Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.1.1.69 (BMT)
2,655 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The use of cytokines such as granulocyte-colony-stimulating factor (G-CSF) to ameliorate chemotherapy-induced myelosuppression may not only stimulate the recovery of normal hematopoietic cells but may also enhance the proliferation of the tumor cells with functional receptors for these cytokines. In this study, we show that administration of recombinant human (rh) G-CSF decreased the in vitro and in vivo cytotoxic effects of Adriamycin or etoposide on L1210 murine leukemic cells with receptors for rhG-CSF. Transplantation of bone marrow cells expressing high levels of bcl-2 from a retroviral construct [MPZenNeo(bcl-2)] (bcl-2-BMT) did not decrease the in vivo cytotoxic effect of etoposide on L1210 cells, but enabled recovery of myelopoiesis following etoposide-induced myelosuppression to almost the same extent as did the administration of rhG-CSF. These findings suggest the possibility that bcl-2 transfection could be used to protect transplanted bone marrow from chemotherapy-induced myelosuppression on behalf of administration of rhG-CSF, in case of treatment of tumors with functional receptors for rhG-CSF.
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PMID:Transfection with a bcl-2 expression vector protects transplanted bone marrow from chemotherapy-induced myelosuppression. 751 94

Recombinant human glycosylated G-CSF (rhG-CSF) may stimulate proliferation of myeloid leukemia cells and thereby increase their susceptibility to anti-cancer agents. By in vitro colony assay, the rhG-CSF-responsive NFS-60 leukemic cell clones are more effectively killed by Ara C in the presence of rhG-CSF than in the absence of rhG-CSF, while the killing of the rhG-CSF-unresponsive HL-60 cell clones is unaffected by rhG-CSF. Leukemia cell colony forming units (L-CFU) derived from most AML patients demonstrate similar results to those of the NFS-60 cell clone when treated in vitro. Encouraged by these in vitro results, we used rhG-CSF as a component of a conditioning regimen for 15 relapsed AML patients who were receiving allogeneic BMT. The patients were conditioned with total body irradiation (TBI) and high-dose Ara C. rhG-CSF was infused continuously at a dose of 5 micrograms/kg/day from 24 h before the beginning of TBI to the end of Ara C therapy. Proliferation of the leukemia cells in vivo in response to rhG-CSF was confirmed in 7 of 14 patients tested and the combined use of rhG-CSF had no additional adverse effects. After BMT, four patients died of non-leukemic causes and three patients had leukemic relapse: the other eight patients have remained disease-free for 200-1600 (median 417) days. The actuarial probabilities of relapse and disease-free survival (DFS) at 4.4 years after BMT were 43.2% and 41.7%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Recombinant human glycosylated granulocyte colony-stimulating factor (rhG-CSF)-combined regimen for allogeneic bone marrow transplantation in refractory acute myeloid leukemia. 751 98

Administration of G- and GM-CSF increases the neutrophil counts in a number of clinical situations. GM-CSF shows the additional effect of increasing the number of monocytes and eosinophil granulocytes. Both G- and GM-CSF affect of neutrophil functions, in the case of GM-CSF there are some potentially negative effects on neutrophil migration and adhesiveness. The clinical relevance of the various effects on mature haematopoietic cells is not fully understood. Clinical data with G-CSF treatment indicate that increased levels of neutrophil granulocytes following cytotoxic chemotherapy may translate into clinical benefit such as a decreased rate of neutropenic infection and an increased cytotoxic chemotherapy dose even though the data are conflicting and the risk of "laboratory cosmetics" is apparent. Regarding treatment with GM-CSF following chemotherapy, the clinical benefit is unclear. The clinical benefit of GM-CSF-induced monocytes and eosinophils is unknown. G- and GM-CSF accelerates neutrophil recovery following autologous or allogeneic BMT. The influence on neutropenic infections is, however, less impressive. Pretreatment with G- or GM-CSF increases the yield of peripheral stem cell harvest, thereby reducing the number of leukaphereses needed. Transplantation of G- and GM-CSF primed autologous peripheral stem cells tends to reduce the period of post-transplant cytopenia, particularly thrombocytopenia, in comparison with traditional ABMT. In patients with MDS, G- and GM-CSF appear to increase the number of neutrophil granulocytes and there is some evidence that patients with severe infectious problems will benefit from this treatment. However, little influence was seen on the main clinical problems with these patients, which are anaemia and thrombocytopenia. In conclusion, G- and GM-CSF are two different proteins with different properties in vivo and in vitro. GM-CSF has, compared with G-CSF, more complex pharmacological effects and a more trouble-some side-effect profile. Early clinical development indicates that both compounds have a substantial influence on the levels of certain blood cells. Whether the increases in different blood cells translate into long-term clinical benefit for greater patient groups is the focus of ongoing research. The effects of G- and GM-CSF may be potentiated by other cytokines, an area which is presently being explored.
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PMID:G- and GM-CSF in oncology and oncological haematology. 751 79

We describe a patient who presented with graft failure following autologous BMT, with an initial response of the neutrophil count to rHuGM-CSF but eventual loss of this response. Subsequently, this patient responded to rHuG-CSF. This could be explained by the fact that rHuG-CSF stimulates both early and late myeloid progenitor cells whereas rHuGM-CSF stimulates mainly the intermediate myeloid progenitor cells. This finding suggests that rHuG-CSF should be investigated for the treatment of patients with graft failure following ABMT.
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PMID:Correction of neutropenia with rHuG-CSF after loss of response to rHuGM-CSF following autologous bone marrow transplant. 751 39

Recombinant granulocyte colony-stimulating factor (rhG-CSF) has been shown to hasten granulocyte recovery after autologous BMT. In current protocols, rhG-CSF treatment starts 1 day after BM reinfusion. Our study retrospectively examined the effects on haematological recovery of a day 6 delayed administration. Seventy-eight patients receiving autologous BMT for malignant lymphoma (21 non-Hodgkin's lymphoma and 9 Hodgkin's disease) or solid tumors (33 breast carcinoma and 5 ovarian carcinoma) were split up into three study groups. Two groups receiving a 5 micrograms/kg/day of rhG-CSF starting either 1 day (day +1 group, n = 25 patients) or 6 days (day +6 group, n = 24 patients) after BM reinfusion were compared with 29 historical control patients. Granulocyte recovery to 0.5 x 10(9)/l was 12 days in day +6 and day +1 groups versus 16 days in control group (p < 0.005) without any difference in other hematological parameters, infectious complications or length of hospitalisation between the three groups. The day +6 administration allows elimination of a median of 7 days rhG-CSF. It has been concluded that the day +6 administration gives the same clinical benefit as day +1 administration with consequent cost reductions.
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PMID:Delayed administration of granulocyte colony-stimulating factor after autologous bone marrow transplantation: effect on granulocyte recovery. 753 61

Preliminary studies in allogeneic BMT suggest that recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) is well tolerated. This is a prospective, multicenter, randomized, double-blind, placebo-controlled trial. Yeast-derived rhGM-CSF 250 micrograms/m2/day or placebo was administered by 4-hour i.v. infusion starting on the day of marrow infusion (day 0) to day 20. All patients received HLA-identical sibling marrow and cyclosporine and prednisone for GVHD prophylaxis. Fifty three patients received rhGM-CSF and 56 received placebo. Comparison of demographics revealed no differences. The time to achieve an absolute neutrophil count of > 0.5 x 10(9) cells/l was shortened in rhGM-CSF treated patients (day 13 vs. 17, P = 0.0001). The incidences of grade III-IV mucositis and infection were significantly reduced (P = 0.005, P = 0.001, respectively) and duration of hospitalization was modestly shortened by 1 day (P = 0.02) in rhGM-CSF treated patients. No differences in platelet recovery, erythrocyte recovery, incidence of veno-occlusive disease, GVHD severity, relapse or survival were observed. In conclusion, rhGM-CSF is well tolerated and reduces post-transplant morbidity in patients undergoing HLA-identical allogeneic BMT.
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PMID:Phase III randomized, double-blind placebo-controlled trial of rhGM-CSF following allogeneic bone marrow transplantation. 758 Oct 96

Myelosuppressive toxicity is dose-limiting for radioimmunotherapy. We have reported on the use of cytokine intervention (rhIL-1 and rmGM-CSF) to stimulate differentiation of progenitor cells and reduce radioantibody-induced leukopenia and thrombocytopenia (J. Natl. Cancer Inst. 84:399, 1992; Cancer 73:1073, 1994). As an alternative to the use of cytokines, we investigated the effect of syngeneic bone marrow transplantation on the ability to dose-escalate radioantibody. Injection of 10(7) bone marrow cells from a donor mouse 6 to 8 days after a 340- to 360-microCi dose of radioantibody (LD100/28)--a 25 to 30% increase above the maximal tolerated dose--resulted in 100% survival. This observation is associated with a recovery in neutrophil and thrombocyte counts within 21 days of therapy (normal recovery after 275 microCi takes 42 days). None of the mice survived when BMT was done at either 4 or 11 days after radioantibody. Marrow from normal donor mice was more effective than that from cytokine-primed mice whose marrow cells were actively cycling after a 5-day course of IL-1/GM-CSF. The combination of the two myeloprotective approaches, BMT plus a 14-day schedule of IL-1 (2 x 10(3) U/d) and GM-CSF (1 microgram/d) intervention, provided a greater stimulation of peripheral WBC counts than either approach alone; however, further dose escalation under these conditions was not feasible. The 30% intensification in radioantibody dose offers a therapeutic advantage for both bulky disease (GW-39 subcutaneous nude mouse model) and micrometastatic disease (GW-39 intrapulmonary model). In the bulky tumor model, the increase in administered dose resulting from BMT extends the 8-week growth delay observed at 275 microCi 131I-MN-14 IgG by an additional 7 weeks. In the metastatic model, dose intensification increased median animal survival from 15 to 23 weeks. Therefore, by optimizing the use of BMT, a greater therapeutic benefit can be derived from radioantibody therapy in a solid tumor model. This study represents a proof of principle, that BMT can be effective for low-dose-rate therapy as it has been for short-duration intense chemotherapy and radiation therapy. It also highlights several important issues to consider when attempting to apply the method in the clinic.
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PMID:Improved experimental cancer therapy by radioantibody dose intensification as a result of syngeneic bone marrow transplantation. 765 29

A multicentre, randomised vehicle-controlled single-blind dose ranging trial of intravenous recombinant granulocyte colony-stimulating factor (rhuG-CSF) administration after BMT has been performed in 121 patients with non-myeloid malignancies. All the doses of rhuG-CSF used (2-20 micrograms/kg/day) resulted in significant acceleration of neutrophil recovery, and a dose-response effect was apparent (p < 0.05). At the 20 micrograms/kg/day dose of rhuG-CSF the median time taken to achieve a neutrophil count of > 0.5 x 10(9)/1 was reduced from 19 to 13 days (p < 0.001) and the time to achieve a neutrophil count > 1.0 x 10(9)/1 on the first of 3 consecutive days, from 26 to 14 days (p < 0.001). There was a trend to less antibiotic use in the rhuG-CSF recipients and the median time in hospital was markedly reduced by 11-15 days (p < 0.01). There was no toxicity in this study attributable to rhuG-CSF.
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PMID:Randomised vehicle-controlled dose-finding study of glycosylated recombinant human granulocyte colony-stimulating factor after bone marrow transplantation. 768 52

The effects of human recombinant granulocyte colony stimulating factor (G-CSF) on neutrophil recovery have been studied in patients undergoing bone marrow transplantation for haematological disease. Nine patients (five autografts and four allografts) were studied while receiving daily doses of G-CSF (range 2-20 micrograms/kg body weight) were compared to eight patients (four autografts and four allografts) who did not receive G-CSF as a control group. In both groups flow cytometry was used to determine neutrophil IgG Fc receptor (FcRII, FcRIII) expression. Phagocytosis and metabolic burst was assessed using IgG opsonized bacteria. The patients' neutrophils were studied prior to conditioning in autografts and donor cells were studied in allografts. Studies were repeated at neutrophil recovery (neutrophil count 1.0 x 10(9)/l) and ten days post recovery. At recovery FcRII expression was slightly increased in all groups, whereas the number of cells expressing FcRIII was reduced. This reduction was significant in the patients receiving rG-CSF at recovery and post recovery compared to the pretreatment levels. The ability to phagocytose bacteria in cells from patients receiving G-CSF was also reduced. The associated metabolic burst was significantly reduced in the autograft group but not the allograft group receiving rG-CSF. The reduced function and reduced expression of FCRIII suggests the presence of immature neutrophils in patients receiving rG-CSF post BMT.
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PMID:Pilot study: effects of G-CSF on neutrophil ex-vivo function post bone marrow transplantation. 768 80

We reviewed the clinical courses of 38 children with acquired aplastic anemia (AA). The patients were classified according to the severity criteria by the Japanese Ministry of Health and Welfare (JMHW) Study Group (22 severe, 15 moderate, 1 mild). Early death was observed only in severe cases. Eight of the non-severe cases progressed to severe in 0.5-125 months, and the long-term survival rate of non-severe AA did not differ from that of severe AA. The frequency of lymphocytes in the bone marrow was significantly higher, and the peripheral blood neutrophil count was lower in patients who died within a year, and these patients should be treated as very severe. These findings suggest that the JMHW Study Group criteria are useful for identifying AA patients with a poor prognosis, but even non-severe cases should be repeatedly evaluated. Sixteen of the 33 patients treated with corticosteroids and/or anabolic steroids (AS) showed hematological recovery. Bolus methylprednisolone (mPSL) therapy was effective in one of the 8 patients. Allogenic marrow transplant (BMT) was performed on 3 patients. One died from sepsis and engraftment was not achieved in the other two. Trilineage recovery was obtained in 3 of 6 patients treated with rhG-CSF and rhEPO with or without AS, and hemopoiesis has been maintained 6-12 months after discontinuation in 2 cases. In the other 3 patients, the neutrophil count showed transient increase. Therefore, the treatment for severe AA patients, who have no sibling donor for BMT, should be started with the combination therapy including these cytokines.
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PMID:The clinical course of acquired aplastic anemia in childhood; a retrospective study. 789 28


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