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Query: UMLS:C0155339 (Brown)
 12,436 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One characteristic feature of human acute leukaemia is a depression of normal haemopoiesis which, according to the results of in vitro colony formation, seems to be more severe in acute myeloid leukaemia (AML) than in acute lymphocytic leukaemia (ALL). In our rat model for AML, the transplantable Brown Norway myeloid leukaemia (BNML), near total suppression of haemopoiesis was observed in a relatively early stage of the disease because of the physical disappearance of haemopoietic stem cells (HSC) from the bone marrow, which was only partly compensated by an increased number of HSC in the spleen. The few HSC remaining in the BNML bone marrow in the terminal stage of the disease were mostly out of cycle, in contrast to the HSC in normal rat marrow. Studies with injected labelled leukaemic cells revealed that both BNML and cells of a transplantable lymphatic leukaemia home in the subendosteal region of the femoral bone marrow. Subsequently, ALL cells become randomly distributed over the whole marrow space, while BNML cells remain localized in the subendosteal region. The latter area contains in normal rat marrow a higher proportion of proliferating blast cells than the central area of the marrow, which is reminiscent of the kinetic gradient described in mouse bone marrow by Shackney et al. [22]. These observations support the hypothesis that the depression of normal haemopoiesis in AML is caused by a specific localization and proliferation of AML cells in the subendosteal area, which normally provides the optimal microenvironment for HSC self-replication. In ALL the more severe depression of haemopoiesis occurs in a later stage and is caused by random replacement of HSC as a result of non-specific overgrowth.
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PMID:The mechanism of inhibition of haemopoiesis in acute leukaemia. 718 49

One of the major problems in the treatment of leukemia with bone marrow transplantation (BMT) remains leukemia relapse. It has been clearly shown that graft-versus-host disease (GVHD) is accompanied by a graft-versus-leukemia reaction (GVLR) which reduces the incidence of leukemia relapse. To date, discussion is still going on as to whether GVHD and GVLR are either two different reactions or are exerting their effects through the same mechanism(s). In two rat leukemia models, namely the Brown Norway acute myelocytic leukemia (BNML) and the WAG/Rij acute lymphocytic leukemia L4415, total body irradiation (TBI) was given to induce a state of so-called minimal residual disease (MRD). Subsequently, it was attempted to evoke a GVLR distinct from GVHD by using semi-allogeneic hybrid-to-parent or parent-to-hybrid BMT, with or without the addition of graded numbers of lymphocytes. In both leukemia models applying hybrid-to-parent BMT, the addition of high numbers of semi-allogeneic lymphocytes to the semi-allogeneic graft had no antileukemic effect. In parent-to-hybrid BMT, the grafts sharing their alloantigens with the leukemia cells did not induce an anti-leukemic effect, irrespective of the number of lymphocytes present in the graft or the induction of evident GVHD. When the parental graft was histoincompatible with the leukemia cells, transplantation of bone marrow alone induced a significant increase in life span correlating with 2.8 log leukemia cell kill (LCK).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Graft-versus-leukemia in rat MHC-mismatched bone marrow transplantation is merely an allogeneic effect. 765 85

One of the major problems in the treatment of leukemia with BMT remains leukemia relapse. It has generally been established that allogeneic BMT, compared with autologous BMT, gives rise to a graft-versus-leukemia reaction (GVLR), usually associated with GVHD. To explore a possible role for post-BMT immunotherapy, recombinant human IL-2 therapy has been studied in the Brown Norway acute myelocytic leukemia (BNML), a rat leukemia model relevant for human AML. The antileukemic efficacy of rhIL-2 therapy is studied applying different doses of rhIL-2 after syngeneic or allogeneic BMT. rhIL-2 treatment post-syngeneic BMT showed a small, borderline significant GVLR. Repeated rhIL-2 treatment after allogeneic BMT resulted either in no significant antileukemic effect or in lethal GVHD when 'low' or 'high' doses were administered, respectively. An intermediate dose, however, induced a significant GVLR without the induction of (lethal) GVHD. Transplantation of allogeneic rat BM, which contains only a few lymphocytes, does not result in a significant GVLR or GVHD and thus resembles human HLA-matched allogeneic T cell-depleted (TCD) BMT. In conclusion, from the rat studies presented it appears that the GVLR lost by TCD of the allogeneic graft, may be more than fully compensated by IL-2 treatment post-allogeneic TCD BMT.
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PMID:Interleukin-2 therapy after allogeneic bone marrow transplantation for acute myelocytic leukemia: studies in a relevant rat model for AML. 771 75

The major shortcoming of present day treatment of leukemia by bone marrow transplantation (BMT) remains leukemia relapse. It has become clear that a graft-versus-host reaction (GVHR) is accompanied by a graft-versus-leukemia reaction (GVLR) which may prevent leukemia relapse. In two non-immunogenic rat leukemia models, the Brown Norway acute myelocytic leukemia (BNML) and the WAG/Rij acute lymphocytic leukemia L4415, total body irradiation (TBI) was given to induce 'minimal residual disease' (MRD). Subsequently, it was attempted to evoke a GVLR by using syngeneic or allogeneic BMT, with or without addition of graded numbers of lymphocytes. In both leukemia models the addition of high numbers of syngeneic lymphocytes to the syngeneic graft had no antileukemic effect. Allogeneic marrow grafts, which contain at the most 8% lymphocytes, only resulted in a GVLR when splenocytes were added. The therapeutic window was found to be narrow, i.e. in fully mismatched BMT the number of allogeneic splenocytes resulting in a significant GVLR (2-3 log leukemic cell kill) without inducing (lethal) acute GVHD was critical. Increasing the number of allogeneic spleen cells added to the allogeneic BM graft induced lethal acute GVHD. To date, our data indicate that the GVLR is an allogeneic effect, inseparable from GVHD.
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PMID:Quantitative studies on graft-versus-leukemia after allogeneic bone marrow transplantation in rat models for acute myelocytic and lymphocytic leukemia. 795 Nov 3

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.
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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

Acetyldinaline [CI-994; GOE 5549; PD 123 654; 4-acetylamino-N-(2'-aminophenyl)-benzamide] is the acetylated derivative form of the original compound Dinaline (GOE 1734; PD 104 208). The efficacy and toxicity of Acetyldinaline for remission-induction treatment of leukemia were evaluated and compared with those observed in previous studies of Dinaline in the Brown Norway acute myelocytic leukemia, as a preclinical model for human acute myelocytic leukemia. There were three treatment groups. Leukemic animals received either 1 or 2 courses of 5 daily p.o. administrations of Acetyldinaline with a "full dose" of 23.7 mg/kg once daily (first group), a twice daily "half dose" of 11.85 mg/kg with an interval of 8 h (second group), or a "half dose" of 11.85 mg/kg once daily (third group). The drug-free interval between the 2 courses was 2 or 9 days. With repeated daily p.o. administrations of 23.7 mg/kg either in a single daily dose or a split daily dose of 2 x 11.85 mg/kg for 1 course, at least an 8-log leukemic cell kill was achieved. In contrast, with these treatment schedules, less than a 1-log cell kill of normal pluripotent hemopoietic stem cells (CFU-S) in the femoral bone marrow was found. Split daily dose treatment was more effective resulting in 37.5% cures, while no cures were observed with the single daily treatment for one course. Treatment with single daily dose of 23.7 mg/kg or a split daily dose of 2 x 11.85 mg/kg for 2 courses, with either a 2- or 9-day interval in between, resulted in lethal toxicity in most of rats. This result was comparable with that previously observed after equimolar doses of Dinaline (20 mg/kg). The half-dose once daily treatment with Acetyldinaline (11.85 mg/kg) for 1 or 2 cycles resulted in about a 4.5 or > 8-log leukemic cell kill, respectively. Toxic side effects, i.e., damage to the gastro-intestinal tract and hemorrhages in the lungs, were more pronounced with full dose either in the single or the split daily dose regimen. No significant toxicity was observed at the half-dose treatment once daily. In conclusion, the impressive differential activity against leukemic cells and normal stem cells observed in this relevant rat model for human acute myelocytic leukemia warrants the introduction of this compound in clinical phase I/II studies.
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PMID:Acetyldinaline: a new oral cytostatic drug with impressive differential activity against leukemic cells and normal stem cells--preclinical studies in a relevant rat model for human acute myelocytic leukemia. 831 8

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.
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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.
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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.
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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.
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PMID:In vitro resistance of the brown Norway rat acute myelocytic leukemia (BNML) to lymphokine-activated killer activity. 848 27


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