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)

The toxicity and hematologic effects of Escherichia coli-derived recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) were studied in 58 treatment cycles in Japanese patients with advanced malignancy as a phase I/II clinical trial. rhGM-CSF in doses from 30 to 250 micrograms/m2/day was administered by 24-hour continuous intravenous infusion, 8-hour intravenous, or a daily subcutaneous injection for 14 days. The most common adverse drug events (ADE) were fever, nausea/vomiting, diarrhea, skin eruption, and phlebitis. The frequency of moderate and severe ADE was 2.9, 14.7, 35.3 and 47.1% at 30, 60, 125, 250 micrograms/m2/day, respectively. In terms of administration routes, the frequency of ADE was 69% with 24-hour continuous intravenous infusion, 39.1% with 8-hour intravenous infusion and 16.7% with subcutaneous injection. Regarding the hematologic effects of rhGM-CSF, leukopenia improved in a dose-dependent manner. The appropriate dose level to be used in the phase II study was estimated to be in the range between 60 and 250 micrograms/m2/day.
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PMID:Phase I/II study of recombinant human granulocyte-macrophage colony-stimulating factor in patients with advanced malignancy. The Multicenter Study Group. 158 68

Chronically immunosuppressed individuals are susceptible to lymphoreticular tumors. Up to 15% of patients with congenital deficiencies such as ataxia=telangiectasia may develop malignancies, mainly high-grade B cell non=Hodgkin's lymphomas (NHLs). AIDS lymphomas are comprised of NHLs including Burkitt's lymphoma (BL) and primary cerebral lymphomas (PCLs). Almost 3% of all AIDS patients (2824 of 97,258 cases) developed NHL. Epstein-Barr virus (EBV) as a co-factor in AIDS lymphomagenesis has been studied: in 12 cases of 24 AIDS lymphomas EBV by DNA in situ hybridization was found. In an analysis of 6 primary cerebral lymphomas, .5 were positive for EBV DNA by Southern blotting. In Burkitt's lymphoma the characteristic genetic alteration affects the c-myc oncogene. In 1/3 of BL p53 mutations were found but none in the 43 NHLs suggesting that p53 mutations and c-myc activation act synergistically in the pathogenesis of these tumors. Cytotoxic agents dideoxyinosine, dideoxycytosine, and zidovudine may cause secondary neoplasia. 8 of 55 AIDS patients under zidovudine treatment developed high-grade lymphoma 23.8 months subsequently; recently doses were reduced. PCL was found in 21 of 90 patients. A 5.2 months survival was associated with combined treatment with cyclophosphamide, Oncovin (vincristine), methotrexate, etoposide, and cytosine arabinoside compared with 11.3 months with chemotherapy. Colony-stimulating factors (CSFs) alleviate drug-induced myelotoxicity and zidovudine-induced neutropenia, however, l8 of 11 patients receiving granulocyte-macrophage CSF developed hematological toxicity. Interleukine-2 produced by T-helper cells enhancing tumor cells cytotoxicity has been used in AIDS-associated cryptosporidial diarrhea and in 4 patients with AIDS lymphoma with modest response, but its stimulation of the HIV-infected substrate may increase viral proliferation.
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PMID:AIDS lymphomas. 161 63

Sixteen patients with relapsed non-Hodgkin's lymphoma underwent autologous bone marrow transplantation and infusion of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). Treatment consisted of involved-field radiotherapy, cyclophosphamide 60 mg/kg/d intravenously (IV) for 2 days, and fractionated total body irradiation (1,200 cGy). Autologous bone marrow was thawed and infused IV, followed 3 hours later by the first infusion of IV rhGM-CSF 11 micrograms/kg/d over 4 hours. Infusions of rhGM-CSF were continued daily until either both neutrophil count exceeded 1,500/microL and platelet count exceeded 50,000/microL, or until 30 days after marrow re-infusion. Toxicities encountered were mild and included fever, chills, hypertension, alopecia, rash, diarrhea, stomatitis, myalgias, and synovial (knee) effusions. Neutrophil recovery greater than 500/microL occurred a median of 14 days (range, 9 to 30 days) after marrow infusion, significantly earlier than in a comparable group of historic controls who recovered counts at a median time of 20 days (range, 12 to 51 days) (P = .00002). Median time to self-sustaining platelet counts greater than 20,000/microL was 23.5 days (range, 12 to 100 days), comparable with the historic group (P = .38). One bacteremia (central venous catheter exit site infection with Staphylococcus epidermidis) and one local infection (Giardia lamblia in stool) occurred. Patients received a median of 11.4 (range, 4.4 to 20.2) x 10(4) colony-forming unit granulocyte-macrophage (CFU-GM) progenitors per kg. Stem cell progenitors CFU-GM, CFU-granulocyte, erythroid, monocyte, megakaryocyte (CFU-GEMM), and burst-forming unit-erythroid (BFU-E) were detected in the bone marrow as early as 7 days after marrow re-infusion, and increased in proportion to peripheral blood counts, but by 30 to 60 days still remained much lower than before transplant. Neutrophils transiently decreased in 13 of 16 patients (median decrease, 42%) within 24 to 72 hours of discontinuing rhGM-CSF infusions. These data suggest that rhGM-CSF therapy enhances neutrophil recovery by forcing stem cells to produce mature elements at an enhanced rate but may not affect marrow stem cell and early progenitor population sizes.
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PMID:Recombinant granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for relapsed non-Hodgkin's lymphoma: blood and bone marrow progenitor growth studies. A phase II Eastern Cooperative Oncology Group Trial. 185 94

Based on in vitro data suggesting that recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) is capable of stimulating acute myeloid leukemia (AML) blast cells to become more sensitive to cell-cycle-specific drugs we conducted a phase I/II study in de novo AML patients (pts). rhGM-CSF (250 micrograms/m2/d, continuous intravenous infusion) was administered in 18 pts suffering from de novo AML in combination with standard induction chemotherapy (3 + 7 = daunorubicin 45 mg/m2 days 1 through 3, cytosine-arabinoside [Ara-C] 200 mg/m2 continuous infusion days 1 through 7). GM-CSF was started 48 or 24 hours before chemotherapy (prephase) in 14 pts. In four pts with high white blood cell counts (WBC) rhGM-CSF was started after chemotherapy-induced cell reduction (WBC less than 30,000/mm3). During prephase GM-CSF induced an increase in neutrophil and blast cell counts in 13 of 14 and 10 of 14 pts, respectively. In vivo recruitment of leukemic cells into drug-sensitive phases of the cell cycle could be demonstrated by multiparameter cell-cycle analyses in peripheral blood (n = 7) and bone marrow (n = 4) specimens. On day 14, complete aplasia was evident in 17 of 18 pts. GM-CSF was administered until recovery from chemotherapy-induced myelosuppression (absolute neutrophil counts, [ANC] greater than 500/mm3). Fifteen pts (83%) achieved complete remission, 12 did so with one cycle. A shorter duration of neutropenia was evident in these pts compared with historical controls (n = 39), (ANC greater than 500/mm3, day 22.5 +/- 3.4 v 25.2 +/- 3.7, P less than .05). Three pts achieved complete remission after a second cycle (same combination of rhGM-CSF and 3 + 7). Two pts died during bone marrow aplasia because of invasive pulmonary aspergillosis. Clinical side effects possibly related to GM-CSF, mainly fever, diarrhea, and weight gain were mild and tolerable (World Health Organization toxicity grade less than or equal to 2). Together, rhGM-CSF recruits kinetically quiescient AML cells in vivo to enter drug-sensitive phases of the cell cycle and promotes early myeloid recovery from aplasia after exposure to standard induction chemotherapy for AML.
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PMID:Recombinant human granulocyte-macrophage colony-stimulating factor in combination with standard induction chemotherapy in de novo acute myeloid leukemia. 199 13

As part of a multicenter trial 12 patients with myelodysplastic syndromes (MDS) were treated with 14-day-cycles of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; 250 micrograms/m2 day s.c.). In addition, all patients received 20 mg/m2/day s.c. cytosine-arabinoside (Ara-C) 12 h after GM-CSF except for patients suffering from refractory anemia (RA) according to FAB classification. Courses were repeated after 4 weeks. In 11 evaluable patients, results according to FAB-classified MDS were as follows: RA, 1/2 response (R), 1/2 stable disease (SD); RAEB, 2/3 R, 1/3 SD; RAEB-T, 1/6 CR, 1/6 PR, 2/6 R, 2/6 progression; CMML, 1/2 SD. In 2 patients with RAEB-T, overt acute myeloid leukemia was observed 2 and 10 weeks after initiation of treatment. With few exceptions, treatment resulted in a prompt increase in granulocytes and eosinophiles. This was associated with improvement of infectious complications. Increases in red cells and platelets occurred variably and was apparently associated with responses of the underlying disease. Dose limiting side effects consisted of fever, severe fatigue and dolent local reactions at the site of GM-CSF injection. In addition, nausea and diarrhoea occurred frequently. Less often, respiratory and cardiovascular side effects were encountered. In summary, GM-CSF +/- Ara-C in MDS results in objective remission with manageable toxicity. Conceivably, this regimen will serve as a base for future treatment strategies against MDS.
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PMID:Recombinant human granulocyte-macrophage colony-stimulating factor and low-dose cytosine-arabinoside in the treatment of patients with myelodysplastic syndromes. A phase II study. 218 22

Poor graft function after bone marrow transplantation is an infrequent complication that is fatal for most patients secondary to severe infections or to bleeding. Even a second marrow infusion is usually not successful in restoring hematopoiesis. We treated nine patients with recombinant Escherichia coli derived human granulocyte-macrophage colony-stimulating factor (GM-CSF) for delayed engraftment or graft failure after autologous (n = 6) or allogeneic (n = 3) bone marrow transplantation (BMT). Six patients were given a dose of 10 micrograms/kg/d over 30 min; three patients received lower doses of 3-5 micrograms/kg/d. Seven patients lived longer than 3 days after commencing GM-CSF and could be evaluated for their response. Six of them had a marked rise in neutrophil counts; there was no effect on platelet and reticulocyte counts. Two patients died within the first 3 days after starting GM-CSF, although both seemed to have some response to GM-CSF (increasing blood neutrophils in one, and increasing macrophages in the bone marrow on autopsy in the other). Side effects most likely attributable to GM-CSF administration were mild and included diarrhea and abdominal pain, low grade fever and mild rash. Severity of graft-vs-host disease (GVHD) was not enhanced in the recipients of allogeneic marrow. We conclude that recombinant GM-CSF can be safely given to patients with poor graft function after marrow transplantation. In some patients, this may lead to a subsequently sustained neutrophil recovery.
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PMID:Recombinant GM-CSF in patients with poor graft function after bone marrow transplantation. 219 16

An immunohistochemical technique was used to examine whether there was a colocalization of cytokine-specific receptors with cytokine-expressing cells. We have previously shown that there is extensive cytokine production and secretion in the rectal mucosa in shigellosis (interleukin 1 alpha [IL-1 alpha], IL-1 beta, IL-1ra, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor alpha [TNF-alpha], TNF-beta, gamma interferon, granulocyte-macrophage colony-stimulating factor, and transforming growth factor beta [TGF-beta]) (R. Raqib, A. A. Lindberg, B. Wretlind, P. K. Bardhan, U. Andersson, and J. Andersson, Infect. Immun. 63:289-296, 1995; R. Raqib, B. Wretlind, J. Andersson, and A. A. Lindberg, J. Infect. Dis. 171:376-384, 1995). Kinetics for receptor expression was compared with that for cytokine synthesis in the inflamed rectal mucosa from Shigella-infected patients during acute (2 to 6 days after onset of diarrhea) and convalescent (30 to 40 days after onset) stages. Quantification of receptor expression was assessed by computer-assisted analysis of video microscopic images. A selective down-regulation of the receptors for gamma interferon, tumor necrosis factor (TNF receptor [TNFR] type I), IL-1 (IL-1 receptor [IL-1R] types I and type II), IL-3, IL-4, and TGF-beta (TGF-beta receptor type I) was observed at the onset of the disease, with a gradual reappearance during the convalescent stage. However, IL-2R, IL-6R, granulocyte-macrophage colony-stimulating factor receptor, TNFR type II, and TGF-beta receptor type II showed no change in expression during the study period and were comparable to controls. Cytokine receptors were predominantly located to the epithelial layer of the mucosal surface and crypts, with variable expression patterns in the lamina propria. A time-dependent kinetic curve was seen for the soluble IL-2R (sIL-2R), sIL-6R, and sTNFR types I and type II shed in stool at the acute stage similar to that observed for cytokine secretion in stool but at four- to six-times-lower concentration. In contrast, soluble receptor levels in plasma were 100-fold higher than the cytokine levels. The results suggest a dissociation in immune regulation between cytokine production and cytokine receptor expression. The down-regulation of the receptors in acute shigellosis was probably a consequence of cytokine-induced internalization and shedding of the receptors during signal transduction as well as due to programmed regulatory roles played by cytokines and the bacterial antigens.
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PMID:Down-regulation of gamma interferon, tumor necrosis factor type I, interleukin 1 (IL-1) type I, IL-3, IL-4, and transforming growth factor beta type I receptors at the local site during the acute phase of Shigella infection. 762 34

Recombinant yeast-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) was administered to 10 patients after autologous bone marrow transplantation for Hodgkin's disease given as a 24-h continuous intravenous infusion from the day of marrow infusion until the patient had obtained an absolute neutrophil count of 1.5 x 10(9)/L for 2 consecutive days or until day 30, whichever occurred first. Results were compared with results from 18 historical control patients who did not receive GM-CSF but were otherwise treated in a similar fashion. The infusion of GM-CSF led to a significantly faster neutrophil and monocyte recovery compared to the patients in the historical control group. The median days to achieve an absolute neutrophil count for the GM-CSF group and the control group were 0.5 x 10(9)/L; 9.5 and 14 days; 1.0 x 10(9)/L: 10 and 18 days; 1.5 x 10(9)/L: 11 and 29 days. No significant difference was found with respect to platelet engraftment and red cell transfusion requirements. GM-CSF therapy was discontinued at a median of 12 days. Hospitalization was also shorter for the GM-CSF group (22.5 vs. 26.5 days) and no patient in the GM-CSF group had to be readmitted after initial discharge. The incidence of documented infections was similar among both patient groups and no difference was noted in terms of antimicrobial usage. Some side effects occurred with the continuous infusion of GM-CSF, particularly fluid retention, dyspnea, fever, diarrhea, and bone pain leading to early discontinuation of GM-CSF in 2 patients. The data suggest that a continuous 24-h infusion of GM-CSF significantly accelerates myeloid engraftment, leading to earlier discharge from the hospital.
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PMID:Granulocyte-macrophage colony-stimulating factor after autologous marrow transplantation for Hodgkin's disease. 770 29

Preclinical studies of recombinant human interleukin-3 (rhIL-3) and granulocyte-macrophage colony-stimulating factor (rhGM-CSF) have shown enhancement of multilineage hematopoiesis when administered sequentially. This study was designed to evaluate the safety, tolerability, and biologic effects of sequential administration of rhIL-3 and rhGM-CSF after marrow ablative cytotoxic therapy and autologous bone marrow transplantation (ABMT) for patients with malignant lymphoma. Thirty-seven patients (20 patients with non-Hodgkin's lymphoma and 17 patients with Hodgkin's disease) received one of four different treatment regimens before ABMT. Patients were entered in one of four study groups to receive rhIL-3 (2.5 or 5.0 micrograms/kg/day) administered by subcutaneous injection for either 5 or 10 days starting 4 hours after the marrow infusion. Twenty-four hours after the last dose of rhIL-3, rhGM-CSF (250 micrograms/m2/d as a 2-hour intravenous infusion) administration was initiated. rhGM-CSF was administered daily until the absolute neutrophil count (ANC) was > or = 1,500/microL for 3 consecutive days or until day 27 posttransplant. The most frequent adverse events in the trial included nausea, fever, diarrhea, mucositis, vomiting, rash, edema, chills, abdominal pain, and tachycardia. Three patients were removed from the study because of chest, skeletal, and abdominal pain felt to be probably related to study drug. Four patients died during the study period because of complications unrelated to either rhIL-3 or rhGM-CSF. The median time to recovery of neutrophils (ANC > or = 500/microL) and platelets (platelet count > or = 20,000/microL) was 14 and 15 days, respectively. There were fewer days of platelet transfusions than seen in historical control groups using rhGM-CSF, rhG-CSF, or rhIL-3 alone. In addition, there were fewer days of red blood cell transfusions compared with historical controls using no cytokines or rhGM-CSF. These data indicate that the sequential administration of rhIL-3 and rhGM-CSF after ABMT is safe and generally well-tolerated and results in rapid recovery of multilineage hematopoiesis.
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PMID:Sequential administration of recombinant human interleukin-3 and granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for malignant lymphoma: a phase I/II multicenter study. 791 29

Irinotecan hydrochloride (CPT-11), a semisynthetic derivative of camptothecin, has been demonstrated to be active against solid tumors such as non-small cell lung cancer and colorectal cancer. Two combination phase I trials were undertaken to determine the maximum tolerated dose of CPT-11 in combination with cisplatin and vindesine in patients with advanced non-small cell lung cancer. All 46 patients (age 32-73 years) entered into these trials had a good performance status (Eastern Cooperative Oncology Group score, 0-1) and had received no prior chemotherapy or radiotherapy. In the first trial, 14 stage IV and 2 stage IIIb patients were studied; in the second trial 30 patients with stage IV disease were accrued. In the first trial, CPT-11 was given as a 90-min i.v. infusion on days 1 and 8 in combination with a fixed dose of cisplatin (100 mg/m2, i.v., on day 1) and vindesine (3 mg/m2, i.v., on days 1 and 8), every 4 weeks. The starting dose of CPT-11 was 25 mg/m2, and the dose was increased in increments of 25 mg/m2. In the second trial, the doses of either CPT-11 (days 1 and 8) or cisplatin (day 1) were escalated with a fixed dose of vindesine (same dose as the first study) given in a 4-week cycle. The starting doses of CPT-11 and cisplatin were 20 and 60 mg/m2, respectively, and the dose of either CPT-11 or cisplatin was increased in increments of 20 mg/m2. At least 3 patients were entered at each dose level in both trials. Use of granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor was not permitted in this trial. In the first trial, grade 4 granulocytopenia and grade > or = 3 diarrhea were dose limiting at 50 mg/m2 CPT-11, which represented the maximum tolerated dose. At the subsequent dose of CPT-11, 7 new patients were requited at the 50% reduced dose level of 37.5 mg/m2 on days 1 and 8. Nine patients were evaluated for response, and 4 of them achieved a partial response. In spite of a low dose of CPT-11 (25-37.5 mg/m2), the maximum concentration in plasma of CPT-11 (> 0.4 micrograms/ml) reached > 10-fold the in vitro concentration of CPT-11 required for 50% inhibition of growth. In the second trial, the dose-limiting toxicities were grade 4 granulocytopenia lasting for > or = 7 days and grade > or = 3 diarrhea.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Phase I clinical trial of irinotecan (CPT-11), 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin, and cisplatin in combination with fixed dose of vindesine in advanced non-small cell lung cancer. 816 91


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