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)

A randomized, double-blind, multicenter study in 181 afebrile cancer patients with ANC levels < 500/microL receiving myelosuppressive chemotherapy was undertaken to compare sargramostim (yeast-derived recombinant human granulocyte-macrophage colony-stimulating factor, RhuGM-CSF) and filgrastim (bacteria-derived recombinant human granulocyte colony-stimulating factor, RhuG-CSF) in the treatment of chemotherapy-induced myelosuppression. Patients received daily subcutaneous (SC) injections of either agent until ANC levels reached at least 1500/microL. There was no statistical difference between treatment groups in the mean number of days to reach an ANC of 500/microL, but the mean number of days to reach ANC levels of 1000/microL and 1500/microL was approximately one day less in patients receiving filgrastim. Fewer patients in the sargramostim arm were hospitalized, and they had a shorter mean length of hospitalization, mean duration of fever, and mean duration of i.v. antibiotic therapy compared with patients who received filgrastim. Both growth factors were well tolerated. No patient was readmitted to the hospital after growth factor was discontinued. Sargramostim and filgrastim have comparable efficacy and tolerability in the treatment of standard-dose chemotherapy-induced myelosuppression in community practice.
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PMID:A comparison of efficacy of sargramostim (yeast-derived RhuGM-CSF) and filgrastim (bacteria-derived RhuG-CSF) in the therapeutic setting of chemotherapy-induced myelosuppression. 1051 2

Myelosuppression is the dose-limiting side effect of most forms of radioimmunotherapy (RAIT). Long-term leukopenia (4-8 weeks) has been documented from a single maximum tolerated dose (MTD) in experimental mice. Several methods for alleviating RAIT-induced marrow toxicity have been evaluated preclinically, including cytokine intervention, bone marrow transplantation (BMT), and hemoregulatory peptide administration. To improve the therapeutic potential of RAIT, multiple doses of radioantibody must be delivered. Maximizing the frequency of radioantibody administration is desirable. However, little is known about the myelotoxic effects of multiple cycles of RAIT. In the studies presented here we compared the magnitude of myelosuppression, the time of nadir, and the duration of toxicity associated with one or two MTDs of 1-131-MN-14 anti-carcinoembryonic antigen immunoglobulin G (250 microCi) administered to BALB/c mice 49 days apart, the shortest interval possible without producing lethality. Studies were conducted with radioantibody alone or with cytokines (interleukin-1/granulocyte-macrophage colony-stimulating factor), BMT, or Hp5b to determine whether bone marrow became more "brittle" after the first dose. Profiles of myelosuppression and recovery were monitored weekly for 7 weeks after each dose in both granulocyte and lymphocyte populations. The results demonstrated that granulocyte suppression was greater and of longer duration after the second dose of RAIT administered alone, with cytokines, or with BMT, but less severe with Hp5b. For example, in the RAIT + BMT treatment, the second dose resulted in an 87% loss of granulocytes, whereas a 30% loss occurred after the first dose. The nadir of toxicity lasted until days 21 to 28 after the second dose and until day 14 after the first dose. Lymphocyte suppression was of greater duration after the second cycle of RAIT alone or RAIT with BMT, plateauing at <50% of untreated levels between days 28 and 49, but was of shorter duration when RAIT was given with cytokines or Hp5b. The results are discussed in terms of 1) the radiosensitivity of each subpopulation, 2) the effects on progenitors and on stromal cells, 3) the benefits of increasing dose frequency vs. increasing dose intensity, and 4) the possibility of using preclinical data to optimize the frequency of dosing in patient trials.
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PMID:Myelosuppressive changes from single or repeated doses of radioantibody therapy: effect of bone marrow transplantation, cytokines, and hematopoietic suppression. 969 7

PIXY321, a granulocyte-macrophage colony-stimulating factor/interleukin 3 (GM-CSF/IL-3) genetically engineered hybrid, has shown greater biological activity in stimulating committed myeloid progenitors than either GM-CSF or IL-3 in vitro, in vivo, and in patients treated with high-dose chemotherapy. However, one concern is that PIXY321 may stimulate the proliferation of malignant cells which have functional GM-CSF or IL-3 receptors. Therefore, using a human tumor cloning assay, we have tested the effects of several concentrations of PIXY321 ranging from 0.1 to 100 ng/ml on tumor cells taken directly from 98 patients with solid tumors and Hodgkin's or non-Hodgkin's lymphomas. Of the 34 evaluable specimens, including 15 breast cancers, 5 ovarian cancers, 5 lung cancers, and 9 lymphomas, none showed stimulation of tumor growth. Interestingly, a significant inhibition of the tumor proliferation was seen in one breast cancer and in one large cell immunoblastic non-Hodgkin's lymphoma after continuous exposure of PIXY321. In conclusion, the use of PIXY321 to reduce myelosuppression after high-dose chemotherapy appears unlikely to result in stimulation of the growth of malignant cells in patients with lymphoma or cancers of the breast, lung, and ovary.
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PMID:Effects of PIXY321, a granulocyte-macrophage colony-stimulating factor/interleukin 3 fusion protein, on human tumor colony-forming units taken directly from patients. 981 21

Interleukin (IL)-3 is a multipotent hematopoietic growth factor produced by activated T cells, monocytes/macrophages and stroma cells. The human IL-3 gene is located on chromosome 5 near segment 5q31. The high-affinity receptor for human IL-3 is composed of alpha and beta subunits. IL-3 shares a common beta subunit with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-5; this subunit has been mapped to chromosome 22q13.1. The biological effects of IL-3 have been studied in human and murine hematopoietic cell lines and normal human marrow cells. Addition of IL-3 to the culture medium induces proliferation, maturation and probably self-renewal of pluripotent hematopoietic stem cells and cells of myeloid, erythroid and megakaryocytic lineages. Human IL-3 was cloned in 1986, and since then various clinical trials have assessed the in vivo potential of recombinant human (rhIL-3). Initial results of phase I/II studies of IL-3 at a dose of 5-10 microg/kg subcutaneously daily for 5-10 days in patients with relapsed lymphomas, small-cell lung cancer, breast cancer and ovarian cancer showed that post-chemotherapy application of IL-3 reduces chemotherapy delays and induces faster regeneration of granulocytes and platelets. However, these results were not confirmed in phase III studies. The role of IL-3 alone in the treatment of myelodysplastic syndromes (MDS), aplastic anemia (AA) and other bone marrow failure disorders have also been disappointing. However, preliminary studies of IL-3 in combination with chemotherapeutic agents and immunosuppression have demonstrated encouraging results in patients with MDS and AA respectively. The therapeutic potential of IL-3 in peripheral blood stem cell (PBSC) harvesting and priming of stem cells before harvest is beginning to be identified. Initial results of IL-3 combination with GM-CSF or later-acting growth factors such as granulocyte colony-stimulating factor (G-CSF) have yielded larger amounts of PBSC during harvesting. In recent years, the availability of synthetic IL-3 receptor (IL-3R) agonists and similar chimeric molecules with greater in vitro biological activity and fewer inflammatory side-effects has extended our options to employ and compare these molecules and rhIL-3 for the prevention of chemotherapy-induced myelosuppression. The role of IL-3 and IL-3R agonists in ex vivo expansion of stem cells, dendritic cell development and gene transfer requires further evaluation. It appears that future application of IL-3 in combination with other cytokines is an attractive way forward in the prevention of treatment-related mortality and morbidity in oncology patients. It also shows prospects for the development of new therapeutic strategies for dose escalation and immune modulation for cancer patients with relapsed and resistant disease.
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PMID:Interleukin-3 in hematology and oncology: current state of knowledge and future directions. 1051 81

Renewed interest in chronic lymphocytic leukemia (CLL) has led to an unprecedented number of investigators contributing to all aspects of research in this disease. In fact, the evolution of research in the area of molecular aberrations in CLL and their impact on treatment resistance alone is striking. These data, along with the advent of the purine analogs, have been central to this paradigm shift. The inferior response rate, the abbreviated response duration, and the inability to prolong survival with alkylating agents such as chlorambucil have resulted in purine analogs being used as first- and second-line therapy for patients with CLL. In fact, patients treated with fludarabine have a higher overall and complete response rate as well as a disease-free survival advantage compared with patients treated with alkylator-based therapy. Pentostatin, the first purine analog to enter clinical trials, was never subjected to extensive schedule optimization despite its demonstrated efficacy and its paucity of significant myelosuppression compared with the other purine analogs. However, pentostatin induced a 25% to 30% response rate in heavily pretreated CLL patients, including some who had received prior fludarabine, suggesting possible non-cross-resistance. Based on preclinical data demonstrating synergistic activity when a DNA damaging agent (eg, an alkylating agent) is followed by an inhibitor of DNA repair (a purine analog), a number of purine analog/alkylator combinations have been and are presently being examined in a variety of lymphoid neoplasms. While the clinical data conflict, at least two phase II studies examining a combination of a purine analog and an alkylator in untreated patients with CLL have generated promising data. This report describes the scientific justification and the design of a new phase II study examining the combination of pentostatin and chlorambucil with granulocyte-macrophage colony-stimulating factor support for patients with untreated, treated, and fludarabine-refractory B-cell CLL.
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PMID:Pentostatin (Nipent) and chlorambucil with granulocyte-macrophage colony-stimulating factor support for patients with previously untreated, treated, and fludarabine-refractory B-cell chronic lymphocytic leukemia. 1087 52

Chemotherapy regimens similar to those used for non-Hodgkin's lymphoma (NHL) not associated with human immunodeficiency virus (HIV) infection have been used for patients with HIV-associated NHL with less success. In a recent trial, patients with intermediate or high-grade NHL were randomized to either low-dose chemotherapy with methotrexate, bleomycin, doxorubicin, vincristine and dexamethasone (m-BACOD) or to standard-dose m-BACOD with sargramostim (granulocyte-macrophage colony-stimulating factor, GM-CSF). With low-dose m-BACOD 41% of patients achieved a complete remission and the median survival was 35 weeks. With standard-dose m-BACOD and sargramostim, the percentage of complete remissions was 52% with a median survival of 31 weeks (P=n.s.). Myelosuppression was greater with standard-dose chemotherapy. In univariate and multivariate analyses of 21 pretreatment features of patients in this trial, four factors emerged as adversely prognostic with respect to survival: age >35 years, intravenous drug use, CD4 counts < 100/mm3 and stage III/IV disease. In an analysis using the proportional hazards model, a "favorable" group was defined by patients with 0 or 1 adverse factor (median survival 46 weeks, survival at 144 weeks 29.5%) as compared with an unfavorable group with 3 or 4 adverse factors (median survival 18 weeks, survival at 144 weeks 0). The outcome of these patients may be improving with the use of highly active antiretroviral therapy (HAART), which seems to improve immune function and tolerance of chemotherapy. A recent trial of the AIDS Malignancy Consortium found that low-dose chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone: CHOP) and standard-dose chemotherapy had similar response rates, acceptable toxicity and minimal alterations in cyclophosphamide, doxorubicin and indinavir pharmacokinetics in HIV-associated lymphoma patients also on HAART (stavudine, lamivudine and indinavir). There is a suggestion that Burkitt-type lymphomas may tend to occur in HIV-infected patients with relatively well preserved immune function and CD4 cell counts. Recent results from our institution suggest that similar outcomes are achievable with intensive chemotherapy in patients with Burkitt's lymphomas with or without HIV infection. With improved immune status and improved bone marrow function with the use of HAART, it will probably become more possible to treat many patients with aggressive HIV-associated NHL with more intensive treatment regimens.
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PMID:Prognostic factors in the treatment of human immunodeficiency virus-associated non-Hodgkin's lymphoma. 1178 38

Myelosuppression is a common side effect in elderly patients undergoing chemotherapy. Neutropenia and anemia cause considerable morbidity, may increase mortality, and can result in a worse outcome of treatment in elderly patients compared to younger patients with comparable type and stage of disease. The availability and proven efficacy of hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO) have had a considerable impact on supportive care in cancer patients: Several randomized trials have demonstrated a reduction of neutropenia and the frequency of severe infections in elderly patients treated with G-CSF following myelotoxic chemotherapy compared with patients without growth factor support. Both for G-CSF and for recombinant human erythropoietin (rHu-EPO) several studies have demonstrated the safety and effectiveness of these molecules in elderly patients with regard to increasing hemoglobin concentrations, improving quality of life (rHu-EPO), and neutrophil recovery. Although a positive effect of the use of growth factors on overall survival in elderly cancer patients is not yet proven, a reduction of chemotherapy-induced side effects could clearly be shown. The National Comprehensive Cancer Network (NCCN) of cancer centers has recommended that all patients aged 70 years and older treated with CHOP or cytotoxic chemotherapy of comparable intensity should receive prophylactic G-CSF administration, and that the hemoglobin concentration be maintained at >or=12 g/dl in elderly patients undergoing chemotherapy.
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PMID:Use of hematopoietic growth factors in elderly patients receiving cytotoxic chemotherapy. 1189 81

Patients with advanced MDS and secondary AML respond poorly to chemotherapy. Granulocyte-macrophage colony-stimulating factor (GM-CSF) can stimulate proliferation of leukemic blasts and sensitize these cells to the cytotoxic effects of S-phase-specific drugs. This is the first report of safety and efficacy of GM-CSF prior to and during cytarabine in a low-dose, intermittent regimen for elderly patients with poor risk acute myelogenous leukemia or myelodysplastic syndrome. Twenty patients, age 68 to 86 years, each received 250 microg/m2 of GM-CSF (Sargramostatin; Immunex, Seattle, WA, USA) subcutaneously (s.c.) or intravenously (i.v.) for 3 days followed by GM-CSF at the same dose and cytarabine 100 mg/m2 i.v. for 3 days. GM-CSF and cytarabine were both administered for 3 days during weeks 2 and 3 followed by a 3-week rest period. Rates of CR and PR were 20% and 40%, respectively. These included clinically significant resolution of cytopenias and transfusion requirements. Many of the responding patients had been heavily pretreated prior to enrollment. One- and 2-year survival estimates are 44% and 19%, respectively. Myelosuppression was the most significant toxicity. Our findings suggest that this novel combination of GM-CSF with sequential and concomitant low-dose cytarabine can benefit patients with poor risk myeloid malignancies.
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PMID:Granulocyte-macrophage colony-stimulating factor (GM-CSF) priming with successive concomitant low-dose Ara-C for elderly patients with secondary/refractory acute myeloid leukemia or advanced myelodysplastic syndrome. 1189 33

More than 50% of all malignancies are diagnosed in patients aged > 65 years and most cancer-related deaths occur in this population. Misconceptions about prognosis and treatment contribute to the undertreatment of elderly cancer patients and consequent poor outcomes. Although older patients have been excluded from cancer treatment trials in the past, response rates to chemotherapy in a variety of common cancers in otherwise healthy elderly patients are comparable to those attained in younger patients. Lower functional reserve in many organ systems alters the pharmacokinetics of chemotherapeutic drugs as well as the patient's response to treatment-induced toxicity. Except for myelosuppression and mucositis, otherwise fit elderly cancer patients are not at significantly enhanced risk of toxicity to chemotherapy. Severe neutropenia and related infection are encountered much more frequently during the treatment of elderly as compared with younger cancer patients. These lead to treatment delays, dose reductions and higher hospitalisation rates. Myelopoietic growth factor support reduces myelosuppression and the associated risk of severe infection, thereby allowing delivery of chemotherapy at full dose intensity. Beneficial responses to granulocyte colony-stimulating factor (G-CSF; filgrastim) in elderly patients have been found in aggressive non-Hodgkin's lymphoma with standard cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) therapy and acute myeloid leukaemia (AML) during induction and consolidation chemotherapy. Granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostim) has been found to reduce myelosuppression in elderly AML patients receiving induction but not consolidation chemotherapy. These prophylactic treatments produce significant cost benefits because of the reduced hospitalisation and antibiotic use associated with neutropenia. To maximise positive outcomes, elderly patients should be included in clinical trials of new cancer agents. Since myelosuppression is the main risk factor for elderly patients undergoing chemotherapy, optimisation of growth factor support and the development of more effective and safer myelopoietic agents may improve success rates and reduce adverse events. Such information will lead to better management of cancer in older patients.
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PMID:The role of myelopoietic growth factors in managing cancer in the elderly. 1247 94

Hematopoietic progenitor cell (HPC) homeostasis is critical in maintaining innate immunity and healing processes. Recently, we demonstrated that Th1 cells regulate HPC homeostasis, partly based on altered homeostasis in Stat4- and Stat6-deficient mice. To explore changes in HPC responsiveness in altered T helper cell environments, we directly examined growth factor-stimulated colony formation and chemokine-induced myelosuppression of HPC in Stat4- and Stat6-deficient bone marrow cells. Stat6-deficient cells have increased responses to the synergy between granulocyte-macrophage colony-stimulating factor (GM-CSF) and steel factor (SLF), compared to wild-type and Stat4-deficient cells. Increased responses are eliminated by in vivo depletion of CD4 cells. Whereas Stat6-deficient bone marrow cells respond to chemokine-mediated myelosuppression, Stat4-deficient bone marrow cells are refractory to the suppressive effects of chemokines. Thus, T helper cell development affects HPC homeostasis through several mechanisms, including the sensitivity to growth factor stimulation and chemokine suppression of HPC colony formation. Since Stat4 and Stat6 regulate opposing programs of T helper differentiation, there are distinct requirements for Stat4 and Stat6 in regulation of growth factor and chemokine responses of HPC.
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PMID:Distinct requirements for Stat4 and Stat6 in hematopoietic progenitor cell responses to growth factors and chemokines. 1296 77


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