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)

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

Preclinical studies of resistance to alkylating agents in the Lewis x Brown Norway hybrid (LBN) rat model of acute myeloid leukemia (AML) have hitherto been limited by the sensitivity of LBN AML cells to cyclophosphamide (CY). We developed a CY-resistant subline of LBN AML by serial intravenous (IV) passage of AML cells followed by in vivo exposure to CY (100 mg/kg) 14 days later. After 18 and subsequent passages, CY-treated AML cells remained viable despite ex vivo incubation with 70 to 100 mumol/L 4-hydroperoxycyclophosphamide (4HC) or in vivo exposure to 100 to 300 mg/kg of CY. Once established, resistance to incubation with 4HC was stable in LBN AML cells after at least six serial in vivo passages without exposure to CY. Nevertheless, both control and CY-treated AML cells demonstrated similar dose-dependent sensitivity to 100 to 500 mumol/L phosphoramide mustard (PhM), the active alkylating end-product of CY activation in vivo. Levels of aldehyde dehydrogenase (ALDH), which inactivates CY by prevention of formation of PhM, were significantly elevated in these CY-resistant AML cells: cytosolic and particulate ALDH fractions from these cells were 11 to 13 times control with NAD cofactor and propanal substrate and three to four times control with NADP cofactor and benzaldehyde substrate. Further studies with this animal model of AML, in which resistance to CY is mediated by elevated ALDH activity, may elucidate mechanisms for effective elimination of drug-resistant leukemic cells ex vivo and in vivo.
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PMID:Development and characterization of a cyclophosphamide-resistant subline of acute myeloid leukemia in the Lewis x Brown Norway hybrid rat. 240 Aug 9

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

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.
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PMID:Dinaline: a new oral drug against leukemia? Preclinical studies in a relevant rat model for human acute myelocytic leukemia (BNML). 316 79

The efficacy of AMSA was evaluated quantitatively in a rat model (BNML) relevant for human acute myelocytic leukemia. The LD50 values observed in normal and leukemic Brown-Norway rats were 26.4 and 28.3 mg/kg respectively. In the higher dose ranges, the major cause of death was acute cardio-pulmonary toxicity. After single dose treatment, 20 mg AMSA/kg resulted in a surviving fraction of 5.5 X 10(2) for normal pluripotent hemopoietic stem cells and 4.1 X 10(-5) for in vivo clonogenic leukemic cells. With repeated administration of the drug amounting to the same total dose, even a 4 log difference in cell kill was observed between both cell populations. These studies provide quantitative information on the therapeutic index of AMSA and support the inclusion of this drug in first-line treatment regimens for acute myelocytic leukemia.
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PMID:AMSA: in vivo log cell kill for leukemic clonogenic cells versus toxicity for normal hemopoietic stem cells in a rat model for human acute myelocytic leukemia (BNML). 346

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

Brown Norway (BN) rats carrying a transplantable acute myelocytic leukemia (BNML) were given a supralethal combination of cyclophosphamide (80-100 mg/kg i.p.) and total-body irradiation (9.0 Gy gamma rays or 8.5 Gy X-rays) followed by isologous bone marrow transplantation. Of 110 long-term survivors (greater than 95 days), 40 (45%) died of a secondary malignancy at a median posttreatment age of 450 days. At a comparable age, non-treated control BN rats show a spontaneous tumor incidence of 5% only, which increased to 83% during the aging process. Thus the latency period for the appearance of tumors was impressively shortened. Tumors of neurogenic origin and acute leukemias were the most prominent types, in contrast with non-treated control rats.
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PMID:Secondary tumors after high-dose cyclophosphamide and total-body irradiation followed by bone marrow transplantation in a rat model for human acute myelocytic leukemia (BNML). 632 63

The efficacy and toxicity of piperazinedione were investigated in a Brown Norway rat model for acute myelocytic leukemia (BNML). Treatment was started at a stage which is comparable to a "full-blown" relapse in human patients. Early toxicity-induced deaths due to the very strong myelosuppressive effect of the drug could be prevented by bone marrow transplantation followed by repeated blood transfusions. However, with a total dose of 16 mg/kg (human dose, 85 mg/m2), death caused by GI tract and lung damage was inevitable. As judged by prolongation of survival, at the most of a 9-log cell-kill was achieved. No cures were obtained, since the total tumor load at the start of treatment was greater than 10(9) cells (about 5 X 10(9)). The possible presence of drug-resistant cells was not excluded. No significant differences in efficacy were found between daily "push" treatment and split daily doses using total doses of 10-12 mg/kg.
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PMID:Efficacy of piperazinedione prior to bone marrow transplantation: studies in a rat model for human acute myelocytic leukemia. 701 79


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