Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0155339 (Brown)
 12,436 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The lineage and state of differentiation of cells in the mammalian haemopoietic compartment is associated with specific patterns of homeobox gene expression (EMBO J. 7, 2131, 1988). Agents which influence homeobox gene expression are thus of great interest in the study of human leukemias. Retinoic acid has direct regulatory actions on homeobox gene transcription (TIBS 158, 52, 1989; Differentiation 37, 773, 1988) and can induce select human leukemia cell lines to undergo terminal differentiation in vitro (Proc. natl Acad. Sci. U.S.A. 77, 2936, 1980). Retinoic acid is also a known teratogen for vertebrate foetal limb-bud development. Some of the teratogenic effects are duplicated by the drug Thalidomide (Embryopathic Activity of Drugs, Little Brown, Boston, p. 167, 1965; Haematological Cytology, Wolf Med. Pub. Ltd, London, p. 118, 1982). To investigate Thalidomide for other retinoid-like effects, we exposed cultures of human leukemia K562 cells to the metabolites generated in a Thalidomide hepatic-microsomal enzyme drug metabolizing system (Proc. natl Acad. Sci. U.S.A. 78, 2545, 1981). Here we report evidence that a single 2 h pulse-exposure to Thalidomide metabolites, induces K562 cells to undergo morphological differentiation in vitro. We also demonstrate a significant cytotoxic effect for these metabolites.
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PMID:Induction of morphological differentiation in the human leukemic cell line K562 by exposure to thalidomide metabolites. 201 4

An animal model of acute myeloid leukemia (AML) has been developed in the Brown Norway (BN) rat and has successfully been introduced into the Lewis x BN F1 hybrid (LBN) and designated LBN AML. The original LBN AML is sensitive to the chemotherapeutic agent cyclophosphamide (CY). Recently, a CY-resistant cell line of LBN AML has been established. To characterize this animal model of human leukemia better, we analyzed and compared the chromosomal makeup of both the CY-sensitive and CY-resistant LBN AML lines. The CY-sensitive LBN AML cultures contained two cell lines--line I (88%): 41,XX,-1,-2,-9,del(12)(q16), + der(1)t(1;?8)(p13;q31), + der(2)t(2;9)(p11;q11); and line II (12%): 41,XX,-1,-2,-9,del(12),del(20)(q13) + der(1)t(1;?8)(p13;q31), + der(2)t(2;9)(p11;q11). The recently developed CY-resistant AML cells contained two cell lines--line I (88%): 41,XX,-1,-2,-9,del(3)(q36q42.1),del(4) (q42.2),?t(5;?)(q35;?),?t(8;?)(q24;?),del(12)(q16), + der(1)t(1;?8)(p13;q31), + der(2)t(2;9)(p11;q11); and line II (12%): 42,XX (probably represents host contamination). The new chromosomal aberrations in the CY-resistant line I [del(3)(q36q42.1),del(4)(q42.2),?t(5;?)(q35;?), and ?t(8;?)(q24;?)] suggest a possible interrelationship between these secondary karyotypic abnormalities and acquisition of resistance to the chemotherapeutic agent.
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PMID:Comparative cytogenetic analysis between cyclophosphamide-sensitive and -resistant lines of acute myeloid leukemia in the Lewis Brown Norway hybrid rat. 226 78

The possibilities for studying minimal residual disease (MRD) in human acute myelocytic leukemia (AML) are limited. Animal models are, therefore, indispensable for gaining insight into the characteristics of leukemia growth during the MRD phase. Studies were done to compare AML to acute myelocytic leukemia in the Brown Norway rat (BNML). The BNML model exhibited a high degree of similarity to human AML with regard to its general growth characteristics, its cell kinetic parameters, its biophysical parameters and its response to chemotherapy. This implied that studies of the BNML model have predictive value for clinical application. In the BNML model a number of independent methods are available to quantify the number of leukemic cells, i.e., indirectly by means of various bioassays or directly by using monoclonal antibody labeling and flow cytometry. Studies of the BNML model in relation to the understanding of various aspects of MRD in leukemia are discussed in this concise review. Insight has been obtained with regard to the kinetics of MRD; the efficacy of certain treatment modalities, e.g., cytostatic drug treatment with or without total body irradiation to eradicate MRD; the efficacy of various methods for eliminating residual leukemic cells from autologous marrow grafts; the emergence of drug resistance during MRD; and the progression of residual disease during the remission phase ultimately leading to a relapse and the implications of these observations for staging leukemia patients during the phase of MRD.
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PMID:Minimal residual disease in leukemia: studies in an animal model for acute myelocytic leukemia (BNML). 240 82

Our recent establishment of several permanent in-vitro cell lines from Brown Norway rat leukemia (BNML) and the development of a clonogenic assay prompted us to undertake detailed studies on the growth control mechanism of a cell type which for several years has served as an animal model for human AML and preclinical studies. So far, these cells have no defined biological regulators but require intricate cellular interactions to sustain their growth. The effects on cell growth and clonogenicity, of agents known to modify the intracellular levels of cyclic nucleotides, were analysed. Here we report that CT binding strongly inhibited cell growth at a wide range of concentrations (10(-6)-10(-14) M) while beta chain pentameric subunits or alpha chain had no effects. Cell growth was inhibited in a dose-dependent manner. The ligand-receptor interactions mediated the alpha chain's transit through the membrane; the adenylate cyclase activation and the rise in c-AMP levels (60 min) resulted in DNA synthesis arrest (5 h), then finally ended in cell death (24-48 h). A significant decrease in the clonal ability of treated cultures was seen. A decrease of up to five logs in the clonogenic cell number was observed after 48 h of toxin treatment (10(-7) M). The growth inhibition of CT were reproduced by several agents (PGE, theophylline, isobutylmethylxanthine) known to raise intracellular c-AMP levels. Data are commented from a biochemical approach to intracellular events controlling the cell growth of this leukemia. The potential interests of c-AMP inducing agents on the eradication of this leukemia by ex-vivo marrow treatments are also considered.
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PMID:On growth regulation of the rat promyelocytic leukemia (BNML): growth inhibition and eradication of clonogenic cells by cholera toxin. 243 59

Using a Brown Norway rat leukaemia model (BNML), which is a realistic model of human myelocytic leukaemia, we compared the antileukaemic activity, influence on cell cycle kinetics and effect on normal haematopoiesis of 5 aza-2-deoxycytidine (aza-dC) and arabinofuranosyl-cytosine (ara-C). The antileukaemic activity was evaluated by means of a survival study. For aza-dC a dose-response relationship was demonstrated for doses up to 50 mg kg-1 (3 times q 12 h); a higher dose resulted in only a slight increase in median survival time (MST). For ara-C a weak dose-response relationship was observed. At the maximum dose of aza-dC and ara-C tested, aza-dC induced a 10-day longer survival time than ara-C, which means 2 logs more of leukaemic cell kill for aza-dC. By means of flow cytometric analysis and a 3HTdR uptake study it was shown that aza-dC does not influence the cell cycle kinetics in the first 24 h after exposure, in contrast to ara-C which caused the characteristic G1/S blockage and synchronization. The influence of aza-dC and ara-C on normal haematopoiesis was evaluated with the CFU-S assay. The dose-response curve for CFU-S did not show a significant difference in stem cell cytotoxicity between aza-dC and ara-C. In the BNML model aza-dC is a much more effective antileukaemic agent than ara-C, while the toxic effect on normal haematopoiesis is comparable to that of ara-C.
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PMID:Comparison of the antileukaemic activity of 5 aza-2-deoxycytidine and arabinofuranosyl-cytosine in rats with myelocytic leukaemia. 246 15

The integration of viral DNA into the host genome is an essential step in the retrovirus life cycle. To understand this process better, we have examined the native state of viral DNA in cells acutely infected by murine leukemia virus (MLV), using both a physical assay for viral DNA and a functional assay for integration activity (Brown et al. 1987). The viral DNA and integration activity copurify during velocity sedimentation, gel filtration, and density equilibrium centrifugation, indicating that viral DNA is in a large (approximately 160S) nucleoprotein complex that includes all functions required for integration activity in vitro. Analysis by immunoprecipitation shows that the viral capsid protein is part of the active nucleoprotein complex, but recognition of the complex by only a subset of anti-capsid sera implies that the protein is constrained conformationally. The viral DNA within this structure is accessible to nucleases; the effects of nucleases on the integrity of the complex suggest that the integration-competent particle is derived from and similar to the core of extracellular virions.
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PMID:A nucleoprotein complex mediates the integration of retroviral DNA. 272 60

A subline of Brown Norway (BN) acute myelocytic leukemia (AML) which can be propagated in suspension culture (designated IPC-81) is described. Injection into Lewis x BN F1 hybrid (LBN) rats resulted in a log-linear correlation between tumor cell dose and time till death from the onset of leukemia even after multiple (greater than 16) passages in vitro. An in vitro clonogenic assay for IPC-81 colony formation (CFU-leuk) was developed with excellent cloning efficiency (55-82%). Colonies grew without the addition of specific growth factors; syngeneic spleen-conditioned medium inhibited CFU-leuk by 40%, but co-culture with untreated normal LBN rat bone marrow cells had no effect on CFU-leuk. CFU-leuk could be detected in the bone marrow 7 to 10 days before morphologic detection of leukemia in injected animals. This cell line should prove useful in the preclinical evaluation of new strategies for treating AML and evaluating new bone marrow purging methods.
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PMID:A subline of the Brown Norway myeloid leukemia in the Lewis x Brown Norway rat: in vivo growth characteristics and development of an in vitro clonogenic assay. 278 72

The efficacy and toxicity of Dinaline (GOE 1734; PD 104 208; NSC 328786; 4-amino-N-(2'-aminophenyl)benzamide) was evaluated in the Brown Norway acute myelocytic leukemia, which is generally accepted as a relevant preclinical model for human acute myelocytic leukemia. Upon repeated daily oral administration at least an 8 log leukemic cell kill was achieved with only less than a 1 log kill for normal pluripotent hemopoietic stem cells. Daily split-dose treatment even proved to be more effective and resulted in 40-50% cures. However, toxicity was also more pronounced in particular in regard to the gastrointestinal tract. So far, the mode of action of Dinaline is unknown, but its striking therapeutic index warrants further clinical investigation.
Leukemia 1988 Apr
PMID:Dinaline: a new oral drug against leukemia? Preclinical studies in a relevant rat model for human acute myelocytic leukemia (BNML). 316 79

Univariate as well as bivariate flow karyotyping has been performed on chromosome suspensions obtained from the Brown Norway myelocytic leukemia (BNML), a rat model for human acute myelocytic leukemia (AML). Flow karyograms were obtained from both the in vivo transplantable parent line and from an in vitro established cell line. Density gradient centrifugation performed on cells arrested in mitosis resulted in an enrichment of mitotic cells. Furthermore, with this procedure leukemic and nonleukemic cells could be separated. Univariate analysis with propididum iodide (PI) as a DNA stain revealed the position of the several tumor-specific marker chromosomes in the in vitro cell line. Estimations of the peak position of the various chromosomes was done by comparing the univariate flow karyogram with a computer-simulated karyogram from the BNML that was derived from the mean length of the individual chromosomes in conventionally prepared metaphase slides. By comparing the bivariate flow karyogram of the in vivo BNML cells with the flow karyogram of normal BN cells, it was clearly demonstrated which peaks are involved in the altered chromosomal pattern of the BNML. No differences were found between the flow karyograms of the in vitro- and the ex vivo-derived chromosome suspensions in this rat leukemia model.
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PMID:Bivariate flow karyotyping of acute myelocytic leukemia in the BNML rat model. 348 Jul 94

Clonogenic assays for M, GM, and G precursors of rat or mouse marrow cells were performed in the presence of medium conditioned by the growth of ASL-1 leukemia X LM fibroblast hybrid cells. Both GM- and M-colony-forming units (CFUs) were present in marrow cultures maintained in conditioned medium (CM) from hybrid cells (up to 162 +/- 10 total colonies per 10(5) cells) and from LM cells (65 +/- 5). Conditioned medium from ASL-1 cells did not lead to the formation of CFUs. The hybrid cell-derived CM supported the development of M and GM-CFUs from the marrows of DBA, CAF1, BDF1, C3D2F1, and C57B1/6 mice as well as Lewis, Brown Norway, and Wistar Furth rats. G-CFU were not detected in any of the preparations. Hybrid cell-CM supported the long-term growth and proliferation of macrophage-like cells from mouse spleen, consistent with the presence of M-colony-stimulating factor (CSF). Evidence that M-CSF formed by the hybrid cells and M-CSF formed by L cells shared structural features was provided by antibody neutralization studies. The CFU-promoting activity of hybrid cell-derived M-CSF was neutralized by an antiserum raised in goats against M-CSF purified from L cells. Independently prepared ASL-1 X LM hybrid cells, like the original, led to the formation of GM and M-CFUs. Attempts to detect each of several other previously defined growth factors in medium conditioned by the hybrid cells were unsuccessful. Interleukins 1, 2, and 3; B cell growth factors interferons alpha, beta, and gamma; erythropoietin; and burst promoting factor were not detected.
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PMID:Formation of macrophage (M) colony-stimulating factor by murine leukemia x fibroblast hybrid cells. 349 13


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