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 drug 3'-azido-3'-deoxythymidine (AZT), a synthetic thymidine analogue, has been used clinically in the management of acquired immune deficiency syndrome (AIDS). The drug is an effective antiviral agent due to its ability to block reverse transcriptase activity. This action of AZT was demonstrated in the Rauscher leukemia virus (RLV)-induced murine erythroleukemia model system. Unfortunately, associated with AZT has been the development of hematopoietic toxicity manifested by anemia, neutropenia, and overall bone marrow suppression. Hematopoietic growth factors (GM-CSF, erythropoietin), cytokines (interleukin-1), and agents known to potentiate hematopoiesis (lithium) have been demonstrated to modulate drug and/or radiation-induced hematopoietic toxicity. We report the results of further studies designed to investigate the ability of GM-CSF, erythropoietin, interleukin-1, and lithium to modulate AZT toxicity on murine hematopoietic granulocyte-macrophage (CFU-GM), megakaryocytic (CFU-Meg), and erythroid (BFU-E) progenitors cultured from bone marrow and spleen cells from mice infected with RLV. Hematopoietic progenitors from either normal or RLV-infected animals when exposed to AZT demonstrated concentration-dependent toxicity and differed for each progenitor with BFU-E being the most sensitive (ID50 concentration, 5 x 10(-9) M) and CFU-GM the least sensitive (ID50 concentration, 5 x 10(-5) M). As has been previously demonstrated using normal murine hematopoietic progenitors, when cultured with RLV-infected marrow or spleen cells, addition of GM-CSF, Meg-CSF or erythropoietin failed to inhibit AZT toxicity in vitro on CFU-GM, CFU-Meg, and BFU-E, respectively. However, in the presence of interleukin-1 (recombinant human IL-1 alpha, 30 ngm) or lithium chloride (ultra-pure, 1.0 mM), AZT toxicity CFU-GM, CFU-Meg, and BFU-E cultured from RLV-infected marrow or spleen cells was reduced. These results further demonstrate interleukin-1 and lithium are effective in modulating the toxic action of AZT on hematopoietic progenitors and that RLV-infected animals serve as a useful viral model system to study the effect of agents capable of modulating hematopoiesis in the presence of the anti-viral drug AZT.
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PMID:Effect of interleukin-1, GM-CSF, erythropoietin, and lithium on the toxicity associated with 3'-azido-3'-deoxythymidine (AZT) in vitro on hematopoietic progenitors (CFU-GM, CFU-MEG, and BFU-E) using murine retrovirus-infected hematopoietic cells. 194 Jun 11

Granulocyte/Macrophage Colony Stimulating Factor (GM-CSF) stimulates the production as well as the function of myeloid cells, i.e. granulocytes and macrophages. Proliferative effects are exerted on the level of the multipotent as well as the unipotent progenitor cell. Functional effects on mature phagocytes comprise bactericidal and tumoricidal mechanisms including induction of cytokine release. GM-CSF receptors are present on normal hematopoietic progenitors as well as on mature granulocytes, on leukemic cells and some non-hematopoietic cells. Alteration of the GM-CSF gene has been associated with distinct features of AML and ALL. The glycosilated molecule is produced by various hemolymphopoietic and possibly non-hematopoietic cells, amongst whom T-lymphocytes and marrow stroma may be most relevant for myelopoiesis. The regulation of gene expression is exerted on both transcriptional and posttranscriptional levels of gene expression. GM-CSF production may play a role in steady state as well as in stress hematopoiesis. In vivo application of GM-CSF leads to a marked increase of phagocytes, in particular granulocytes. GM-CSF reduces the duration of neutropenia following aplasiogenic and ablative therapy. GM-CSF may possibly be helpful in the treatment of victims of radiation accidents and in patients with acquired neutropenias and glykogenosis IB. The curative potential for the underlying malignant disease is to be investigated in the present cooperative european Ewing's sarcoma study.
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PMID:The granulocyte/macrophage-colony stimulating factor (GM-CSF): basic science and clinical application. 194 37

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

A therapeutic trial of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was attempted in a patient with neutropenia and frequent infections secondary to T-gamma lymphoproliferative disease (T-gamma LPD). During the 14 days of subcutaneous rhGM-CSF (500 micrograms/m2/day), the absolute eosinophil count increased from 0 to 9,455/microliters. By contrast, the absolute neutrophil count decreased. Toxicity related to rhGM-CSF included arthralgia and nonspecific chest pain. The possible mechanism for the rhGM-CSF induced selective eosinophilia is discussed.
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PMID:Eosinophilia resulting from administration of recombinant granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in a patient with T-gamma lymphoproliferative disease. 201 68

Granulocyte-macrophage colony stimulating factor (GM-CSF) has been tested for tolerability and efficacy on a compassionate need case basis in 17 patients (5 females, 12 males aged 4-72 years, median 35 years). GM-CSF was given at the rate of 3.5-32 micrograms/kg for 2-64 days as a continuous infusion for the following indications: impending rejection following bone marrow transplantation (5 patients), severe neutropenia secondary to chemotherapy in tumor patients (5), severe aplastic anemia (3), immune granulocytopenia (2) and accidental overdose with cytostatic agents (2 patients). Tolerance of GM-CSF was good in regard to doses of up to 16 micrograms/kg. Fever, myalgia and eosinophilia were the most frequent side effects. The patient treated with 32 micrograms/kg developed thrombosis of the vena cava. Efficacy is more difficult to assess in this heterogenous population, but 11 of 17 patients showed increased granulocyte counts and 3 patients clearly recovered from severe neutropenia. The role of GM-CSF in this recovery, however, cannot be proven. The results further indicate that GM-CSF cannot reverse ongoing rejection following allogenic BMT and cannot correct immune neutropenia. The value of GM-CSF therapy in patients with severe aplastic anemia and in the context of chemotherapy still needs to be defined. It is certainly indicated in patients with an accidental overdose of chemotherapeutic agents.
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PMID:[Emergency therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF)]. 202 44

Twenty-five children with refractory solid tumors were given recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in escalated doses of 60 to 1,500 micrograms/m2 as 2-hour intravenous infusions, beginning 24 hours after myelosuppressive treatment with cisplatin and etoposide. Tolerance to rhGM-CSF was exceptional even at dose levels that exceeded the maximum-tolerated dosage (MTD) reported for adults. The agent produced dose-related increases in platelet and neutrophil counts, resulting in significantly shorter durations of severe neutropenia and thrombocytopenia (P less than .01 for each analysis). At the higher dosages (greater than or equal to 750 micrograms/m2), treatment with rhGM-CSF reduced the median number of days of antibiotic therapy for fever and neutropenia by approximately one half. We conclude that rhGM-CSF is well tolerated by leukopenic children in doses as high as 1,500 micrograms/m2. An MTD was not reached in this study. The ability of the growth factor to reduce severe neutropenia and thrombocytopenia suggests it will have an important role in the management of childhood solid tumors.
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PMID:Therapeutic effects and pharmacokinetics of recombinant human granulocyte-macrophage colony-stimulating factor in childhood cancer patients receiving myelosuppressive chemotherapy. 203 15

Thirty patients with human immunodeficiency virus (HIV)-associated non-Hodgkin's lymphoma (NHL) receiving chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) were randomized to receive either subcutaneous recombinant human granulocyte-macrophage colony-stimulating factor (rGM-CSF) or no additional therapy. Recombinant rGM-CSF (at a dose of 10-20 micrograms/kg/d) was given on days 1 to 10 (early rGM-CSF) to the first five patients, but was changed to days 4 to 13 (delayed rGM-CSF) of each chemotherapy cycle in subsequent patients. Compared with the control group (N = 10), the delayed rGM-CSF group (N = 11) had higher mean nadirs of the absolute neutrophil count (0.36 v 0.89 x 10(9)/L; P = .009), shorter mean durations of neutropenia (4.9 v 1.3 days; P = .02), fewer chemotherapy cycles complicated by neutropenia and fever (67% v 27%; P = .001), fewer days hospitalized for fever and neutropenia (4.9 v 1.8; P = .004), fewer reductions in chemotherapy dosages, and less frequent delays in chemotherapy administration. No significant differences were observed between patients in the control group and those in the early rGM-CSF group (N = 5). Median levels of serum HIV-1 p24 antigen decreased to 18% and 17% of baseline values in control (N = 4) and rGM-CSF groups (N = 6), respectively, 1 week following administration of the first cycle of chemotherapy. In the third week after chemotherapy, median antigen levels remained below baseline in the control group, but rose to 243% of baseline values in the rGM-CSF group (P = .01), suggesting stimulation of HIV replication. The effect of this change in HIV activity on clinical outcome of treated patients could not be determined, and therefore the clinical significance of this finding remains unclear. Complete response rates of 67%, 70%, and 60% were observed in the control, delayed rGM-CSF, and early rGM-CSF groups, respectively, with corresponding survival times of 9.0, 11.4, and 8.0 months.
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PMID:Clinical and virologic effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients receiving chemotherapy for human immunodeficiency virus-associated non-Hodgkin's lymphoma: results of a randomized trial. 203 29

Data from several clinical trials in patients with solid tumors clearly demonstrate that recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) is able to shorten the time period of neutropenia after chemotherapy and to reduce neutropenia-related morbidity such as infections, time in hospital, etc. A placebo-controlled, double-blind multicenter trial including 81 patients with acute lymphoblastic leukemia and non-Hodgkin's lymphoma demonstrates the efficacy of rhGM-CSF to enhance engraftment (neutrophils greater than 0.5 x 10(3)/mm3) after autologous bone marrow transplantation (p less than 0.001) and to reduce the frequency of bacterial infections (34% vs. 56%). In addition, GM-CSF is able to shift the cell cycle of myeloid leukemic cells from the G0 to S phase in vitro and in vivo, which results in an increased sensitivity to cell-cycling-dependent cytostatic agents. Dose intensification of chemotherapy in patients with soft tissue sarcoma and metastatic breast cancer is possible due to adjuvant treatment with GM-CSF and results in a higher frequency of remissions. Further controlled clinical studies are warranted to support these results.
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PMID:New therapeutic modalities for the clinical use of rhGM-CSF in patients with malignancies. 204 60

The effects of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on neutrophil lactoferrin (LF) and transcobalamin (TC) 1 and 3 secretion were determined in vitro and during in vivo administration in humans. In whole blood, in vitro incubation with GM-CSF reproducibly produced a rise in plasma LF concentration (P less than 0.05) whereas in purified neutrophils the results were variable. Exposure of whole blood to GM-CSF also resulted in a significant rise in plasma TC 1 and 3 (190 +/- 60%, P less than 0.05). The response was dose dependent with maximal effect at GM-CSF concentrations of 10 ng/ml and above. rhGM-CSF was administered on seven occasions to six patients with malignant disease prior to chemotherapy. Plasma LF and unsaturated TC 1 and 3 levels rose significantly in each patient studied and the rise coincided with the initial neutropenia due to margination that occurs during infusions of rhGM-CSF. Patients receiving rhGM-CSF may therefore have hypofunctional neutrophils due to secondary granule depletion.
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PMID:Secretion of neutrophil secondary granules occurs during granulocyte-macrophage colony stimulating factor induced margination. 217 71

Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) has been used in two clinical studies at the Christie Hospital in Manchester, United Kingdom. Short daily "bolus" injections (over 30 min) were associated with serious toxicity which included bone pain, pruritus and pericarditis. In contrast, continuous infusions did not cause any toxicity and produced significantly higher increments of the peripheral neutrophil counts. rhGM-CSF reduced the period of life-threatening neutropenia following high-dose i.v. melphalan (120 mg/m2). Also, rhGM-CSF shortened the duration of thrombocytopenia induced by this chemotherapy to less time than has been seen historically in conjunction with autologous bone marrow rescue.
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PMID:Clinical studies with recombinant human granulocyte-macrophage colony-stimulating factor. 218 43


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