Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The objective of this phase I trial was to determine the maximal tolerated dose (MTD) of Taxol and doxorubicin administered as a simultaneous intravenous infusion over 72 hours every 21 days. Granulocyte-colony stimulating factor (G-CSF) 10 micrograms/kg, was administered on days 4-18 of each cycle. The treated population consisted of metastatic breast cancer patients previously untreated with chemotherapy for metastatic disease, who had not received doxorubicin in the adjuvant setting and who had bidimensionally measurable disease. The MTD was determined to be 75 mg/m2 of doxorubicin and 160 mg/m2 of Taxol. The dose-limiting toxicity of the combination was clinical typhlitis in three of three patients. Other significant toxicities included grade 3 diarrhea at the higher dose levels and grade 4 neutropenia in all patients. Eighteen patients were treated on this initial phase I study. The overall response rate was 62%, with 6% complete responses and 56% partial responses. The combination of doxorubicin and Taxol by 72-hour continuous infusion with G-CSF is an active regimen in patients with metastatic breast cancer.
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PMID:Phase I study of Taxol, doxorubicin, plus granulocyte-colony stimulating factor in patients with metastatic breast cancer. 751 54

To determine whether granulocyte-colony stimulating factor and erythropoietin are effective in the therapy of neutropenia and anaemia related to human immunodeficiency virus (HIV) infection and to anti-retroviral agents, we recruited 11 HIV-infected children (mean age 4 years 10 months). All the children were given granulocyte-colony stimulating factor at a dosage of 5 micrograms/kg twice or three times a week while erythropoietin was administered additionally to three patients at a dosage of 50 U/kg twice a week. Both agents were administered subcutaneously for at least 4 months. Leukocyte and neutrophil counts significantly increased during the treatment (after 1 months, P = 0.003 and P = 0.009, respectively). Erythropoietin prevented blood transfusions and increased haemoglobin levels in the three children treated. No side-effects were recorded during the administration of either agent. Granulocyte-colony stimulating factor and erythropoietin appear to be safe and useful agents in the management of HIV-infected children.
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PMID:Granulocyte-colony stimulating factor and erythropoietin therapy in children with human immunodeficiency virus infection. 867 88

Granulocyte-colony stimulating factor (G-CSF) is known to induce proliferation and differentiation of granulocyte progenitors, and is widely used to treat neutropenia induced by intensive chemotherapy for malignant lymphoma or adult T-cell leukaemia/lymphoma (ATL). G-CSF is thought not to stimulate malignant lymphoid cells. In the present study we examined the ability of G-CSF to induce in vitro growth of primary ATL cells from 14 patients (nine acute-type, two chronic-type and three lymphoma-type), and we analysed the in vivo counts of ATL cells in patients who received G-CSF for neutropenia. FACS analysis using phycoerythrin-labelled recombinant G-CSF demonstrated that ATL cells from 11/14 patients express some G-CSF receptor (G-CSFR), with a range between 5.4% and 87.3%. Cells expressing G-CSFR also expressed CD4. Reverse polymerase chain reaction (PCR) analysis demonstrated expression of G-CSFR messenger RNA in G-CSFR expressing cells. Leukaemic cells derived from seven (four acute-type, one chronic-type and two lymphoma-type) of the 14 patients proliferated in vitro in response to G-CSF, as measured by [3H]thymidine incorporation; maximum responses were at G-CSF concentrations of 10-100 ng/ml. Nine of 14 patients receiving rG-CSF for neutropenia were analysed retrospectively for ATL cell numbers. Four patients whose primary tumour cells proliferated in response to rG-CSF in vitro showed a significant increase in ATL cell count after administration of rG-CSF (P = 0.038), whereas five patients whose leukaemic cells did not proliferate in vitro showed no significant increase in ATL cell count. G-CSF can stimulate proliferation of ATL cells which may complicate therapy for this disease.
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PMID:Granulocyte-colony stimulating factor-induced proliferation of primary adult T-cell leukaemia cells. 907 11

Granulocyte-colony stimulating factor (G-CSF) was originally found to induce proliferation and differentiation of normal granulocyte progenitors. Recent studies demonstrated that G-CSF induces growth of some malignant cells, including lymphoid cells. G-CSF is now widely and successfully used to treat neutropenia induced by intensive chemotherapy, and the responsive growth of malignant cells becomes a major clinical issue. Adult T-cell leukemia (ATL) is a malignant lymphoid disease of T cells, etiologically associated with human T cell lymphotropic virus type I (HTLV-I). We demonstrated that primary ATL cells in about 80% of patients expressed cell surface G-CSF receptor (G-CSFR). Our recent data also show that ATL cells from a third of the patients show responsive growth to G-CSF ex vivo. Several patients whose ATL cells proliferated in response to G-CSF showed a significant increase of the ATL cell count after administration of G-CSF in vivo. These observations suggest caution for it's routine clinical use in ATL. The molecular mechanism of G-CSF responsive growth of ATL cells is obscure, however the population of G-CSFR expressing cells is larger in responsive cases than in nonresponsive cases. Expression of G-CSFR on ATL cells may relate to the expression of Tax protein encoded by HTLV-I. Precise studies on G-CSFR signaling in ATL cells are necessary for the safe use of G-CSF routinely for ATL patients.
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PMID:Involvement of granulocyte colony-stimulating factor in proliferation of adult T-cell leukemia cells. 986 93

This Phase I study was designed to determine the maximally tolerated dose (MTD) of paclitaxel with standard doses of cisplatin and etoposide for patients with untreated extensive stage small cell lung cancer (SCLC). Secondary objectives were to determine the toxicities, response rate, response duration, and overall survival in this cohort. Twenty-eight SCLC patients were enrolled into four dose levels. All patients received a fixed dose of cisplatin at 80 mg/m2, i.v., day 1. The first group received etoposide 50 mg/m2, i.v. day 1 and 100 mg/m2 p.o., days 2-3, whereas all subsequent groups received etoposide 80 mg/m2, i.v., day 1 and 160 mg/m2, p.o., days 2-3. The paclitaxel starting dose was 135 mg/m2, i.v., over a 3-h period and was escalated to 175 and 200 mg/m2. Cycles were repeated every 21 days for a maximum of six cycles. Granulocyte-colony stimulating factor was not given prophylactically but was allowed in subsequent cycles according to the American Society of Clinical Oncologists guidelines. All 28 SCLC patients were evaluable for toxicity, and 23 patients were evaluable for response. Myelosuppression was the major toxicity, with grade 4 neutropenia occurring in 23 of 28 patients (82%), but febrile neutropenia was uncommon and developed in 4 patients (14%). Grade 4 thrombocytopenia and anemia were rare, occurring as isolated events in one patient each. Dose-limiting peripheral neuropathy was observed at a paclitaxel dose of 200 mg/m2. Grade 4 nausea/vomiting and diarrhea were also noted at this dose level. Five patients had complete responses (22%), and 14 patients had partial responses (61%). The overall response rate was 83% with a median time to progression of 7.5 months, a median survival of 10 months, and a 1-year survival rate of 39%. This three-drug combination of paclitaxel with cisplatin and etoposide is active with acceptable toxicity. Neurotoxicity was dose limiting at 200 mg/m2 of paclitaxel. Neutropenia was frequent but not associated with significant morbidity. The recommended doses for future clinical trials are 175 mg/m2 paclitaxel, i.v., over a 3-h period on day 1 with 80 mg/m2 cisplatin, i.v., on day 1 and 80 mg/m2 etoposide, i.v., on day 1 and 160 mg/m2 p.o. on days 2 and 3 with growth factor support. The Southwestern Oncology Group has instituted a Phase II study with this dose schedule.
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PMID:A phase I study of paclitaxel, etoposide, and cisplatin in extensive stage small cell lung cancer. 1058 53

Granulocyte-colony stimulating factor (G-CSF) is used worldwide to prevent neutropenia caused by high-dose chemotherapy. It has limited stability, strict formulation and storage requirements, and because of poor oral absorption must be administered by injection (typically daily). Thus, there is significant interest in developing analogs with improved pharmacological properties. We used our ultrahigh throughput computational screening method to improve the physicochemical characteristics of G-CSF. Improving these properties can make a molecule more robust, enhance its shelf life, or make it more amenable to alternate delivery systems and formulations. It can also affect clinically important features such as pharmacokinetics. Residues in the buried core were selected for optimization to minimize changes to the surface, thereby maintaining the active site and limiting the designed protein's potential for antigenicity. Using a structure that was homology modeled from bovine G-CSF, core designs of 25-34 residues were completed, corresponding to 10(21)-10(28) sequences screened. The optimal sequence from each design was selected for biophysical characterization and experimental testing; each had 10-14 mutations. The designed proteins showed enhanced thermal stabilities of up to 13 degrees C, displayed five-to 10-fold improvements in shelf life, and were biologically active in cell proliferation assays and in a neutropenic mouse model. Pharmacokinetic studies in monkeys showed that subcutaneous injection of the designed analogs results in greater systemic exposure, probably attributable to improved absorption from the subcutaneous compartment. These results show that our computational method can be used to develop improved pharmaceuticals and illustrate its utility as a powerful protein design tool.
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PMID:Development of a cytokine analog with enhanced stability using computational ultrahigh throughput screening. 1196 78

Granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) are being administered to patients with neutropenia. However, little is known about the endogenous levels of both factors in these patients. We measured the endogenous G-CSF levels in patients with chemotherapy-induced neutropenia (n=15, study group A), in patients who had not received chemotherapy with neutropenia caused by a number of primary diseases (n=14, study group B) and in healthy volunteers (n=15, control group). Both the study groups and the control group did not show any clinical or laboratory findings of infection. The G-CSF levels were elevated in patients following chemotherapy and in patients who had neutropenia without chemotherapy, but the mean G-CSF levels in patients with chemotherapy-induced neutropenia were significantly higher than in patients with primary diseases. The levels of endogenous G-CSF were also higher in both neutropenic groups, compared to the control group. In conclusion, endogenous G-CSF levels in chemotherapy-induced neutropenia were significantly higher than non-chemotherapy related neutropenia and controls. This may be explained as G-CSF synthesizing bone marrow stromal cells may be more affected in primary disease related neutropenia than in chemotherapy induced neutropenia.
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PMID:Endogenous granulocyte colony-stimulating factor (G-CSF) levels in chemotherapy-induced neutropenia and in neutropenia related with primary diseases. 1263 92

Granulocyte-colony stimulating factor (G-CSF), a hematopoietic growth factor, is widely used to accelerate recovery from neutropenia after severe chemotherapy, both decreasing the risk of infection and mobilizing peripheral blood stem cells. Adverse effects occur with G-CSF use in approximately 30% of cases, comprised predominantly of bone pain, headache, and general fatigue. Pulmonary toxicity is very rare. Here, we describe a healthy donor for allogeneic hematopoietic stem cell transplantation who developed acute lung injury (ALI) after 4 days of G-CSF administration. Among the serum cytokines examined, only Interleukin (IL)-1beta level was elevated in this case. As a high level of IL-1beta was detected at the onset of ALI, on day 4 after G-CSF administration, and decreased to below the level of detection on day 11, it is possible in a certain part that IL-1beta was involved in the onset of G-CSF-related ALI in the present case. Granulocyte-colony stimulating factor (G-CSF) is commonly administered to healthy donors to mobilize peripheral blood stem cells (PBSC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Adverse events from G-CSF use in healthy donors have been described in approximately 30% of cases, and are comprised predominantly of bone pain, headache, and general fatigue. Pulmonary complications caused by G-CSF include cough, dyspnea, and interstitial or alveolar pulmonary edema with mild-to-severe deterioration of blood oxygen level. Few cases of acute respiratory distress syndrome (ARDS) following G-CSF administration have been reported. The present report describes a healthy donor for allo-HSCT with acute lung injury (ALI) after 4 days of G-CSF administration. The cytokine-related mechanisms of G-CSF administration that contribute to ALI are discussed.
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PMID:Acute lung Injury in a healthy donor during mobilization of peripheral blood stem cells using granulocyte-colony stimulating factor alone. 1575 51

Granulocyte-colony stimulating factor (G-CSF) is a growth factor which stimulates proliferation, differentiation, and survival of hematopoietic progenitor cells. G-CSF is being used extensively in clinical practice to accelerate recovery of patients from neutropenia after cytotoxic therapy. However, growing evidences have suggested that G-CSF has important non-hematopoietic functions in central nervous system. Recent studies have shown the presence of G-CSF/G-CSF-receptor (G-CSFR) system in the brain, and their roles in neuroprotection and neural tissue repair as well as improvement in functional recovery. The increased expression of G-CSF/G-CSFR on neurons subjected to hypoxia provides evidence that G-CSF may have an autocrine protective signaling mechanism in response to neural injury. G-CSF exerts neuroprotective actions through the inhibition of apoptosis and inflammation and the stimulation of neurogenesis. Moreover, G-CSF has been shown to mobilize bone marrow stem cells into the injured brain improving neural plasticity. In this review, we summarize some of the recent studies on G-CSF and the corresponding signal transduction pathways regulated by G-CSF in neuroprotection.
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PMID:Neuroprotective effect of granulocyte-colony stimulating factor. 1712 31

Granulocyte-colony stimulating factor (G-CSF) is widely administered to donors who provide peripheral blood stem cells (PBSC) for individuals who undergo hematopoietic stem cell transplants. Questions have been raised about the safety of G-CSF in this setting. Herein, the Research on Adverse Drug Events and Reports (RADAR) project investigators reviewed the literature on G-CSF-associated adverse events in healthy individuals or persons with chronic neutropenia or cancer. Toxicities identified included bone pain and rare instances of splenic rupture, allergic reactions, flares of underlying autoimmune disorders, lung injury and vascular events. Among healthy individuals, four patients developed splenic rupture shortly after G-CSF administration and three patients developed acute myeloid leukemia 1 to 5 years after G-CSF administration. Registry studies identified no increased risks of malignancy among healthy individuals who received G-CSF before PBSC harvesting. However, more than 2000 donors would have to be followed for 10 years to detect a 10-fold increase in leukemia risk. Our review identifies bone pain as the most common toxicity of G-CSF administration. There are questions about a causal relationship between G-CSF administration and acute leukemia, but more long-term safety data from database registries are needed to adequately evaluate such a relationship.
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PMID:Granulocyte-colony stimulating factor administration to healthy individuals and persons with chronic neutropenia or cancer: an overview of safety considerations from the Research on Adverse Drug Events and Reports project. 1756 36


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