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

Proliferation and differentiation of hematopoietic progenitor cells are regulated by a network of stimulatory and inhibitory cytokines. An understanding of the molecular mechanisms of growth control may provide a physiologic basis for the innovative therapy of bone marrow disorders. Among various accessory cells, bone marrow T lymphocytes are capable of stimulating, as well as inhibiting, hematopoietic progenitor cells. We have now elucidated molecular mechanisms regulating the differential expression of T cell genes encoding for the stimulatory and inhibitory hematopoietic programs. Stimulation of hematopoiesis requires granulocyte-macrophage colony stimulating factor (GM-CSF), whereas inhibition requires interferon-gamma (IF gamma). Both cytokines can be induced by interleukin-2 (IL2). The T cell IL2 receptor consists of a 75 kD chain (p75) mainly expressed on a subset of resting T cells and a 55 kD chain (p55) which is strongly expressed upon T cell activation. P55 and p75 associate on activated T cells to form a dimeric receptor molecule exhibiting high affinity for IL2. The p75 monomer has an intermediate affinity for IL2. Expression of p55 in the context of the high affinity IL2 receptor constitutes a requirement for T cell IFg release. In contrast, p75 alone is capable of mediating the production of GM-CSF. Thus, T cells may be capable of selective production of cytokines with specific effects in hematopoietic growth control. Utilizing a human peripheral blood leukocyte genomic library, we identified various clones containing the entire GM-CSF gene, including coding and regulatory regions. Cloning of the GM-CSF gene allowed clinical studies utilizing recombinant DNA-derived GM-CSF. Chemotherapy-induced neutropenia contributes to both complications of cytotoxic therapy as well as increased relapse incidence of underlying disease. In a prospective randomized study, we have demonstrated that GM-CSF abrogates neutropenia following aplasiogenic chemotherapy in children and adolescents with solid tumors, and that GM-CSF may reduce the duration of infectious episodes after cytotoxic therapy. Next, we escalated the cumulative doses of cytotoxic therapy in an ablative regimen followed by hematopoietic stem cell transplantation to treat patients with poor prognosis pediatric tumors. Morbidity of this highly toxic ablative regimen depends on the duration of myeloid aplasia. Median duration of aplasia following hyper-VAMP was 13 days with CM-CSF and 29 days without GM-CSF. In addition, we have employed p55 blocking monoclonal antibody for prevention of graft vs. host disease in bone marrow transplantation. The understanding of specific molecular mechanisms of hematopoietic immuno-regulation can thus be utilized to provide novel approaches to the treatment of bone marrow failure and cancer.
 ...
PMID:Molecular regulation of hematopoietic cytokines: implications and indications for clinical use in pediatric oncology. 130 80

Several glycoproteins that control blood formation have recently been characterized. Through their overlapping, synergizing, and antagonistic effects, they regulate hematopoiesis in a highly differentiated network. Large scale production of these colony stimulating factors (CSFs) has been made available by recombinant DNA technology, and a series of clinical studies in a variety of indications has been finished. In general, the subcutaneous application seems to be superior to the intravenous injection and causes less toxicity. Erythropoietin has been shown to be a highly effective treatment for anemia in patients with chronic renal failure. Granulocyte colony stimulating factor and granulocyte-macrophage colony stimulating factor are capable of ameloriating the chemotherapy induced neutropenia, and to abbreviate the time span of myeloaplasia after bone marrow transplantation. The potentials of other colony stimulating factors like Interleukin 1 and Interleukin 3, and combination regimens of several CSFs will be discussed.
 ...
PMID:Biology and pharmacology of hematopoietic growth factors. 130 82

It was the specific aim of this study to test the stimulatory effects of recombinant human GM-CSF (rhGM-CSF) on haemopoietic regeneration in dogs which had received total-body irradiation (TBI) with a dose of 2.4 Gy. In normal dogs rhGM-CSF given subcutaneously at 10 microgram/kg per day or 30 microgram/kg per day for 21 days caused strong but transient increases in the peripheral blood neutrophils. The monocyte counts also showed a transient rise during treatment in a dose-dependent fashion, whereas the lymphocyte counts increased only at the higher dose of rhGM-CSF and the platelet counts were transiently depressed during the course of the treatment. In the irradiated animals treatment with rhGM-CSF decreased the severity and shortened the duration of neutropenia but had no significant influence on monocyte or lymphocyte recovery. The granulocyte values showed a characteristic pattern of fluctuations with the first peak occurring at the same time (day 10 to day 13) when the abortive rise was observed in the untreated dogs. In contrast the GM-CFC in the peripheral blood remained depressed during the whole treatment course, similar to the untreated irradiated controls. These results indicate that treatment with GM-CSF can be an effective biological monotherapy for radiation-induced bone marrow failure, but that for higher radiation doses the number of GM-CSF responsive target cells will become a critical determinant of therapeutic efficacy.
 ...
PMID:Haematological effects of rhGM-CSF in dogs exposed to total-body irradiation with a dose of 2.4 Gy. 134 34

GM-CSF represents an important advance in bone marrow transplantation. The drug can be given safely and does not appear to increase the risk of graft-versus-host disease or tumor relapse. This is a rare example of a new technology reducing the cost of health care. By shortening the duration of hospitalization, GM-CSF can significantly reduce the cost of a bone marrow transplant (Table 2). However, there are few data to support the conclusion that the reduction in the duration of neutropenia is associated with a superior survival. This attests to the excellent supportive care that has been developed for patients undergoing bone marrow transplantation. At present, GM-CSF has become a standard therapy in autologous bone marrow transplantation. However, the future will undoubtedly see the development of combinations of hematopoietic growth factors and/or new growth factors that will further improve our ability to perform bone marrow transplantation.
 ...
PMID:The use of granulocyte-macrophage colony-stimulating factor in bone marrow transplantation. 136 21

Recent reports of neutropenia associated with the use of recombinant human erythropoietin (r-HuEpo) in preterm infants with the anaemia of prematurity have raised concern over the clinical use of this hormone. The present studies were undertaken to determine whether high-dose r-HuEpo has an effect on granulocyte production in vitro. The studies used a serum deprived, optimized semi-solid cell culture system to investigate the effect of lineage specific and non-specific granulocyte and erythroid colony stimulating factors on circulating peripheral blood granulocyte-macrophage colony forming units (CFU-GM), erythroid burst forming units (BFU-E) and multilineage colonies (CFU-Mix) from nine premature infants and seven healthy adults. CFU-GM were grown in the presence of interleukin 3 (IL3) 8 ng/ml, granulocyte-macrophage colony stimulating factor (GM-CSF) 20 ng/ml and granulocyte colony stimulating factor (G-CSF) 15 ng/ml alone and combinations of G-CSF with GM-CSF or IL3. The number, size and differentiation of CFU-GM colonies were then analysed in the presence and absence of high dose r-HuEpo (4 U/ml). High-dose r-HuEpo did not exert any significant modulatory effects on the number of CFU-GM colonies produced in the presence of IL3, GM-CSF and G-CSF alone or in combination. The number of cells within each CFU-GM colony did not change significantly, nor was there a significant change in the degree of differentiation. The combined number of BFU-E, CFU-GM and CFU-Mix colonies increased with r-HuEpo in both adults (1.8 x) and preterm infants (1.4 x), almost exclusively due to an increase in BFU-E derived colonies. Thus, no evidence was found for an r-HuEpo mediated redirection of multipotential haemopoietic stem cells into committed erythroid precursors at the expense of myeloid precursors.
 ...
PMID:The in vitro effect of high-dose recombinant human erythropoietin on granulocyte-macrophage colony production in premature infants using a defined serum deprived cell culture system. 138 42

Twenty children 1-17 (median, 5.5) years of age received GM-CSF during chemotherapy-induced neutropenia at the dose of 5 micrograms/kg/day, continued until the absolute neutrophil count (ANC) exceeded 500 x 10(6)/liter. Twelve children with solid tumors received GM-CSF after courses of conventional chemotherapy (VP-16 + ifosfamide or "6 in 1"). One course followed by GM-CSF was compared to identical courses without GM-CSF in the same patients. Eight children with recurrent/poor risk malignancies received GM-CSF after marrow-ablative therapy and autologous bone marrow transplantation (ABMT). Their engraftment data were compared to matched historical controls. In both groups GM-CSF accelerated myeloid recovery, which was preceded by the appearance of immature myeloid elements in bone marrow. The ANC levels of 200, 500, and 1,000 x 10(6)/liter were exceeded 2, 3 (P < 0.05), and 6 (P < 0.005) days earlier with GM-CSF in the conventional chemotherapy group, and 6, 10 (P < 0.05), and 9 days earlier in the ABMT group, as compared to the controls. All adverse effects observed were mild, including skin rashes, nasal stuffiness, general achiness, nausea, and fever. We conclude that GM-CSF is well tolerated in children and accelerates myeloid recovery in chemotherapy-induced neutropenia.
 ...
PMID:Recombinant human granulocyte-macrophage colony-stimulating factor in children with chemotherapy-induced neutropenia. 143 19

Opportunistic pulmonary infections are a leading cause of morbidity and mortality in patients with chemotherapeutically treated neoplasias. With increasingly aggressive cytotoxic regimens causing prolonged neutropenia, the risk of systemic mycoses and in particular of invasive pulmonary aspergillosis has increased. We review the case of a 10-year-old child suffering from relapsed lymphoblastic leukaemia and from high-dose amphotericin B-treated invasive pulmonary aspergillosis acquired during long-standing neutropenia in the initial phase of remission induction chemotherapy. The patient died in remission after GM-CSF-induced bone marrow recovery and clinical and radiological improvement with stable plasmatic coagulation and normal thrombocyte count. Peracute massive pulmonary bleeding caused by the simultaneous arrosion of a greater pulmonary artery and a lobar bronchus by a liquefactive fungal focus was responsible. In patients with chemotherapeutically induced neutropenia and invasive aspergillosis, bone marrow recovery may lead to the liquefaction of pulmonary foci, and, in view of the well-known vasotropic nature of the infection, to a potentially lethal arrosion bleeding. With the emerging use of colony-stimulating factors for shortening and overcoming neutropenia, this so far rare complication may become of increasing importance.
 ...
PMID:Fatal haemoptysis associated with invasive pulmonary aspergillosis treated with high-dose amphotericin B and granulocyte-macrophage colony-stimulating factor (GM-CSF). 143 49

Neutropenias, especially extended an long-lasting stages, lead to life-threatening endogenous infection. Therefore, after taking off materials for bacteriological investigations an empirical schedule of a combined high dose, treatment with broad-band antibiotics and/or antimycotics has immediately to be introduced and to continue until the body temperature and the peripheral blood granulocytes are normalized. In case of treatment failure one should complete the therapy by other additional antibiotics or correct the combination of its in respect to the results of the microbiological investigations. Supplements of this antimicrobial treatments are immunoglobulins and growth factors (G-CSF, GM-CSF). In case of an expected neutropenica the use of the selective gut decontamination or the reverse isolation of the patient can be of essential advantage.
 ...
PMID:[Therapy of bacterial infections in neutropenic and immunocompromised patients]. 144 70

In a phase II study, 21 patients with MDS (RAEB, RAEBt, CMML and RA and RAS with severe cytopenia) were randomized to be treated with 3 courses of GM-CSF (3 micrograms/kg/day s.c.) alone (11 patients) or in combination with AraC (20 mg/m2/d s.c.) (10 patients) for 14-d periods, interrupted by 14-d rest periods. Eight patients discontinued the treatment. In the GM-CSF group a marked increase in WBC and neutrophil counts during each course of treatment administration were seen in most patients. Platelet counts decreased in 14 of 24 courses of treatment in the GM-CSF plus AraC group but in none of the GM-CSF group. Although the changes in the circulating blood cells were transient and the counts tended to return to the pretreatment levels during the rest periods, some more durable effects were seen. In 3/6 patients of the GM-CSF group who completed the designed treatment, both WBC and neutrophils remained elevated above the pretreatment levels throughout the 3-month period of treatment, while in one of them thrombocytopenia improved considerably. In the GM-CSF plus AraC group, 4 out of the 7 patients who completed the treatment showed an improvement of neutropenia as well as anaemia. In these 4 patients the BM percentage of blasts was also decreased. In conclusion, the results of this study indicate that GM-CSF given intermittently improves leukopenia in some patients with MDS. In addition, the administration of GM-CSF seems to prevent granulocytopenia of concurrent AraC treatment and may be of benefit in the treatment of these diseases.
 ...
PMID:Treatment of myelodysplastic syndromes with human granulocytic-macrophage colony stimulating factor (GM-CSF) or GM-CSF combined with low-dose cytosine arabinoside. 144 28

A 61-year-old female patient, treated for hyperthyroidism with thiamazole, developed a severe maturation arrest in the granulocytic lineage and a total agranulocytosis. Subcutaneous GM-CSF was started immediately and given for 6 days. Bone marrow samples were taken before GM-CSF therapy and on days 3 and 8. An increased number of colonies per 10(5) bone marrow cells documented before institution of GM-CSF treatment was followed by a gradual decline to normal values. An increase of granulocyte count to > 0.5 x 10(9) l-1 was recorded on the 4th day of treatment and was preceded by an increase in the number of immature granulocyte precursors in the bone marrow on day 3. The patient was discharged on day 8 and experienced no adverse effects of GM-CSF treatment. Haematopoietic growth factor therapy has a place in the management of patients with drug induced neutropenia/agranulocytosis, which should be further delineated by prospective studies.
 ...
PMID:Haematologic effects of granulocyte-macrophage colony stimulating factor in a patient with thiamazole-induced agranulocytosis. 145 30


1 2 3 4 5 6 7 8 9 10 Next >>