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)

High-dose administration of anticancer agents is attractive both on theoretic and clinical grounds. Yet, high-dose regimens are usually used as salvage treatments, mainly as a consequence of their considerable hematologic toxicity. One pertinent example is represented by cyclophosphamide, an alkylating agent with a wide spectrum of marked antitumor activity. When used at doses up to 7 g/m2 (190 to 200 mg/kg) this drug does not cause myeloablation, but induces a severe, albeit transient, myelosuppression, which requires platelet transfusions in approximately 50% of treated patients, and is frequently complicated by infectious episodes, occasionally lethal. To accelerate hematopoietic recovery, we continuously infused for 14 consecutive days 5.5 micrograms/kg/d of the glycosylated human recombinant granulocyte-macrophage colony-stimulating factor (rhGM-CSF) into 15 patients with breast cancer and non-Hodgkin's lymphoma treated with 7 g/m2 cyclophosphamide. This schedule was chosen having obtained the fastest hematopoietic recovery among four different options during an initial schedule-finding phase on 12 overall patients. Twenty-one comparable subjects with solid tumors served as controls. We report here that this relatively low, well-tolerated dose of rhGM-CSF reduces from 20 to 14 (median) and from 24 to 14, the number of days required to recover circulating granulocyte counts over 1,000 and 2,500/microL, respectively. The stimulatory effect was associated with a remarkable clinical benefit. In fact, treated patients experienced less infectious complications (7% v 24%) were eligible to receive chemotherapy earlier (median, by day +14 v day +20 for controls), and fewer required prophylactic platelet transfusions (13% v 43%). Our results show that even very high doses of cyclophosphamide can be administered with improved hematologic toxicity, tolerable morbidity, and reduced supportive care requirements. The increase in the therapeutic index made possible by rhGM-CSF infusion prompts the use of high-dose cyclophosphamide, and possibly of other agents with similar myelotoxic activity, early in the clinical course of chemotherapy-sensitive tumors.
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PMID:Recombinant human granulocyte-macrophage colony-stimulating factor reduces hematologic toxicity and widens clinical applicability of high-dose cyclophosphamide treatment in breast cancer and non-Hodgkin's lymphoma. 169 86

Previous study has shown that the combination of mitoxantrone (Novantrone, NO) and Ara-C (AC) (NOAC) was active in refractory non-Hodgkin's lymphoma (NHL) but myelosuppression was dose-limiting. In a pilot study, we investigated the effects of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) after NOAC chemotherapy in patients with refractory NHL. NO was applied at a dosage of 10 mg/m2/day on days 2 and 3 and AC at 3 g/m2/12h on days 1 and 2. RhGM-CSF was administered at 250 ug/m2/day as a continuous i.v. infusion from day 6 until the neutrophils were greater than 3.0/nl for 3 consecutive days. Twenty-three patients from five of the nine participating centers were treated with NOAC chemotherapy plus rhGM-CSF, whereas 14 patients from the other four centers received chemotherapy alone. With rhGM-CSF, the median duration of severe neutropenia (less than 0.5/nl) after NOAC was 8 days versus a median of 13 days without rhGM-CSF (P = 0.0058), and that of thrombocytopenia (less than 20.0/nl), 3 days versus 7 days (P greater than 0.4, NS). The rates of infections and stomatitis were 25% and 17%, respectively, for patients treated with rhGM-CSF as compared to 53% (P = 0.0547, NS) and 60% (P = 0.0078), respectively, without rhGM-CSF. The following side effects were associated with the administration of rhGM-CSF: pleural and/or pericardial effusions in five patients, thrombosis in two patients, bone pain in two patients, and respiratory distress syndrome in one patient. A complete remission was achieved in nine of the 23 patients treated with NOAC plus rhGM-CSF, and in two of the 14 patients treated with chemotherapy alone. The median survival of patients treated with rhGM-CSF was not reached at 400 days and seemed to be longer than that of patients treated with chemotherapy alone (median, 109 days; P = 0.036). RhGM-CSF after chemotherapy can be applied safely to patients with NHL, shorten the period of severe cytopenia, reduce the rates of stomatitis, and did not seem to cause adverse effects on response.
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PMID:Mitoxantrone/high-dose Ara-C and recombinant human GM-CSF in the treatment of refractory non-Hodgkin's lymphoma. A pilot study. 219 41

Mitoxantrone (Novantrone, American Cyanamid Company; NO) and high-dose cytarabine (Ara-C; AC) have each been shown to be active in non-Hodgkin's lymphomas (NHL) in various studies. The studies reported here are sequential. The first study (NOAC I) combined high-dose cytarabine (3 g/m2/12 h as a 3 h infusion on day 1) with mitoxantrone (10 mg/m2/d on days 2 and 3). Of 31 patients with relapsed and refractory NHL, 7 achieved complete remission (CR) and 7, partial remission (PR). Myelosuppression was the major toxicity of this regimen. In the second study (NOAC II), the dosage of cytarabine was escalated to 3 g/m2/12 h on days 1 and 2 (4 doses) while mitoxantrone remained 10 mg/m2/d on days 2 and 3. The effects of recombinant human (rh) granulocyte-macrophage colony-stimulating factor (GM-CSF) were simultaneously studied. Twenty-three patients from five centers were treated with NOAC plus rhGM-CSF while 14 patients from four centers received NOAC II alone. A CR was achieved in 9 of 23 patients who received the additional rhGM-CSF and in 2 of 14 patients treated with NOAC alone. With rhGM-CSF, the median duration of severe neutropenia (less than 0.5/nL) after chemotherapy was 8 days versus a median of 13 days without rhGM-CSF, while the duration of severe thrombocytopenia (less than 20/nL) was not significantly different. The rates of infection and mucositis were 25% and 17%, respectively, with rhGM-CSF compared to 53% and 60% without rhGM-CSF. Thus, this last nonrandomized pilot study indicates that administration of rhGM-CSF reduces the duration of chemotherapy-induced cytopenia and the rate of mucositis. This growth factor does not appear to result in stimulation of lymphoma cells. At present, a controlled randomized trial is being conducted using NOAC II with rhGM-CSF or placebo to establish the definitive role of this growth factor in the treatment of NHL.
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PMID:Sequential studies on the role of mitoxantrone, high-dose cytarabine, and recombinant human granulocyte-macrophage colony-stimulating factor in the treatment of refractory non-Hodgkin's lymphoma. 225 18

Therapeutically efficacious doses of 131I-antibody result in a loss in circulating white blood cells; the granulocyte population is suppressed by 80-85% and the agranulocytes by 60-65% following 2 mCi of 131I-antibody in hamsters. The administration of 100,000 units of human recombinant interleukin 1 24 h prior to radioantibody can prevent the loss in WBC from 1 mCi of radioantibody and reduce the loss from 2 mCi of antibody. Recombinant murine granulocyte-macrophage colony-stimulating factor is also a potent stimulator of myelopoiesis and may also be useful as a method of reducing radioantibody-induced myelosuppression. The tumor uptake of radioantibody in animals treated with recombinant interleukin 1 is reduced by 30% 1 day after injection of radioantibody but returns to levels seen in animals not treated with the cytokine at 96 and 168 h. Therapeutic efficacy is not compromised by doses of interleukin 1 used to prevent myelosuppression. Therefore, the use of cytokines will permit the use of higher doses of radioantibody for greater tumor therapy with less myelotoxicity than in the absence of cytokine treatments.
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PMID:Use of hematopoietic growth factors to control myelosuppression caused by radioimmunotherapy. 240 78

Granulocyte-macrophage progenitors (CFU-GM) from four patients with childhood onset cyclic neutropenia demonstrated abnormal in vitro proliferative responses to purified, recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) when examined in detailed dose-response studies. Marrow aspirate specimens were obtained for these studies from cyclic neutropenia patients (both during neutropenic nadirs and during recovery phases of cycles), from leukemia patients in remission who had received myelosuppressive chemotherapy, and from healthy normal volunteers. Nucleated marrow cells were then isolated by density-gradient centrifugation and cryopreserved to permit studies of CFU-GM from patients and controls to be carried out at the same time and in replicate. Maximum clonal growth of CFU-GM from normal subjects and from individuals recovering from drug-induced myelosuppression was elicited by 20-100 pmol/liter rhGM-CSF, and the CSF concentrations that induced half-maximal responses (ED50) were between 1.0 and 3.0 pmol/liter. In contrast, maximum growth of CFU-GM from the cyclic neutropenia patients required greater than or equal to 1.0 nmol/liter rhGM-CSF and ED50's were greater than 30.0 pmol/liter. These abnormalities in the GM-CSF responsive growth of myeloid progenitors were independent of cycle time and were most apparent with the predominantly neutrophilic 7-d CFU-GM. Moreover, differences in the growth of 14-d CFU-GM could be attributed mostly if not entirely to differences in the generation of neutrophilic colonies. These findings indicate that childhood onset cyclic neutropenia is associated with an underlying disturbance in the GM-CSF responsive growth of myeloid progenitors committed to neutrophilic differentiation.
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PMID:Abnormal responses of myeloid progenitor cells to granulocyte-macrophage colony-stimulating factor in human cyclic neutropenia. 264 15

Solid tumor biopsies from 33 patients were tested in vitro to evaluate the growth modulatory effects of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). In 29 of 33 studies (88%), addition of GM-CSF either had no effect on in vitro growth, or induced growth inhibition. While significant growth inhibition was observed in 10 studies, marked inhibition was only observed in three studies. However, all dose-response curves were usually flat, suggesting indirect effects. Moderate growth stimulation was observed in four instances, which may have been due to residual granulocyte-macrophage progenitors within the biopsies. We conclude that GM-CSF has little or no growth-modulatory effect on most nonhematopoietic neoplasms. The primary role of GM-CSF in patients with solid tumors appears to be in prevention or reversal of myelosuppression associated with therapy. Thus, while GM-CSF seems unlikely to have a role in monotherapy of cancer, it is also unlikely to have its utility compromised by enhancement of tumor growth.
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PMID:Effects of granulocyte-macrophage colony-stimulating factor on in vitro growth of human solid tumors. 267 Dec 90

An increase in the dose of chemotherapy enhances the response of many experimental and clinical cancers, but the extent of dose escalation is often limited by myelosuppression. In preliminary trials, recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) has augmented leukocyte numbers and function, but the optimal dose is not established. We treated 16 adults who had inoperable or metastatic sarcomas with escalating doses of rhGM-CSF before and immediately after a first cycle of chemotherapy (cycle 1) to assess hematologic response and toxicity. A second cycle of chemotherapy (cycle 2) was given without rhGM-CSF. RhGM-CSF was tolerated well at doses of 4 to 32 micrograms per kilogram of body weight per day. At 64 micrograms per kilogram per day, edema and thrombi around a central venous catheter developed in two of four patients. Leukocyte and granulocyte counts increased significantly during the rhGM-CSF infusion. Neutropenia after cycle 1 was significantly less severe and shorter in duration than after cycle 2 (P less than 0.01). Mean total leukocyte and platelet nadirs were 1.0 and 101 x 10(9) per liter for cycle 1 and 0.45 and 44 x 10(9) per liter for cycle 2 (P less than 0.01), and the median intervals from day 1 of chemotherapy to neutrophil recovery (greater than 0.500 x 10(9) per liter) were 15 and 19 days, respectively (P less than 0.01). The duration of neutropenia was 3.5 days with cycle 1 and 7.4 days with cycle 2 (P less than 0.01). We conclude that rhGM-CSF is tolerated well at doses up to 32 micrograms per kilogram per day and is biologically active in leukopenic patients. It merits further evaluation for the prevention of morbidity from chemotherapy.
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PMID:Effect of recombinant human granulocyte-macrophage colony-stimulating factor on chemotherapy-induced myelosuppression. 264 49

The immunomodulator AS101 has previously been found to induce mouse and human hematopoietic cells to secrete cytokines such as interleukin-1 alpha (IL-1 alpha), IL-2, tumor necrosis factor-alpha (TNF-alpha), and gamma interferon (IFN-gamma). The compound was shown to protect mice from lethal and sublethal effects of chemotherapy and irradiation. AS101 prevented the decrease in the number of bone marrow (BM) and spleen myeloid progenitor cells, and increased the survival of lethally treated mice. In this study, we show a dose-dependent response of AS101 in the induction of high secretion levels of IL-6, IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), and stem cell factor (SCF). Since these growth factors are known to induce the proliferation and differentiation of multilineage progenitors, including megakaryocytic and erythroid progenitors, we designed this study to evaluate the role of AS101 in attenuating thrombocytopenia, anemia, and multilineage myelosuppression associated with chemotherapy. We demonstrate that pretreatment of mice with AS101 24 hours before intraperitoneal injection of 250 mg/kg cyclophosphamide (CYP) or intravenous injection of 150 mg/kg 5-fluorouracil (5-FU) significantly increased the number of circulating white blood cells (WBC) and platelets. The numbers of both neutrophils and lymphocytes were significantly increased in AS101-treated mice subjected to chemotherapy. In addition, AS101 attenuated erythropenia caused by 5-FU. It could also increase megakaryocyte and erythroid progenitor cells (CFU-MK and CFU-E) in the BM of treated mice severely affected by chemotherapy. We demonstrate that the protective effect of AS101 could be abrogated by treatment with anti-IL-1R or anti-SCF antibodies. We suggest that the endogenous production of cytokines such as IL-1, IL-6, IL-3, SCF, and GM-CSF in mice treated with AS101 offers protection to circulating blood elements and ameliorates the reconstitution of megakaryocytic and erythroid progenitors. The simultaneous protection by AS101 of multilineage cell compartments is probably due to stimulation by AS101 of a selective subpopulation of primitive stem cells resistant to chemotherapy. On the basis of these studies, phase II clinical trials with patients treated with chemotherapy in combination with AS101 have been initiated.
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PMID:Effect of the immunomodulator AS101 on chemotherapy-induced multilineage myelosuppression, thrombocytopenia, and anemia in mice. 749 64

Colony-stimulating factors (CSFs) shorten the duration of myelosuppression following chemotherapy and, thus, allow the administration of higher doses. This study evaluates the efficacy of granulocyte macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) in allowing administration of high-dose cyclophosphamide in combination with doxorubicin. Ninety women with metastatic, locally advanced, or high-risk (> or = 10 positive nodes) breast cancer and no prior anthracycline treatment were given doxorubicin (60 mg/m2) with progressively increased doses of cyclophosphamide (1,200 mg/m2, 1,800 mg/m2, and 2,400 mg/m2). The first 60 patients received GM-CSF; the remaining 30, G-CSF. The maximum tolerated dose was not reached with 2,400 mg/m2 of cyclophosphamide. When compared to GM-CSF, G-CSF significantly reduced the duration of granulocytopenia (P < .001). No differences in duration of thrombocytopenia were noted. The results were not sufficiently consistent to indicate a trend toward reduction in rates of febrile neutropenia with one CSF versus the other. However, patients who received G-CSF were hospitalized less frequently than those receiving GM-CSF. With CSFs, high-dose cyclophosphamide in combination with doxorubicin can be safely administered on an outpatient basis. A shorter duration of granulocytopenia resulted from the use of G-CSF than from GM-CSF.
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PMID:The efficacy of recombinant human granulocyte colony-stimulating factor and recombinant human granulocyte macrophage colony-stimulating factor in permitting the administration of higher doses of cyclophosphamide in a doxorubicin-cyclophosphamide combination. An NSABP pilot study in patients with metastatic or high-risk primary breast cancer. National Surgical Adjuvant Breast and Bowel Project. 752 93

Fever and neutropenia are life-threatening complications of chemotherapy in children with cancer. Prompt initiation of empiric broad-coverage antimicrobial therapy at the first signs of fever has reduced the mortality rates to about 2-5%. However, myelosuppression with febrile neutropenia is the major dose-limiting side effect of anticancer chemotherapy, results in prolonged hospitalization, and frequently delays the scheduled cycles of chemotherapy. Prophylactic use of hematopoietic growth factors has been shown to reduce the incidence of fever and infectious complications in children with cancer and neutropenia. Therapeutic use of recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) in combination with antibiotics in children with febrile neutropenia has also shown a clear beneficial effect. The number of hospital days due to treatment of febrile neutropenia, the number of days on broad-spectrum antibiotics and the duration of neutropenia were significantly reduced with the use of rHuGM-CSF. Importantly, rHuGM-CSF did not prolong the days with fever in children admitted with febrile neutropenia. In the treatment of documented fungal superinfection, it may be beneficial if rHuGM-CSF and an antifungal drug are used as combination therapy. rHuGM-CSF is non-toxic and well tolerated in children with cancer.
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PMID:Recombinant human granulocyte-macrophage colony-stimulating factor in combination with antibiotics in the treatment of febrile neutropenia in children. 761 88


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