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 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

The efficacy of acetyldinaline [4-acetylamino-N-(2'-aminophenyl)-benzamide] for eradication of minimal residual disease (MRD), which is left after bone marrow transplantation, and the risk of a bone marrow graft being jeopardized by this treatment was studied in the Brown Norway rat acute myelocytic leukemia model (BNML). To mimic the clinical situation, MRD induction treatment was given to rats showing clinical signs of leukemia and consisted of 80 mg/kg cyclophosphamide and 7.0 Gy X-rays total body irradiation resulting in a 6-8 log leukemic cell kill leaving 10-1000 leukemic cells in the animals. Treatment was completed with a syngeneic bone marrow transplant. A high dose level (HD) treatment of 23.7 mg acetyldinaline/kg per day and a low dose level (LD) treatment of 11.85 mg/kg per day, each given orally for five consecutive days, were compared. The increase in the survival time, the cure rate, and the toxic death rate were evaluated. One 5-day course of LD treatment, started at a time interval of 10, 17, or 24 days following MRD induction, resulted in 44%, 11% or 0% cures. With two 5-day courses of LD treatment, 89%, 22%, or 0% cures were achieved. With LD treatment, maximally an 8 log leukemic cell kill was obtained and no toxicity-related deaths were observed (only less than a 1 log kill of normal hemopoietic stem cells). In contrast, a single course of HD treatment resulted in 56% of the rats (10/18) dying from intestinal tract toxicity, while from the remaining eight rats at risk for relapse, three (37%) showed a very late relapse and five were cured (63%). It was evident that the leukemic cell load at the start of the acetyldinaline treatment determined the probability of relapse. An important finding was that acetyldinaline did not interfere with bone marrow regeneration. The highly curative potential of acetyldinaline treatment in the BNML model during the phase of MRD warrants the introduction of this compound in clinical phase I/II studies.
Leukemia 1993 Nov
PMID:Efficacy of acetyldinaline for treatment of minimal residual disease (MRD): preclinical studies in the BNML rat model for human acute myelocytic leukemia. 823 Dec 48

The cytostatic drug acetyldinaline [ACD, CI-994, 4-acetylamine-N-(2-aminophenyl)-benzamide] shows an extreme antileukemic effect in the Brown Norway (BN) rate model for acute myelocytic leukemia (BNML) with only minor toxicity for normal pluripotent hemopoietic stem cells. So far, the mode of action is unknown. A resistant subline (BNML/ACD-R) was developed in vivo in the BNML model. Leukemic rats received repeated oral administrations of ACD. When the leukemia relapsed after initial remission-induction with ACD, the cells were transferred to new recipients which were again treated. In total, the animals received 247 oral administrations of ACD (33 x 2 mg/kg per day and 214 x 5 mg/kg per day) before full resistance was reached. The cell line was transferred 17 times in total. Treatment of the final resistant cell line with therapeutically highly active doses of 23.7 mg/kg per day and 11.85 mg/kg per day ACD for 5 days, that resulted in an increase of life span (ILS) of 57 and 18 days, respectively, when applied to the sensitive parent BNML line (BNML/S), resulted in only 10 and 3 days ILS, respectively. These results indicate that a significant degree of resistance has been achieved, which can be overcome partially by increasing the dose of ACD. Whether the development of a resistant subpopulation of the BNML is a result of acquired resistance or whether a naturally resistant subpopulation has been selected out after prolonged treatment with ACD remains to be established. The currently available resistant subline BNML/ACD-R now offers the possibility for further studies on the mechanism of action of ACD.
Leukemia 1993 Aug
PMID:In vivo development of an acetyldinaline resistant subline of the BN rat acute myelocytic leukemia (BNML). 835 Jun 29

The role of the complement system in the pathogenesis of pulmonary leukostasis in myelocytic leukemia was studied in a rat model. Acute myelocytic leukemia was induced in six Brown-Norway rats, and complement levels were assayed during the course of the disease. Whole complement activity (CH50) and hemolytic activity of C1q, C3, and C4 decreased from day 16 after induction of the leukemia, when the rats developed pulmonary leukostasis. In addition, local complement activation was established in the lung vessels by immunofluorescence microscopy in advanced stages of pulmonary leukostasis. Finally, following systemic activation of the complement system by injection of cobra venom factor (CVF), leukemic rats (n = 6) died of pulmonary leukostasis 4.5 days earlier than did leukemic controls (n = 6). These findings suggest that, in acute myelocytic leukemia in Brown-Norway rats, pulmonary leukostasis is induced by activation of the complement system. This finding could lead to new modes of treatment for a life-threatening complication of leukemia.
Leukemia 1993 Oct
PMID:Involvement of the complement system in the pathogenesis of pulmonary leukostasis in experimental myelocytic leukemia. 841 22

To study minimal residual disease (MRD) in leukemia, we transferred the Escherichia coli genes encoding beta-galactosidase (lacZ) and neomycin resistance (neo(r)) into the subline LT12 of the Brown Norway rat acute myelocytic leukemia (BNML), employing the retroviral BAG vector. In this way leukemic cells were genetically marked. Ten independent cell lines were characterized during in vitro growth as well as during two subsequent in vivo passages for expression of neo(r) for which the neomycin analogue G418 was used, and for lacZ expression for which the substrate 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-gal) was used. Out of 10 lines, four revealed permanent high expression of lacZ in all cells. In four other lines greatly varying lacZ expression between the individual cells from these lines was observed. In the remaining two lines lacZ expression was gradually lost. In contrast, neo(r) expression was gradually lost in eight out of the 10 lines, particularly rapidly during in vivo passaging. In the remaining two lines neo(r) expression was retained. The genetic modification did not alter the in vitro leukemogenicity of the cells. Long term in vivo expression of neo(r) and lacZ was followed in two selected lines up to 12 subsequent passages, i.e. one from the group of homogeneous high lacZ expression and one from the group of heterogeneous lacZ expression. In both lines lacZ expression was retained whereas neo(r) expression was rapidly lost after the third passage. The feasibility of using genetically marked leukemic cells for studies of minimal residual disease (MRD) was explored by injecting rats with leukemic cells, treating them with chemotherapy at full blown leukemia development to reduce the tumor load, mimicking the induction of a state of MRD and studying lacZ expression at relapse. LacZ expression was evident in 100% of the cells whereas neo(r) expression was lost in a considerable fraction. These results indicate that the viral vector BAG can be used to mark leukemia cells genetically although a selection of clones with the desired stability of long-term expression is required.
Leukemia 1993 Jan
PMID:Retrovirus-mediated transfer and expression of marker genes in the BN rat acute myelocytic leukemia model for the study of minimal residual disease (MRD). 841 72

In in vivo allogeneic bone marrow transplantation studies with the Brown Norway (BN) rat as recipient and the WAG/Rij rat as allogeneic donor a significant graft-versus-leukemia (GVL) effect is observed. Studies were performed to investigate whether lymphokine-activated killer (LAK) cells play a role in this GVL effect. Splenocytes from WAG/Rij and BN rats were activated in vitro by recombinant human interleukin-2 (rhIL-2) for 5-6 days. The cytolytic activity of these LAK cells was tested on four rat solid tumor cell lines, i.e. an ureter carcinoma, a rhabdomyosarcoma, and two lung tumors, and on leukemic cells derived from the BN rat acute myelocytic leukemia (BNML) and the WAG/Rij acute lymphocytic leukemia (L4415). The panel of target cells also included the murine cell lines P815 and YAC. Both WAG/Rij and BN LAK cells were not capable of lysing the leukemic cells in contrast to significant cytolytic activity on the rat solid tumor cell lines and P815 and YAC. BNML cells showed to be resistant to lysis by human NK cells. Phenotypical analysis of the rat LAK population revealed a decrease in the CD4/CD8 ratio compared to the unstimulated splenocyte population. Rat LAK cells displayed no antibody-dependent cellular cytotoxicity (ADCC) on the leukemic cells, whereas IL-2-stimulated human peripheral blood cells showed moderate ADCC activity on the leukemic cells. To investigate whether cytokines play a role in lysis of leukemic target cells, graded numbers of LAK cells and leukemic cells were co-cultivated for seven days in an agar-based colony culture system. This resulted in moderate suppression of leukemic colony formation. From the current in vitro studies it appears that the graft-versus-leukemia observed in in vivo allogeneic bone marrow transplantation studies is probably not due to a direct leukemic cell kill by LAK cells.
Leukemia 1993 May
PMID:In vitro resistance of the brown Norway rat acute myelocytic leukemia (BNML) to lymphokine-activated killer activity. 848 27

We studied the applicability of interleukin-6 Pseudomonas exotoxin fusion protein (IL-6PE4E) for treatment of acute myelocytic leukemia (AML). Leukemic cells from five out of 10 AML patients studied expressed IL-6 receptor (IL-6R) and proliferation in vitro was inhibited in four of these cases. The potential of this approach in vivo was tested in a pre-clinical model for AML; the Brown Norway acute myelocytic leukemia (BNML). To obtain IL-6R expression levels on BNML cells comparable to the numbers expressed on human AML, human IL-6R gene transfectants of the BNML sub-line LT12 (LT12/IL-6R) were generated. IL-6PE4E is cytotoxic in vitro to LT12/IL-6R expressing 1400 high affinity IL-6R per cell with 50% inhibition of DNA synthesis at 1 ng/ml. In vivo treatment of leukemic rats carrying LT12/IL-6R leukemia indicated that the maximal tolerated dose of IL-6PE4E was 275 +/- 25 microg/kg/day, when continuously administered for 7 days and resulted in a 90% reduction in leukemic cell load. At this dose level of IL-6PE4E no reduction of normal hemopoietic progenitors was seen in non-leukemic rats. At higher dose levels (350-1050 microg/kg/day) severe systemic toxicity was encountered. On the basis of these pre-clinical studies the feasibility of growth factor-toxins for selective in vivo targeting to AML cells is evaluated.
Leukemia 1996 Nov
PMID:Treatment of acute myelocytic leukemia with interleukin-6 Pseudomonas exotoxin fusion protein in a rat leukemia model. 889 84

The multiple functions of the phenol moiety that are widely present in disparate sources such as drugs, pesticides, teas, fuel additives and surfactants have not been clearly delineated. The differences in behavior of phenols, which run the gamut from aberrations in DNA/chromosomes to suppression of genotoxic activity of carcinogenic compounds, merit further attention. In this study, a through examination of the growth inhibition patterns of 37, simple 3- and 4-substituted phenols in mouse leukemia cells was carried out and the following quantitative structure-activity relationship (QSAR) was obtained for the 23 electron releasing substituents in X-phenols: log 1/IC50 = -1.58 sigma(+) +0.21 log P + 3.10. In this QSAR, IC50 is the concentration of phenol that induces 50% inhibition of growth. P is a measure of the hydrophobicity of each phenol and Brown's electronic parameter, sigma+, represents the electronic effect of the substituent. The negative dependence on sigma+ is strongly reminiscent of what is observed in the developmental toxicity of phenols on rat embryos as well as for the radical abstraction of a hydrogen atom from phenolic groups. The other 15 electron-attracting substituted X-phenols clearly show a linear dependence on hydrophobicity alone: Log 1/IC50 = 0.62 log P + 2.35. The bifurcation in mechanism of action of this large set of diverse phenols is novel and unusual. It suggests that two distinct processes are operative. In the case of electron releasing substituted phenols, the observations are not inconsistent with a radical mediated process while with electron attracting substituted phenols, non-specific toxicity as modulated by hydrophobicity, appears to predominate.
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PMID:Phenol toxicity in leukemia cells: a radical process? 971 17

In this study, the cytotoxicities of a series of X-thiophenols vs rapidly growing mouse leukemia cells in vitro are determined. The resulting ID(50) values are then used to formulate a quantitative structure-activity relationship, which is well-correlated by the Brown variation of the Hammett electronic parameter, sigma-plus (sigma(+) ), such that Log 1/ID(50) = -0.93 (+/-0.18) sigma(+) + 0.86 (+/-0.24) I(H) + 3.99 (+/-0.13). I(H) represents an indicator variable that calls attention to the unusual activity of halogens and pseudohalogens. In lieu of sigma(+), homolytic bond dissociation energies (BDE) are also used successfully to correlate the cellular cytotoxicities of thiophenols. The nature of substituent effects on cellular toxicity is examined, and they reveal that electron-releasing substituted thiophenols such as 4-amino thiophenol and the 4-alkoxy thiophenols are highly cytotoxic and effective at inhibiting cellular proliferation at physiological pH. On the other hand, electron-attracting substituted thiophenols such as the 4-cyano and 4-halogen analogues show a reduced ability to inhibit the cell growth of this cell line. Thus, there is a clear parallel between enhanced biological activity and electron releasing ability as measured by sigma(+) constants or BDE values. The susceptibility of the cellular interaction to electronic effects as delineated by the coefficient with the sigma(+) term (also called the Hammett rho value) is high (-0.96), suggesting that substantial energetic assistance is provided by the substituents and that a weak initiating radical reactant such as superoxide radical may be involved. Previous cytotoxicity studies of a large diverse data set of X-phenols in this cell line and embryo cells have also revealed a more pronounced dependence on sigma(+) and deltaBDE. A comparison of reaction constants obtained from thiophenoxy radical formation reactions and phenoxy radical formation reactions in organic media suggests radical-mediated involvement in cell cytotoxicity. Such cells could be more vulnerable to the effects of reactive thiyl species on their metabolism and subsequent proliferation.
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PMID:Synthesis, cytotoxicity, and QSAR analysis of X-thiophenols in rapidly dividing cells. 1264 27

It has been proved that oxidative stress increases when leukemia is accompanied by depression. This fact may indicate the role of oxidative stress in the development of depression in cancer patients. The aim of this study was to determine whether the acute myeloid leukemia of Brown Norway rats, which is accompanied by oxidative stress, evoked behavioral and receptor changes resembling alterations characteristic of rat models of depression. The rats were divided into two groups: leukemic rats and healthy control. Leukemia was induced through intraperitoneal injection of 10(7) promyelocytic leukemia cells to the Brown Norway rats. Depression-like behavior was evaluated in the forced swim test at 30 or 34 days after leukemic cells injection. The rats were killed after the evaluation and the spleen, brain cortex and hippocampus were excised. The red-ox state was assessed in homogenates of tissues by measuring total glutathione (GSH) content, the ferric ion reducing ability of plasma (FRAP) level, expression of heme oxygenase-1 (HO-1), biliverdin reductase (BvR) and ferritin mRNA, superoxide dismutase (SOD) activity, as well as malondialdehyde (MDA) concentration. Radioligand binding assay was used to assess of the effect of leukemia on cortical receptors. Leukemic cells were identified using RM-124 antibody by FACS Calibur flow cytometry. Leukemia influenced locomotory activity as well as forced swim test behavior in a 34-day series of experiments. Signs of oxidative stress in leukemic rats were observed in each examined stage of leukemia development. The FRAP values and glutathione contents, were significantly lowered whereas HO-1 mRNA expression, and malonodialdehyde concentrations were significantly increased in the spleen and brain structures of leukemic rats in comparison with the healthy controls. A significant increase in the potency of glycine to displace [(3)H]L-689,560 from the strychnine-insensitive glycine site of the N-methyl-D-aspartic (NMDA) receptors receptor complex in cortical homogenates of the leukemic rats in 30- and 34-day experimental series was observed in comparison with the control. Upregulation of 5-HT(2A) receptors was observed in rat cortex after 30 days of leukemia development but not in 34-days series compared with the control. It is concluded that disturbances in antioxidant system in brain cortex were accompanied by an activation of glycine sites of the NMDA receptor complex, regardless of stage of leukemia development, which are characteristic of model of depression. Findings of our study demonstrate the link between glutamatergic activity, oxidative stress and leukemia.
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PMID:Evaluation of oxidative status and depression-like responses in Brown Norway rats with acute myeloid leukemia. 1926 4


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