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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new megakaryoblastic cell line (CMK), which also exhibits erythroid and myeloid markers, was established from a Down's syndrome patient suffering from acute megakaryoblastic leukaemia. The CMK cells were found to be positive in reactions with anti-platelet antibodies (anti-glycoproteins IIb/IIIa and Ib, and Plt-1). Platelet peroxidase (PPO) reactivity was found to be associated with the nuclear envelope and the endoplasmic reticulum but not with the Golgi apparatus. Some cells possessed cytoplasmic granules with the characteristics of alpha-granules and demarcation membranes. Karyotyping revealed near-tetraploidy (modal chromosome number of 95; ranging 87-98) and a translocation der(17)t(11;17), also found in the original leukaemic cells, confirming that the cells were derived from the patient's malignant blasts. The CMK cells were also found to be positive in reaction with anti-glycophorin A antibody, as well as with anti-myeloid antibodies (MY4, MY7 and MY9). Treatment of CMK cells with phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) greatly enhanced the reactivity with anti-platelet antibodies, increased the number of cells in which cytoplasm was dissociated into numerous segments and suppressed the reactivity with anti-glycophorin A. The proliferation of CMK cells was stimulated by interleukin-3 (IL-3) and granulocyte-macrophage colony stimulation factor (GM-CSF). This cell line should be a useful tool for analysing the basis of the afferent association between megakaryoblastic leukaemia and Down's syndrome, as well as for further study of megakaryocytic differentiation.
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PMID:Establishment of a human leukaemic cell line (CMK) with megakaryocytic characteristics from a Down's syndrome patient with acute megakaryoblastic leukaemia. 252 57

An in vivo model system for assaying the induction of differentiation by therapeutic agents was developed using WEHI-3B D+ Y1 myelomonocytic leukemia cells in BALB/c mice, which exhibit characteristics analogous to those of human acute non-lymphocytic leukemia. An integrated copy of the non-mammalian 3'-aminoglycoside phosphotransferase gene in WEHI-3B D+ Y1 cells permitted the unambiguous identification of these leukemia cells in vivo by in situ hybridization. The administration of aclacinomycin A to BALB/c mice bearing this leukemia produced an increase in survival time. In situ analyses of peritoneal cells obtained from anthracycline-treated animals supported the concept that the increase in life-span was due in part to the induced maturation of WEHI-3B D+ Y1 cells to more mature granulocytic elements. This action was accompanied by an order of magnitude decrease, relative to vehicle-treated animals, in the peritoneal leukemic cell burden. The schedule and dosage of the anthracycline antibiotic that produced the maximum prolongation of life had no effect on peripheral platelet levels or packed red cell volume. Elevated white blood cell levels were observed in leukemia-bearing mice; these increases were reversed in animals receiving 2 mg/kg of aclacinomycin A and reached control levels by day 8. Treatment with aclacinomycin A had no effect on body weight, or femoral or splenic cellularity. Increased numbers of granulocyte-macrophage colony forming units were observed in leukemia-bearing animals. Leukemia-bearing mice receiving aclacinomycin A decreased these stem cell levels to that of drug-treated non-leukemia bearing animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:WEHI-3B D+ Y1 leukemia cells as a model system to assess the induction of differentiation in vivo. 256 37

The effectiveness of ex vivo chemotherapy with drugs, such as vincristine, etoposide, and Adriamycin (doxorubicin, Adria Labs, Columbus, OH) for elimination of residual tumor cells from human bone marrow grafts could be undermined by the presence of multidrug-resistant tumor cells in the bone marrow. Therefore, to supplement chemoseparation, we investigated whether MRK-16, a monoclonal antibody (MoAb) to the surface moiety of multidrug resistance-associated P-glycoprotein antigen, can eliminate drug-resistant tumor cells in the presence of rabbit complement (RC). Two doxorubicin (DOX)-resistant human myeloma tumor cell line, 8226/DOX40 (resistant to 4 x 10(-7) mol/L DOX) and 8226/DOX6 (6 x 10(-8) mol/L DOX) with high and low amounts of cell surface P-glycoprotein, respectively, and the drug-sensitive parent cell line 8226/S were used as tumor models in this study. Using the limiting dilution assay, we have shown that three cycles of treatment with 25 micrograms/mL of MRK-16 MoAb and a 1:4 final dilution of RC eliminated 2.90 +/- 0.10 logs of 8226/DOX40 cells and 1.94 +/- 0.18 logs of 8226/DOX6 cells. One and two cycles of treatment were less effective, eliminating 0.47 +/- 0.40 and 1.94 +/- 0.36 logs of 8226/DOX40 and 0.12 +/- 0.20 and 1.63 +/- 0.58 logs of 8226/DOX6 cells, respectively. The 8226/S cell growth was unaffected by one to three cycles of treatment. The cell kill was not impaired when the antibody plus complement treatment was carried out on a mixture of 8226/DOX40 or 8226/DOX6 cells with a ninefold excess of irradiated bone marrow mononuclear cells (MNCs). The three cycles of treatment with antibody plus complement did not adversely affect granulocyte-macrophage colony-forming unit (GM-CFU) survival in hematologically normal marrows (92.5% to 104% survival) or in myeloma patient marrows (85% to 100%). These results show that it is possible to eliminate drug-resistant myeloma tumor cell lines from the admixed human bone marrow by treatment with MRK-16 MoAb plus RC. This method could prove to be effective for elimination of other drug-resistant tumor cell lines including those of leukemia and solid tumors, and will be further useful for supplementing chemopurging, and immunopurging of bone marrow with other antitumor cell antibodies.
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PMID:Elimination of drug-resistant myeloma tumor cell lines by monoclonal anti-P-glycoprotein antibody and rabbit complement. 257 83

Blood-derived stem cell (BDSC) autografting represents an interesting theoretical approach to the treatment of acute nonlymphoblastic leukemia (ANLL). The feasibility and safety of this procedure have now been established by several observations of rapid hematopoietic recovery following high-dose chemotherapy and autologous reinfusion of BDSCs harvested during remission. Using clonogenic assays for granulocyte-macrophage colony-forming units (CFU-GM) and granulocyte erythrocyte monocyte colony-forming units (CFU-GEM), we tested peripheral blood samples from 20 consecutive patients recovering from induction chemotherapy for ANLL. Results were correlated with other clinical and hematological factors in order to define optimal criteria for successful BDSC harvesting. Two different patterns of increment were observed in the number of peripheral blood progenitor cells during early recovery from chemotherapy in our patients, suggesting that a total period of 10-12 days should be covered for ideal BDSC harvesting by cytapheresis. Associated clinical factors that appear predictive for a better yield are: 1) chemotherapy with daunorubicin, cytosine arabinoside, and thioguanine (DAT), 2) synchronous recovery of monocytes and platelets, and 3) a good overall performance status of the patient. Complete remission status and absence of ongoing infection should also be considered when selecting patients for BDSC harvesting. No correlation was found between the number of circulating CFUs, as indicated by the clonogenic assays, and that of either My-10- or HLA-Dr-positive cells identified by immunofluorescence on the same blood samples. In this study, less than 50% of patients with newly diagnosed ANLL would have been considered good candidates for a BDSC harvesting program.
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PMID:Blood-derived stem cell collection in acute nonlymphoblastic leukemia: predictive factors for a good yield. 257 43

Human continuous bone marrow cultures were established from intraoperative marrow specimens and infected with amphotropic murine leukemia virus (Am-MuLV) pseudotypes of Kirsten or Harvey murine sarcoma virus, and the biologic effects were compared with mouse continuous bone marrow cultures. Cultures were tested for production of total nonadherent granulocytes and granulocyte-macrophage progenitor cells (GM-CFUc); virus replication by supernatant reverse transcriptase activity; percentage of adherent and nonadherent cells and GM-CFUc that released virus by infectious center assay; and for synthesis of Harvey ras p21 protein. High-efficiency, stable Am-MuLV infection of over 90% of human marrow-culture nonadherent and adherent cells and both seven- and 14-day GM-CFUc were detected as Kirsten or Harvey pseudotype virus release by infectious center assay. Synthesis of Harvey ras p21 was detected in the adherent and nonadherent cell populations of human as well as mouse continuous marrow cultures infected with Kirsten or Harvey pseudotype virus. In contrast to data with mouse cultures, cumulative production of GM-CFUc and differentiated granulocytes in human cultures was not detectably altered by Harvey or Kirsten virus infection, and all cultures ceased to produce hematopoietic cells by 20 weeks. Of 54 virus-infected cultures in ten separate experiments, 13 produced a second peak of nonadherent cells (greater than 10(5) per flask) after 20 weeks, significantly more frequently than did control uninfected cultures (one of 32). When subcultured, these harvests produced permanent Epstein-Barr virus (EBV)-transformed pre-B cell lines that released the original inoculating pseudotype virus. Thus, Am-MuLV is a potentially valuable vector for inserting genetic sequences by recombinant techniques into human hematopoietic and stromal cells in culture; however, activation of EBV may be a significant complication.
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PMID:Amphotropic retrovirus vector transfer of the v-ras oncogene to human hematopoietic and stromal cells in continuous bone marrow cultures. 257 39

The effect of alpha interferon (alpha IFN) on colony forming unit, granulocyte-macrophage (CFU-GM) formation by normal bone marrow (BM) as compared with chronic granulocytic leukaemia (CGL) BM and peripheral blood (PB) was tested in semi-solid assay systems employing either 5637CM or recombinant granulocyte-macrophage colony stimulating factor (GM-CSF) to support growth. alpha IFN (greater than 125 U/ml) caused consistent inhibition (P = 0.02) of day-7 (late progenitor) colonies, but had little or no effect on either day-7 clusters or day-14 colonies/clusters. This selective effect on day-7 colonies was quantitatively similar for both normal and CGL (P greater than 0.5). Similar results were obtained whether or not the mononuclear preparations were depleted of potential accessory cells, suggesting that the alpha IFN-suppression is directly mediated. Morphological examination of colonies and clusters showed that IFN had no effect on cell maturation and that colony inhibition is not, therefore, a consequence of blocked maturation. Since the late-progenitor compartment is preferentially expanded in CGL, we suggest that our demonstration that alpha IFN selectively inhibits this compartment is relevant to the clinical effects of the cytokine in the disease.
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PMID:Mechanism of action of alpha interferon in chronic granulocytic leukaemia: evidence for preferential inhibition of late progenitors. 261 Nov 35

Factors which may influence haematopoietic recovery after allogeneic bone marrow transplantation were analysed. Forty-six evaluable patients transplanted with lymphocyte-depleted marrow for acute lymphoblastic leukaemia, acute non-lymphoblastic leukaemia, chronic myeloid leukaemia, myelodysplastic syndrome and severe aplastic anaemia were studied. The median time for platelet recovery to greater than or equal to 20 and to greater than or equal to 50 x 10(9)/l was 21 (9-72) and 26 (11-86) days respectively. The neutrophil recovery to greater than or equal to 0.5 x 10(9)/l and the leucocyte recovery to greater than or equal to 1.0 x 10(9)/l was 19 (8-47) and 18 (6-47) days respectively. No relation was found between the number of infused granulocyte-macrophage colony-forming cells, erythroid burst-forming cells, diagnosis, graft-versus-host disease, antibiotic administration and recovery. Addition of a continuous 6-day infusion of anthracyclines to the conditioning regimen delayed the median recovery of platelets, neutrophils and leucocytes by 7-9 days. Fever during aplasia also inhibited haematopoietic recovery. It is speculated that leakage of intracellular anthracyclines after bone marrow infusion or fever secondary to anthracyclines-induced oromucositis is responsible for the delayed bone marrow recovery.
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PMID:Anthracyclines added to the conditioning regimen for allogeneic bone marrow transplantation are associated with a slower haematopoietic recovery. 265 Jul 86

The toxicity, pharmacokinetics, and hematologic effects of granulocyte-macrophage colony-stimulating (GM-CSF) were studied in a phase I/II trial of 16 patients with myelodysplastic syndrome (MDS). The GM-CSF was administered subcutaneously (SC) daily so as to achieve prolonged blood levels and to establish an outpatient treatment regimen. Four dose levels were administered for ten days: 0.3 microgram/kg/d (three patients), 1.0 microgram/kg/d (three), 3.0 micrograms/kg/d (four), and 10.0 micrograms/kg/d (six). The most common toxicities were fever and a flu-like syndrome, which were dose-dependent. The maximum-tolerated dose was 10.0 micrograms/kg/d, which induced severe rigors (two patients), fever greater than 40 degrees C (one), severe bronchospasm (one), and WBC 60,000 (one). In one patient, refractory anemia with excess blasts in transformation (RAEB-T) progressed to acute nonlymphocytic leukemia after two doses of GM-CSF, and the patient died of leukemia that did not respond to chemotherapy. After doses of 3.0 and 10.0 micrograms/kg, serum GM-CSF levels peaked at 3.8 to 6.3 hours, and persisted for 14 and 24 hours, respectively. Circulating granulocytes (neutrophils and bands) increased in a dose-dependent manner, as 11 of 13 patients who received greater than or equal to 1.0 microgram/kg/d responded with a two- to 194-fold increase. Although the neutrophils usually returned to pretreatment levels shortly after stopping GM-CSF, two patients continue to exhibit an elevation of neutrophils for 6 months. Dose-related increases in circulating monocytes and eosinophils were also noted. Transient increases in platelet and reticulocyte counts were observed in two and three patients, respectively. Five of the 16 patients later received maintenance GM-CSF at 3 micrograms/kg/d for 2 to 9 weeks. All showed a dramatic increase in neutrophils after 2 weeks. Thereafter, despite continued therapy, the neutrophil count in four patients declined markedly. In conclusion, GM-CSF is well tolerated by the SC route and induces striking, but usually temporary, improvement in the neutropenia of MDS. Larger prospective phase III trials will determine the duration of hematologic responses and the impact on infection, morbidity, and mortality.
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PMID:Subcutaneous granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndrome: toxicity, pharmacokinetics, and hematological effects. 265 78

The thermal sensitivity of normal myeloid and leukaemic cells was compared using morphology, cytochemistry and cultures of granulocyte-macrophage and leukaemic progenitor cells (GM-CFU and L-CFU). We have clearly demonstrated that blast cells from eight cases of acute nonlymphoblastic leukaemia (ANLL) showed greater morphological deterioration and loss of cytoplasmic enzymes with continuous heating at temperatures of 40-43 degrees C than normal marrow mononuclear cells obtained from ten controls. Survival of L-CFU also decreased exponentially with rising temperature whereas GM-CFU were not markedly affected, even at a temperature of 43 degrees C for 30 min. These results suggest that human L-CFU are more sensitive to hyperthermic killing than normal human GM-CFU and that hyperthermia might selectively purge residual leukaemic cells in vitro. Hyperthermia may have a role in clinical autologous bone marrow transplantation (ABMT) for acute leukaemia.
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PMID:Studies on sensitivity of human GM-CFU and L-CFU to hyperthermic killing in vitro. 265 11

The in vitro effect of recombinant human GM-CSF (rHuGM-CSF) was tested on bone marrow-derived multilineage (CFU-GEMM) as well as megakaryocytic (CFU-Mk), erythroid (BFU-E), and granulocyte-macrophage (CFU-GM) progenitors in a group (n = 16) of patients with myelodysplastic syndromes (MDS). Hematopoietic progenitor cell growth was markedly impaired in MDS patients as compared to normal controls (p less than 0.05, at least). Recombinant HuGM-CSF supported the growth of CFU-GEMM, CFU-Mk, and BFU-E at lower, equivalent, or slightly higher frequencies that those found in cultures plated with medium conditioned by peripheral blood leukocytes (PHA-LCM), but it was invariably ineffective in improving growth values. Recombinant HuGM-CSF supported the growth of granulocyte-macrophage colonies in 15 of 16 cases. The overall incidence (mean +/- SEM) of CFU-GM in cultures containing rHuGM-CSF (5 ng/ml) was significantly higher than the one found in cultures stimulated with PHA-LCM (40 +/- 15 vs. 17 +/- 7, p less than 0.05). Upon culture with rHuGM-CSF (5 ng/ml), in 5 of 15 patients de novo colony formation was observed (8 +/- 4) and in 4 of 15 patients CFU-GM growth (129 +/- 33) fell within normal range. Doses of rHuGM-CSF higher than 5 ng/ml did not result in a further increase of MDS-derived colony formation. It is concluded that rHuGM-CSF (a) does not improve the growth of CFU-GEMM, CFU-Mk, and BFU-E; (b) may completely restore the growth of CFU-GM in a subgroup of MDS patients; (c) while ineffective in improving anemia and thrombocytopenia, its in vivo in MDS may correct leukopenia through an effect at the level of granulocyte-macrophage progenitor cell compartment, at least in a subset of highly responsive patients.
Leukemia 1989 May
PMID:Growth of human hematopoietic colonies from patients with myelodysplastic syndromes in response to recombinant human granulocyte-macrophage colony-stimulating factor. 265 96


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