K562 cell lines and in primary blasts from 12 acute myeloid leukemia (AML) cases, by reverse-transcriptase polymerase chain reaction (RT-PCR) and Northern blot and by the evaluation of sensitivity to DT. The release of functional HB-EGF was assessed by evaluation of its proliferative effects on the HB-EGF-sensitive Balb/c 3T3 cell line. HB-EGF was expressed by all myeloid and T, but not B (L428, Raji), lymphoid cell lines tested, as well as by the majority (8 of 12) of ex vivo AML blasts. Cell lines (except for the K562 cell line) and AML blasts expressing HB-EGF mRNA underwent apoptotic death following exposure to DT, thus demonstrating the presence of the HB-EGF molecule on their membrane. Leukemic cells also released a fully functional HB-EGF molecule that was mitogenic for the Balb/c 3T3 cell line. Factors relevant to the biology of leukemic growth, such as tumor necrosis factor-alpha (TNF-alpha), 1alpha,25-(OH)2D3, and especially all-trans retinoic acid (ATRA), upregulated HB-EGF mRNA in HL-60 or ML-3 cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) induced HB-EGF mRNA and acquisition of sensitivity to DT in one previously HB-EGF-negative leukemia case. Moreover, the U937 and Karpas 299 cell lines expressed HER-4 mRNA. This work shows that HB-EGF is a growth factor produced by primary leukemic cells and regulated by ATRA, 1alpha, 25-(OH)2D3, and GM-CSF.
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PMID:Heparin-binding epidermal growth factor-like growth factor/diphtheria toxin receptor expression by acute myeloid leukemia cells. 1002 1

Morphophenotypic lineage switches occur in a small percentage of those with acute leukemia, and the underlying mechanisms are not clear. In this study, we attempted to induce a lineage switch in acute myelocytic leukemia (AML) with monosomy 7, whose lineage had switched from acute T-lymphocytic leukemia (T-ALL) during chemotherapy, in severe combined immunodeficient (SCID) mice. Although the transplanted myeloid cells were engrafted in SCID mice without cytokine administration, T-ALL developed in SCID mice treated with recombinant human granulocyte-macrophage colony-stimulating factor or recombinant human interleukin 3. Analysis of the nucleotide sequences of the rearranged T-cell receptor gamma-chain (TCR-gamma) gene revealed that this lineage switch resulted from the selection of the T-lineage subclone in SCID mice, which had expanded at onset. In addition, we found that the T-lineage and myeloid cells belonged to the distinct subclones, which were different in TCR-gamma gene rearrangements, but were derived from a common clone with an identical N-ras gene mutation for both subclones. In in vitro cultures, only the myeloid subclone grew; the T-lineage subclone failed to grow even in the presence of recombinant human granulocyte-macrophage colony-stimulating factor or recombinant human interleukin 3. These results suggested that the initial diagnostic T-lymphoid subclone, whose growth was dependent on these cytokines and the hematopoietic microenvironment, emerged from a bipotential T-lymphoid/myeloid leukemic stem cell, and further genetic event(s) induced the myeloid subclone, which grew independently of these cytokines and the microenvironment.
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PMID:Lineage switch in childhood leukemia with monosomy 7 and reverse of lineage switch in severe combined immunodeficient mice. 1034 Mar 98

We showed in a phase I trial that the maximum tolerated dose of the ProMACE-CytaBOM regimen in patients with aggressive lymphoma was 200% (Gordon et al, J Clin Oncol 14:1275, 1996). Based on these observations, we initiated a phase II trial designed to determine response, toxicity, and dose intensity using this regimen. We analyzed 74 patients with advanced-stage (III or IV) or bulky stage II aggressive lymphoma. The overall complete response rate was 69% (72% in evaluable patients). With a median follow-up of 4.5 years, the median survival has not yet been reached. The 4-year survival rate is 73% (95% confidence interval [CI] 62, 83%) and no difference was observed among International Prognostic Index (IPI) groups. The 4-year disease-free survival was 71% (95% CI 58, 84%) with no statistical difference between patients with IPI 0 to 1 versus 2 to 4. The toxicity was acceptable, though the grade 4 hematologic toxicity rate for this regimen was 100%. Grade 4 nonhematologic toxicity was 36%. Three cases of either myelodysplastic syndrome or acute leukemia occurred at 7 months, 3.4 years, and 4.2 years after registration. Cytogenic analysis was available in two cases, showing inv(16) without French American British classification (FAB) M4 EO histology in one patient and a 5q-syndrome in the other. These data suggest that 200% ProMACE-CytaBOM with either granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF results in a high complete remission rate and a disease-free survival comparable to any prior risk-based analysis in aggressive lymphoma. Before using this regimen in general practice, phase III clinical trials should be conducted.
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PMID:A phase II trial of 200% ProMACE-CytaBOM in patients with previously untreated aggressive lymphomas: analysis of response, toxicity, and dose intensity. 1055 39

Conventional chemotherapeutic treatments of acute leukemias are often associated with life-threatening toxic effects due to a lack of specificity for hematopoietic cells. Monoclonal antibodies and fusion proteins that target antigens on leukemic blasts are being explored for their antileukemic effects and as a means of delivering chemotherapy or radiation directly to malignant cells. This approach might be safer and more effective than current non-specific chemotherapeutic agents. The cell surface antigens CD33 and CD45 are attractive targets. Although CD33 is expressed on acute myelocytic leukemic blast cells from about 90% of patients, normal hematopoietic stem cells lack this antigen, as do essentially all non-hematopoietic tissues. Anti-CD33 antibodies have been engineered to selectively target malignant myeloid and immature normal cells while sparing normal stem cells. Recently, anti-CD33 antibodies have also been used to deliver radiation or a cytotoxic agent directly to leukemic cells. The strategy for using CD45 as a target differs from CD33 in that it is expressed not only by the vast majority of leukemias, but also by normal stem cells. Therefore, 131I-labeled anti-CD45 antibody has been used in combination with conventional preparative regimens for patients receiving marrow transplantation for acute leukemia. Because the receptor for granulocyte-macrophage colony-stimulating factor is expressed by most myeloid leukemias, fusion proteins consisting of granulocyte-macrophage colony-stimulating factor ligand associated with diphtheria toxin have been proposed as a means of delivering a toxic agent directly to leukemic cells. Both unconjugated and conjugated antibodies show significant promise in the treatment of acute myelocytic leukemia.
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PMID:Clinical studies of new "biologic" approaches to therapy of acute myeloid leukemia with monoclonal antibodies and immunoconjugates. 1068 26

Traditional chemotherapy for acute leukemia often causes life-threatening toxic effects due to a lack of specificity for hematopoietic cells. Monoclonal antibodies and fusion proteins that target cell surface antigens on leukemic blasts are being evaluated for their cytotoxic effects and as a means of delivering chemotherapeutic agents or radiation directly to malignant cells. It is hoped that this strategy might selectively ablate malignant cells without many of the toxic effects commonly associated with conventional chemotherapy. In acute myeloid leukemia (AML), the cell surface antigens CD33 and CD45 are especially suitable targets. Although CD33 is expressed on AML blast cells from about 90% of patients, normal hematopoietic stem cells lack this antigen, as do essentially all nonhematopoietic tissues. For that reason, anti-CD33 antibodies have been created to target malignant myeloid and immature normal cells selectively while sparing normal stem cells. Anti-CD33 antibodies have also been used to deliver radiation or a cytotoxic agent directly to leukemic cells. Since the vast majority of leukemias and normal stem cells express the cell surface antigen CD45, another targeting approach allows the delivery of myeloablative radiation to bone marrow and spleen, common sites of leukemic involvement. Consequently, 131I-labeled anti-CD45 antibody has been combined with traditional preparative regimens for patients receiving bone marrow transplantation for acute leukemia. Finally, fusion proteins such as those combining diphtheria toxin with granulocyte-macrophage colony-stimulating factor (GM-CSF) to target the GM-CSF receptor are now being evaluated in clinical trials. Both unconjugated and conjugated antibodies have shown promise in early clinical trials, and may represent appealing therapeutic alternatives for patients with AML.
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PMID:Targeted therapy of acute myeloid leukemia with monoclonal antibodies and immunoconjugates. 1095 Jan 42

Remission induction chemotherapy for acute myelogenous leukemia typically combines cytarabine with an anthracycline or anthracycline derivative. To date, no specific combination has emerged as more efficacious than any other. To reduce toxicity and shorten the duration of neutropenia, hematopoietic growth factors are often added to the chemotherapy regimen, especially in elderly patients. In all prospective, randomized, growth factor trials to date, daunorubicin has been the drug selected for combination with cytarabine. We hypothesized that mitoxantrone might be as efficacious in this patient population with perhaps less toxicity when combined with granulocyte-macrophage colony-stimulating factor (GM-CSF). Patients older than age 55 years with a diagnosis of either de novo or secondary, untreated acute myelogenous leukemia were eligible for this clinical trial. Eligible patients were treated with cytarabine 100 mg/m2 infused as a continuous infusion daily for 7 days and mitoxantrone 12 mg/m2 bolus intravenously for the first 3 days of cytarabine. A second cycle of chemotherapy was administered on the fourteenth day of treatment if marrow aplasia was not achieved with the first cycle. Once aplasia was achieved, GM-CSF 250 microg/m2 was given subcutaneously daily until neutrophil recovery. Those patients who achieved complete remission were treated with two cycles of intermediate-dose cytarabine (400 mg/m2 daily for 5 days) and with GM-CSF as consolidation therapy. Of the 30 patients treated, the median age was 69 years (range: 55-76 years) and 18 patients were older than 65 years of age. Seven (23%) patients had secondary acute leukemia and 12 (40%) had poor-risk cytogenetics. Nineteen (63%) achieved a complete remission. Eleven patients were either refractory to treatment or died during their treatment. The toxicity encountered was no more than that reported in similar studies using daunorubicin in combination with cytarabine. Long-term survival was poor, with a median disease-free survival of only 8.1 months in patients who achieved complete remission. In this elderly population of patients with high-risk acute myelogenous leukemia, this combination of cytarabine, mitoxantrone, and GM-CSF resulted in an adequate remission rate with acceptable toxicity. Long-term survival, however, was poor and innovative treatment approaches to maintain remission are needed.
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PMID:Chemotherapy for acute myelogenous leukemia in the elderly with cytarabine, mitoxantrone, and granulocyte-macrophage colony-stimulating factor. 1123 51


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