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)

Murine fibrosarcoma cell line BMT-11 was induced with 3-methylcholanthrene and maintained in culture. Transplantation of BMT-11 into syngeneic C57BL/6 mice produced leukocytosis consisting of marked increments of neutrophils and monocytes associated with massive splenomegaly. In order to elucidate the mechanisms of this leukemoid reaction, we studied the changes occurring in hematopoietic progenitor cells in BMT-11-transplanted mice. The numbers of granulocyte-macrophage colony-forming units (CFU-GM), erythroid colony-forming units (CFU-E), erythroid burst-forming units (BFU-E), and mixed colony-forming units (CFU-Mix) in the spleen showed dramatic 216-fold, 18-fold, 64-fold, and 80-fold increases, respectively, relative to the value in the control mice 5 weeks after the BMT-11 implantation. In contrast, the levels of progenitor cells in the bone marrow remained within normal limits. The nature of the colony-stimulating factor (CSF) secreted from BMT-11 tumor cells was also studied. BMT-11-conditioned medium (BMT-11-CM), BMT-11 tumor extract, and sera from the mice bearing transplanted BMT-11 tumor contained CSF that stimulated mainly granulocyte and macrophage lineages. Furthermore, the expression of the granulocyte colony-stimulating factor (G-CSF) gene in BMT-11 cells were detected by Northern blot analysis.
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PMID:Methylcholanthrene-induced murine fibrosarcoma cell line BMT-11 secretes granulocyte colony-stimulating factor. 170 45

We have recently reported that a combination of lymphokine-activated killer (LAK) cells and bispecific antibodies (BsAb) efficiently lysed autologous and allogeneic leukemic blasts that had surface antigens reactive with the BsAb. The effector cells used in that experiment were peripheral blood mononuclear cells stimulated with interleukin-2 (IL-2) for 2 weeks, with the initial addition of anti-CD3 moAb; these were termed T3-LAK effector cells. In this study, we examined the effects of T3-LAK cells and BsAb on autologous normal CD34+ BM cells in both cytotoxicity and colony formation assays. When T3-LAK cells were incubated with CD34+ BM cells, low levels of cytotoxicity were induced against the CD34+ BM cells and the cytotoxicity was enhanced by the addition of anti-CD3 Fab' x anti-CD 13 Fab' BsAb but not by the addition of anti-CD3 Fab' x anti-CD10 Fab' BsAb. This enhancement appeared to be due to the lysis of CD34+CD13+ BM cells. When T3-LAK cells were preincubated with CD34+ BM cells in the presence or absence of the BsAb and plated for colony assay, neither the T3-LAK cells nor the BsAb affected granulocyte-macrophage or mixed-cell colony formation by CD34+ BM cells. Taken together with our previous finding that T3-LAK cells used in combination with the BsAb markedly inhibited colony formation by leukemic progenitor cells, these results indicate that this combination provides a potential new strategy for CD34+ BM cell purging in autologous BMT.
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PMID:Combination of interleukin-2-stimulated lymphocytes and bispecific antibodies that efficiently lyse leukemic cells does not affect bone marrow CD34-positive stem cell function in vitro. 752 85

Emergence of drug resistance with conventional cytotoxic therapy is a major challenge towards the curability of many cancers, especially in patients undergoing autologous BMT with ex-vivo purged hematopoietic support. We have explored the potential role of photoradiation therapy in purging hematopoietic stem cells of various hematological malignancies. Benzoporphyrin derivative, monoacid ring A (BPD-MA), dihematoporphyrin ether (DHE), and MC-540 were evaluated for the "ex-vivo" purging of residual tumor cells from autologous bone marrow (BM) grafts. BPD-MA and DHE photosensitizing activity was tested against two human large cell lymphoma cell lines and colony forming-unit leukemia (CFU-L) derived from patients with acute myelogenous leukemia (AML). In mixing experiments four log elimination of tumor cell lines was observed after 1 hr of incubation with BPD-MA or DHE followed by white light exposure. By comparison, using the same concentration of BPD-MA or DHE, the mean recovery of normal BM progenitors was 4-5.2% for granulocyte-macrophage colony forming unit (CFU-GM) and 5-9.8% for burst forming unit erythroid (BFU-E). The T lymphoblastic leukemia cell line CEM and its vinblastine (VBL)-resistant subline CEM/VBL100, along with the acute promyelocyte leukemia cell line HL-60 and its vincristine (VCR)-resistant subline HL-60/VCR, were also tested. Our results demonstrated the preferential cytotoxicity of BPD-MA and DHE toward neoplastic cell lines and CFU-L from AML patients. In addition, DHE was slightly more effective in purging tumor cells expressing the p-170 glycoprotein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Newer options for treating drug-resistant (MDR+) cancer cells using photoradiation therapy. 818 Jun 6

Current assays of human committed-stem cells are of limited value in predicting the rate of engraftment or in assessing the integrity of the stem cell pool after allogeneic bone marrow (BM) transplantation (BMT). We have used a limiting dilution assay of mafosfamide-resistant progenitors (pre-colony-forming units [CFU]), which are ancestral to committed progenitors such as CFU-granulocyte-macrophage (GM) to analyze the kinetics of myeloid engraftment after BMT and to assess the size of the stem cell pool at intervals up to 66 months thereafter. In 24 patients transplanted for chronic myeloid leukemia in chronic phase (eight with matched unrelated donors and 16 with sibling donors), the rate of neutrophil engraftment correlated strongly with the number of pre-CFU transfused per kilogram recipient body weight (r = .7, P < .005) but not with CFU-GM per kilogram or nucleated cells per kilogram. In 25 patients studied 6 to 66 months after allogeneic BMT, the mean number of pre-CFU in the marrow was 3.1/10(5) mononuclear cells (MNC) (median, 3.47; range, 0.4 to 23.3), compared with 24.7/10(5) MNC (median, 27.3; range, 4.2 to 180) in 25 normal subjects. CFU-GM were also reduced in these patients, but with considerable overlap into the normal range (mean +/- SD: 54 +/- 45.6 per 10(5) MNC; normal, 129 +/- 61.6). Low pre-CFU but not low CFU-GM levels were associated with reduced peripheral blood white blood cell counts in post-BMT patients. Pre-CFU and CFU-GM levels were not related to the interval posttransplant and remained low for up to 66 months. We conclude that the pre-CFU assay measures a population of stem/progenitor cells that are important in the kinetics of engraftment after allogeneic BMT. Our data suggest that pre-CFU levels may remain low for some years after BMT in humans.
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PMID:Quantitation of mafosfamide-resistant pre-colony-forming units in allogeneic bone marrow transplantation: relationship with rate of engraftment and evidence for long-lasting reduction in stem cell numbers. 861 28

Growth factor administration to donors prior to bone marrow (BM) harvesting results in an enrichment of the graft for myeloid precursors. In animals, growth factor-primed BM has a higher repopulating ability than untreated BM. Ten patients received an HLA-identical sibling, allogeneic transplant using granulocyte colony-stimulating factor (G-CSF)-stimulated BM. Stimulation consisted of G-CSF at 10 microg/kg/day for 2 days prior to harvest. Patients were transplanted for various benign and malignant hematological conditions. The GVHD prophylaxis consisted of cyclosporine, methotrexate and/or prednisone. Compared to untreated historical control BM, stimulated BM infusions contained similar number of nucleated cells (mean +/- s.d.: 3.5 +/- 1.5 vs 4.0 +/- 0.9 x 10(8)/kg), CD34+ cells (mean +/- s.d.: 7.5 +/- 3.0 vs 9.4 +/- 6.7 x 10(6)/kg), and CD3+ cells (mean +/- s.d.: 129 +/- 30 vs 190 +/- 59 x 10(6)/kg) but higher numbers of granulocyte-macrophage colony-forming units (mean +/- s.d.: 20 +/- 12 vs 96 +/- 34 x 10(4)/kg). Patients receiving stimulated BM had prompt and stable engraftment of white cells and platelets. On average they attained an ANC of > or = 1 x 10(9)/l 9 days earlier and a platelet count of > or = 20 x 10(9)/l 6 days earlier than historical controls receiving unstimulated HLA-identical sibling BM. Hospitalization was shortened by a mean of 10 days and transfusion requirements were modest. None of the patients developed severe GVHD or disease relapse. Two patients died of severe VOD post-BMT and thus were unevaluable for platelet engraftment. A third patient died of TTP on day 76 post-BMT. Seven patients are alive and well 49-585 days post-BMT. Stimulated BM may provide a valuable alternative to allogeneic BM and PBSC transplants. Ideal stimulation regimens need to be investigated.
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PMID:A pilot study of allogeneic bone marrow transplantation using related donors stimulated with G-CSF. 946 75

High-dose busulphan is an important component of many BMT conditioning regimens. High-dose busulphan therapy is associated with an increased risk of acute toxicity such as CNS toxicity and veno-occlusive disease (VOD). The toxicity was reported to correlate with a high AUC (area under the curve) during therapy. An intravenous form of busulphan would overcome the problems caused by inter-individual variability and bioavailability of busulphan and most probably minimize the problems with dose adjustment during therapy. The liposomal form of busulphan is an attractive alternative for intravenous administration of busulphan. In the present study, we compared the myeloablative effect of liposomal busulphan (LB) with that of the oral administration form and busulphan dissolved in organic solvent (Bus/DMSO) in mice. The pharmacokinetics of LB and Bus/DMSO were described by one compartment model while the oral data were fitted to one compartment model with first order absorption. The bioavailability of LB was 0.86+/-0.02 compared to that obtained after the oral administration (0.40-0.74). Myelosuppression was determined using the colony-forming unit granulocyte-macrophage assay (CFU-GM) on days 1, 3, 6 and 9 after the conditioning regimen. LB resulted in significant myelosuppression from day 1 to day 9. The decrease in CFU-GM after conditioning regimen with LB was not significantly different from that observed after oral busulphan. Moreover, the administration of liposomes only to the mice did not affect the bone marrow. No side-effects of the liposomal formulation were observed. We suggest that the novel form of busulphan is a promising drug for clinical use.
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PMID:Liposomal busulphan: bioavailability and effect on bone marrow in mice. 982 21

BMT is used as an established therapy for patients with malignant and nonmalignant diseases. Many techniques for ex vivo treatment have been developed, but these techniques must be preceded by BM processing. We report our experience in processing 99 BM using the Fenwal CS-3000 Plus cell separator using the 1-special program. Ninety-nine procedures were performed in BM harvested from 73 patients and 26 healthy donors. The number of nucleated cells (NC), mononuclear cells (MNC), RBC, platelets, colony-forming units-granulocyte-macrophage (CFU-GM), CD34+ cells, relative purity of MNC and PMN, and volume were determined in the unprocessed BM and in the final product. BM processing resulted in NC, MNC, CFU-GM, and CD34+ cell recoveries of 31%, 82.2%, 117.6%, and 97.8%, respectively. RBC, PMN, platelets, and volume removal, respectively, were 96%, 92%, 37.2%, and 85.1%. In pediatric patients, the volume reduction was significantly lower than in adult patients (79.6% versus 88.8%). No other significant differences were found between pediatric and adult results. We conclude that BM processing with the Fenwal CS-3000 Plus cell separator provides a product that can undergo further ex vivo treatments or cryopreservation.
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PMID:Bone marrow processing using the fenwal CS-3000 plus blood cell separator: results of 99 procedures. 1073 75

The present studies were designed for investigation of the requirements for cytotoxic function in donor T-cells transplanted to support engraftment after infusion of allogeneic bone marrow. The experiments examined the capacity of donor CD8 T-cells lacking Fas ligand and/or perforin function to facilitate donor B6 congenic (B6-Ly5.1) BM engraftment across major histocompatibility complex class I/II barriers after transplantation. T-cell-depleted BM cells from B6-Ly5.1 donors were transplanted into sublethally irradiated (5.5 Gy) BALB/c recipients together with different lymphocyte populations from wild-type B6 (B6-wt) donors or donors lacking functional cytotoxic pathways. Early presence of lineage-committed donor progenitor cells was assessed by the presence of day 5 splenic colony-forming units-granulocyte-macrophage (CFU-GM). Recipients of BMT without donor T-cells did not demonstrate significant CFU-GM activity 5 days post-BMT. Lineage-committed progenitor cells in recipient spleens could be supported by addition to the BM of wild-type (B6-wt) and cytotoxically single- (perforin, B6-pko or FasL, B6-gld) or double-deficient (B6-cdd) CD8 T-cells. However, B220+-enriched B-cells could not support the presence of day 5 donor CFU-GM. For further assessment of the capacity of cytotoxically impaired T-cells to participate in the engraftment process, the ability of these and normal CD8 cells to support the homing of donor cells to the BM was examined after infusion of carboxyfluorescein diacetete succinimidyl ester-labeled progenitors. In a syngeneic model lacking resistance, cytotoxically impaired donor T-cells supported increased numbers of progenitor cells in the marrow equivalent to the support provided by wild-type donor T-cells. Examination of peripheral chimerism indicated that during the first month after B6-->BALB/c BMT, donor chimerism was detected in BMT recipients receiving unfractionated T-cells or CD8+ T-cells from B6-wt donors, and chimerism was maintained at least 80 days after BMT. In contrast, B6-cdd unfractionated or CD8+ T-cells failed to maintain long-term B6 donor chimerism in the host. Experiments with highly enriched populations of positively selected CD8+ T-cells from B6-pko, B6-gld, or B6-cdd donors demonstrated that although each of these T-cell populations could promote the initial presence of donor CFU-GM early post-BMT, B6-pko and B6-cdd CD8+ T-cell populations were not able to support long-term peripheral chimerism. These results demonstrate that donor T-cells lacking major cytotoxic effector pathways have functions that support initial donor progenitor cell presence in the host hematopoietic compartment after BMT. They also demonstrate that support of long-term donor BM engraftment requires CD8+ T-cells with intact cytotoxic, that is, perforin, function. Finally, syngeneic B6-->B6 BMT suggests activation of CD8+ T-cells posttransplantation apparently is required to support enhanced progenitor cell activity. This study provides new findings concerning the role of cytotoxic function in the process of facilitating allogeneic donor BM engraftment.
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PMID:The contribution of cytotoxic and noncytotoxic function by donor T-cells that support engraftment after allogeneic bone marrow transplantation. 1246 77

The BMT program at Princess Margaret Hospital performed 105 transplants using cryopreserved peripheral blood stem cells (PBSC) from related allogeneic donors. The outcomes were compared with those of a historic control of 106 patients transplanted with freshly procured PBSC. The infusions were tolerated with limited toxicity related to nausea/vomiting or bradycardia, correlated with the total amount of DMSO infused. The average viability of the total nucleated cell (TNC) population after thawing was 71%. The survival of clonogenic progenitors amounted to 75% for colony-forming unit-granulocyte-macrophage (CFU-GM), 69% for burst-forming units erythroid (BFU-E), and 78% for colony-forming units granulocyte-erythrocyte-monocyte-megakaryocyte (CFU-GEMM). In contrast, colony-forming units megakaryocyte (CFU-MEG) was significantly more cryosensitive with recovery rates of 39%. The number of viable CD34(+) cells transplanted was correlated with the number of transplanted viable CFU-GM (P < .001), BFU-E (P < .001), CFU-MEG (P < .001), and CFU-GEMM (P = .049), but not with the TNC dose. The number of transplanted CD34(+) cells was correlated with engraftment of neutrophils (P = .012) and platelets (P = .013). The outcomes of cryopreseved or fresh PBSC transplants (PBSCT) with respect to engraftment of neutrophils (P = .178) and platelets (P = .785), lymphocyte recovery (P = .926), acute (P = .113), and chronic graft-versus-host disease (P = .673), recurrence (P = .295), nonrelapse mortality (P = .340), and overall survival (P = .668) were not significantly different. It is therefore reasonable to consider the option of cryopreserved allografts.
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PMID:Similar outcomes of cryopreserved allogeneic peripheral stem cell transplants (PBSCT) compared to fresh allografts. 1788 61

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