摘要:

Abstract:Most cytostatic drugs exert their effect on cells in active cell cycle. To improve the effect of cytostatic drugs we have tried, prior to treatment in vitro, to recruit tumor cells from G0with growth factors. Leukemic cells from the bone marrows of 26 patients with AML and CML in blast crisis were incubated with G‐CSF, GM‐CSF and IL‐3 for 24 h prior to incubation with cytostatic drugs. The cells were incubated with mitoxantrone, etoposide or daunorubicin for 1 h, or with Ara‐C continuously. Prior to treatment, 4 patients with AML received GM‐CSF for 24 h, after which blast cells from bone marrow were incubated with cytostatic drugs. After incubation with the cytostatic drugs, cells were cultured in a suspension culture for 4 d. The drug effect was determined with a bioluminescence ATP method. Leukemic cells were significantly stimulated by all three cytokines compared to an untreated control. GM‐CSF and IL‐3 increased the amount of cells 3‐ to 4‐fold and G‐CSF increased the amount 3 times compared to untreated cells. G‐CSF significantly enhanced the cytotoxic effect of daunorubicin, mitoxantrone, etoposide and Ara‐C by 20–40%, while GM‐CSF and IL‐3 showed a significantly increased toxicity for Ara‐C only. Although the cytokines induced a higher percentage of cells killed with the cytostatic drugs, proliferation of the remaining cells resulted in an increased total number of cells from 1.5 to 3 times compared to the unstimulated incubations. We conclude that cytokines induce a higher level of toxicity of cytostatic drugs on leukemic cells, but the increased proliferation of the remaining cells

ISSN:0902-4441    

DOI:10.1111/j.1600-0609.1996.tb00285.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Abstract:The use of recombinant erythropoietin for treatment of anemia in myelodysplastic patients has so far produced poorer results than expected. Most clinical studies have been conducted without any selection of patients. In the present study we report our experience with the use of rhEPO in a population of selected MDS subjects. Only patients affected by refractory anemia according to FAB criteria, without significant WBC and platelets reduction, with normal LDH and short history of disease were eligible for the study and were treated with rhEPO at a dosage of 150 mg/kg three times a week for 2 months. Among 12 so treated patients, 7 (58.3%) achieved complete remission, 2 partial remission and 3 failed to respond. This high response rate makes more than acceptable the cost/benefit ratio for rhEPO in RA patients and may identify a subgroup of patients that can be treated successfully with rhEPO alone.

ISSN:0902-4441    

DOI:10.1111/j.1600-0609.1996.tb00286.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Abstract:Daunorubicin (DNR) accumulation studies as functional tests of the multidrug resistance (MDR1) gene product P‐glycoprotein have produced diverging results when correlated to response to chemotherapy in acute leukaemia. To investigate possible reasons for this diversity a starvation experiment, based upon prolongation of medium exchange, was set up in the multidrug resistant cell line CEM/VBL100. DNR accumulation (1 μg/ml) was measured flow cytometrically in the presence or absence of Verapamil (10 μmol/1). In cells permanently kept under ideal growth conditions, addition of Verapamil resulted in an average 90% increase in DNR enhancement in five successive experiments. In contrast, DNR accumulation increased by only 26% when the medium exchange was prolonged by 30 h to 42 h. This effect was not accompanied by changes in the MDR1 gene expression at the RNA or protein level. Consequently, 53 leukaemic blast samples of 30 newly diagnosed and 18 relapsed or refractory patients with acute leukaemia (ALL‐18, AML‐37) were processed without any delay and under the most stringent conditions possible. Evidence of the classical MDR phenotype was arbitrarily defined by a greater than 20% enhancement in DNR accumulation in response to Verapamil (10 μmol/1) or Cyclosporin A (3 μmol/1). Using this cutoff point for analysis of newly diagnosed leukaemia we found DNR uptake better correlated to response to treatment (p = 0.002) than P‐gp detection by means of immunocytochemistry, using a panel of monoclonal antibodies (p = 0.03). We conclude that DNR accumulation studies are a sensitive method for predicting therapy outcome in acute leukaemia when performed with necessary

ISSN:0902-4441    

DOI:10.1111/j.1600-0609.1996.tb00287.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Abstract:The transfusional need in patients treated with myeloablative chemotherapy appears to be greater than that resulting from bone marrow suppression alone. The erythrocyte transfusional need may be expressed as Δhb = the daily loss of haemoglobin (mmol/1/day), and multivariate analyses of factors influencing Δhb have been carried out. We have studied 124 patients, mainly with acute myeloid leukaemia, treated with 537 courses of chemotherapy, inducing cytopenia (a white cell count<1.0 times 109/1) in 476 cases. The transfusional need was 2.5–3 times greater than expected, suggesting the presence of haemolysis and/or occult bleedings. Using multiple regression analysis and repeated measurement analysis the main factor influencing the transfusional need was type/dose of chemotherapy. The higher the dose of cytarabine the greater the transfusional need. Other factors significantly influencing the transfusional need were tumour burden, fever, treatment‐related events such as positive blood cultures, systemic fungal infection, mucosal bleeding, melaena/haematemesis and diarrhoea. Finally, it was found that the transfusional need decreased gradually during the cytopenic p

ISSN:0902-4441    

DOI:10.1111/j.1600-0609.1996.tb00288.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Abstract:The aim of this study was to evaluate the usefulness of serum osteocalcin (OC) levels in multiple myeloma (MM) in order to assess its significance and activity, and to predict its course. Serum OC was measurement in 117 patients with MM and 116 healthy controls matched for age and sex. Serum OC levels were weakly correlated with Karnofsky index (r = 0.22; p<0.03). Lowest OC levels were observed when lytic bone lesions increased (p<0.05). There was no relationship between serum OC levels and vertebral crush fractures, serum calcium concentrations or stage of MM, neither was there any relationship between initial serum OC levels and survival. Progression of the disease was associated with a clear fall of serum OC in 61.5% of the “progressive” patients, versus 41% of the persisting “stabilized” cases. Serum OC level was strongly correlated with bone formation (p = 0.005), but not with bone resorption. Serum OC level is a sensitive marker of osteoblast activity, but a poor marker of the severity of MM. We do not consider it as a marker of MM activity or pr

ISSN:0902-4441    

DOI:10.1111/j.1600-0609.1996.tb00289.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Abstract:Acquired deficiency of antithrombin (AT), which in some patients could lead to thrombosis, has been a serious side effect of protocols which incorporateE. coliL‐asparaginase (ASP) for the treatment of acute lymphoblastic leukaemia (ALL). In a longitudinal, prospective, non‐randomized study children with ALL (n= 27) were treated according to the protocol ALL‐BFM‐90. During the induction phase using prednisone, vincristine, daunorubicin and ASP, AT substitution was performed in 15/27 patients, when their plasma concentration decreased below 60% of normal with a concomitant increase of D‐dimer formation. After the administration of the AT concentrate the patients, plasma concentration of AT increased and remained elevated after 18, 48 and 72 h. In addition, the plasma concentration of enhanced thrombin generation, D‐dimer formation and plasminogen activator inhibitor 1 decreased towards normal levels. Although the observed laboratory findings may serve as evidence for a possible clinical benefit of AT substitution during ASP treatment, further randomized studies are requested to evaluate whether the use of prophylactic AT administration could reduce the incidence of thromboembolic events in childhood acut

ISSN:0902-4441    

DOI:10.1111/j.1600-0609.1996.tb00290.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Abstract:The correlation between the bromodeoxiuridine (BrdU)‐labelling index (LI) of plasma cells and a new proliferation marker, the Argyrophilic Nucleolar Organizer Regions (AgNORs), was investigated in 44 myeloma patients at diagnosis. A preliminary analysis was made to verify the reproducibility of the assessment of plasma cell infiltration (PC%) in bone marrow aspirates, used to collect cells for LI determination, and in bone marrow biopsies, used for AgNORs evaluation. Although an overall good correlation was observed between PC% in biopsies and aspirates (r= 0.58,p= 0.001), the ratio between PC% in biopsies and in aspirates ranged from 0.35 to 7.5. Only 17 patients (38.6%) were within the 0.5–1.5 range. A positive correlation between LI and AgNORs was observed in these patients (r= 0.68,p= 0.003), whereas the correlation was lost in patients with higher ratio between PC% in biopsies and in aspirates (r= 0.08,p= 0.69). The prognostic significance of AgNORs was confirmed by survival analysis, showing a reduced survival for patients with high (>4.4) AgNOR counts (14 monthsvs35 months,p= 0.004). The AgNORs analysis therefore allows the simultaneous evaluation of myeloma cell infiltration, degree of differentiation and kinetics of growth in bone marrow biopsies. AgNOR counts deserve to be included in the procedures for diagnosis and prognostic evaluation of myeloma patie

ISSN:0902-4441    

DOI:10.1111/j.1600-0609.1996.tb00291.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Abstract:Samples of lymph nodes from 88 patients with B‐cell non‐Hodgkin's lymphoma (B‐NHL) grouped by the Working Formulation (WF) and from 15 patients with benign lymphadenopathies were investigated immunohistochemically and ultrastructurally for changes in angiogenesis and stromal distribution of two subendothelial basement membrane (BM) components, namely laminin and type IV collagen. The microvessel number was usually low in lymphadenopathies, and increased significantly in low‐grade B‐NHL. Intermediate‐grade tumors displayed a further significant increase that was mainly due to their diffuse subtypes rather than to the follicular subtype. High‐grade B‐NHL showed the highest counts. By contrast with the lymphadenopathies studied, the stroma of B‐NHL reacted intensely with both BM components, whose linear co‐expression was significantly associated with low‐grade and follicular intermediate‐grade B‐NHL, while expression of laminin alone in a granular pattern was detected in diffuse intermediate‐grade and high‐grade tumors. Ultrastructural analysis revealed immature vessels more frequently in diffuse intermediate‐grade, and in high‐grade B‐NHL. Thesein situdata suggest that angiogenesis occurring in B‐NHL increases along their progression path, and emphasize the importance of angiogenesis as an epige

ISSN:0902-4441    

DOI:10.1111/j.1600-0609.1996.tb00293.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Abstract:The effects of the bacterial extract broncho‐vaxom (BV; radioprotective immunomodulator; 500 μg/mouse i.p., 24 h) and indomethacin (INDO; inhibitor of prostaglandin production; 2 times 40 μg/mouse i.m., ‐ 24 h and ‐ 3 h) on the post‐irradiation recovery of hemopoietic functions in mice were investigated. Both agents were administered either alone or in combination. Endogenous spleen colony formation was increased in all treatment groups, with combination‐treated mice exhibiting the greatest effects. Similarly, 24 h after combined administration of BV and INDO (i.e. at the time of presumed irradiation) to the non‐irradiated mice granulocyte‐macrophage colony‐forming cell (GM‐CFC) numbers were greater in the bone marrow and spleen. Also, as determined by hydroxyurea injection, there was an increase in the number of GM‐CFC in the S‐phase of the cell cycle in the bone marrow. However, GM‐CFC in the spleen of combination pretreated mice was not stimulated to significant proliferation as compared to GM‐CFC in the spleen of mice injected with BV alone. Combined modality treatment was also more effective than single agent treatments in accelerating bone marrow cellularity and GM‐CFC regeneration, but not in accelerating GM‐CFC regeneration in the spleen. Combined administration of BV and INDO to mice prior to lethal irradiation exerted an additional radioprotective effect and pr

ISSN:0902-4441    

DOI:10.1111/j.1600-0609.1996.tb00294.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Abstract:The present study examines genetic mechanism(s) possibly involved in the observed 3′‐azido‐3′‐deoxythymidine (AZT)‐induced inhibition of globin gene transcription by evaluating the direct phenotypic erythroid effects of AZT on erythroid‐specific transcription factors which regulate globin gene promoters. In vitro binding of GATA‐1 or NFE‐2 to its consensus sequence was decreased in the presence of AZT reaching a maximum inhibition as early as 24 h after AZT treatment. Nuclear extracts from butyric acid‐induced K562 cells treated with an IC50concentration of AZT exhibited a decrease in GATA‐1 and NFE‐2 binding by approximately 30% and 35%. In contrast, 2′,3′‐dideoxycytidine which inhibits cell growth without affecting hemoglobin synthesis, had no effect on binding of GATA‐1 and NFE‐2 factors. Northern blot analysis revealed a 25% decrease by AZT in GATA‐1 mRNA steady‐state levels at 24 h and this inhibitory effect was maintained until 72 h after drug addition. A similar decrease in NFE‐2 mRNA steady‐state levels was observed at 72 h after AZT treatment. This study suggests that AZT inhibition of erythroid differentiation is subsequent to a decrease of nuclear factors gene

ISSN:0902-4441    

DOI:10.1111/j.1600-0609.1996.tb00296.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY