RESUMEN
An elevated level of fibroblast growth factor-2 (FGF-2) in peripheral blood is considered to play a role in regulating the growth of leukemia cells. Here, we show that the level of plasma FGF-2 is increased in 54% of B cell chronic lymphocytic leukemias (B-CLL) and in 44% of chronic myeloid leukemias (CML). Notably, white blood cells (WBCs) from B-CLL patients contain 18, 22 and 24 kDa isoforms of FGF-2 whereas WBCs from CML patients contain only the 24 kDa isoform. Furthermore, as cultured B-CLL WBCs release 18 kDa FGF-2 into the medium, they constitute a potential source of FGF-2 in the blood. In a receptor binding assay, 125I-FGF-2 binds weakly to B-CLL WBCs, whereas the ligand binds more strongly to CML WBCs. Correspondingly, FGF-2 is unable to activate mitogen-activated protein kinase kinase (MEK) and its substrate, extracellular signal-regulated kinase (ERK), in B-CLL cells, whereas phosphorylation of both these cell growth-related kinases increases following treatment of CML WBCs. We conclude that B-CLL WBCs secrete FGF-2 with no apparent autocrine actions. In contrast, WBCs in CML bind FGF-2 provided by other FGF-2-hyperproducing cells and activate the MEK/ERK kinase cascade, possibly to modulate cell growth.
Asunto(s)
Factor 2 de Crecimiento de Fibroblastos/sangre , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Medios de Cultivo Condicionados , Cartilla de ADN , Femenino , Factor 2 de Crecimiento de Fibroblastos/química , Humanos , Masculino , Persona de Mediana Edad , Peso Molecular , ARN Mensajero/genética , Receptores de Factores de Crecimiento de Fibroblastos/genéticaRESUMEN
Chronic myelogenous leukemia (CML) is associated with a translocation of the protooncogene c-abl from chromosome 9 to chromosome 22, where it fuses to proximal exons of the bcr gene. The expression of the hybrid gene bcr-abl is regulated by the bcr promoter and results in a translation product with high tyrosine kinase activity. In most CML cases, one of two abl promoters (Pa) is nested within the bcr-abl transcription unit, but appears to be usually silent. Recently, de novo methylation of the Pa region and its correlation with disease progression were reported. As these previous studies were limited to the use of methylation-sensitive restriction endonucleases, our aim here was to obtain a complete map of methylcytosines and its variants in CML patients and in model cell lines. To achieve this, bisulfite conversion of cytosines (but not methylcytosines) to uracils in genomic DNA was employed. After modification, the region of interest was PCR-amplified and the products were cloned and sequenced. The results show methylation at a high level and in a homogenous pattern in the BV173 cell line, corresponding to the translocated abl alleles. Variant methylation observed in K562 cells correlates with multiple bcr-abl loci and an intact chromosome 9. Patients that were methylation-positive in restriction analysis showed sporadic and heterogenous occurrence of methylcytosines in bisulfite modification assays. Corresponding results were obtained using a quantitative Southern analysis of the extent of methylation. We conclude that restriction analysis combined with PCR is able to find rare cases of hypermethylation, e. g., for diagnostic purposes, but does not reflect the dominating level of methylation in Ph-positive cells.
Asunto(s)
Proteínas de Fusión bcr-abl/genética , Genes abl , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Regiones Promotoras Genéticas , Secuencia de Bases , Crisis Blástica/genética , Cromosomas Humanos Par 22 , Cromosomas Humanos Par 9 , Citosina/análogos & derivados , Metilación de ADN , Fosfatos de Dinucleósidos/análisis , Fosfatos de Dinucleósidos/química , Humanos , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Datos de Secuencia Molecular , Células Tumorales CultivadasRESUMEN
The neighborhood relationships of chromosomes can be of great importance for basic cellular processes such as gene expression or translocation induction. In this study, the topological organization of chromosomes 9 and 22 was investigated in cell nuclei of G0-phase lymphocytes. We found that the territories of both chromosomes are predominantly located in the central region of cell nuclei. In addition to this, chromosomes 9 and 22 were frequently associated in pairs detected as false-positive ABL-BCR fusions. Both effects might substantially increase the probability of interaction between chromosomes. Because of this, exchange aberrations were studied in chromosomes 9 and 22 of human lymphocytes irradiated by neutrons. The rate of aberration induction between these chromosomes was 11 times higher than the expected frequency based on the fractional molecular weight of these chromosomes. We show that the increased rate of exchange between chromosomes 9 and 22 induced by neutrons corresponds to the neighborhood relationships of both chromosomes. Similar topological characteristics of ABL and BCR genes were found in several cell lines: T- and B-lymphocytes. HL60 cells and bone marrow cells. This finding suggests that the specific chromatin structure mentioned might be responsible for the high rate of induction of t(9;22)-positive leukemias in the human population.
Asunto(s)
Núcleo Celular/genética , Cromosomas Humanos Par 22 , Cromosomas Humanos Par 9 , Leucemia/genética , Proteínas Tirosina Quinasas , Translocación Genética , Fusión Artificial Génica , Células de la Médula Ósea/fisiología , Línea Celular , Aberraciones Cromosómicas , Cromosomas Humanos Par 22/química , Cromosomas Humanos Par 22/ultraestructura , Cromosomas Humanos Par 9/química , Cromosomas Humanos Par 9/ultraestructura , Genes abl , Humanos , Procesamiento de Imagen Asistido por Computador , Linfocitos/fisiología , Linfocitos/efectos de la radiación , Masculino , Neutrones , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-bcrRESUMEN
BACKGROUND: Treatment of Hodgkin's disease (HD) and non-Hodgkin lymphomas (NHL) is still unsatisfactory in patients resistant to primary therapy or those with early relapses. The objective of the trial was to test whether salvage regimens based on a combination of iphosphamide and etopozide have a sufficient anti-lymphoma effect, while the toxicity is still acceptable, and in conjunction with growth factors as satisfactory mobilizing potential for the collection of peripheral stem cells (PBSC). METHODS AND RESULTS: A group of 40 patients with relapsing and/or primary therapy resisting lymphomas (14 NHL, 26 HD) were treated by life saving or stimulating chemotherapy VIM (etopozide, iphosphamide, methotrexate) and MINE (iphosphamide mitoxanthrone, etopozide; mostly NHL). If the response to these regimes was inadequate, to some patients in addition mini (dexa) regimes were administered, BEAM and DHAP resp., with the objective to achieve maximum reduction of the tumourous mass before high-dosage treatment with the support of autologous PBSC. The authors administered 119 cycles of salvage chemotherapy (51 VIM, 46 MINE, 22 mini-dexa-BEAM and DHAP). The toxicity of chemotherapy and the therapeutic response were evaluated according to WHO criteria. The toxicity of VIM and MINE, with the exception for mobilization of desirable transient leukopenia, was not serious. During stimulation of PBSC on average three leukophereses were made and on average 9.9. 10(6) CD34+ cells/kg body weight of the patient were obtained and 53.2. 10(4) CFU-GM/kg (VIM), and 13.5. 10(6) CD34+ cells/kg 53.4. 10(4) CFU-GM/kg (MINE) resp. A total of 64% (MINE) and 61% (VIM) therapeutic responses were obtained, 14% (MINE) and 26% (VIM) complete remissions and 50% (MINE) and 35% (VIM) partial remissions. CONCLUSIONS: Life saving regimes, VIM and MINE, have a good antilymphoma activity, low toxicity and in combination with growth factors (filgrastim) they ensure a good collection of PBSC. As compared with other regimens, in particular for stimulation, VIM and MINE appear to be better.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/tratamiento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Resistencia a Antineoplásicos , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Ifosfamida/administración & dosificación , Ifosfamida/efectos adversos , Leucaféresis , Masculino , Mesna/administración & dosificación , Mesna/efectos adversos , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Mitoxantrona/efectos adversos , Recurrencia , Terapia Recuperativa , Acondicionamiento PretrasplanteRESUMEN
Quantitative measurements of the nuclear localisation of the ABL and BCR genes and the distance between them were performed in randomly oriented bone marrow cells of control donors and patients with chronic myeloid leukaemia (CML). Most ABL and BCR genes (75%) are located at a distance of 20-65% of the local radius from the nuclear centre to the nuclear membrane. A chimeric BCR-ABL gene located on a derivative chromosome 22 resulting from t(9;22)(q34;q11) [the so-called Philadelphia (Ph) chromosome] as well as the intact ABL and BCR genes of patients suffering from chronic myeloid leukaemia are also located mostly in this region, which has a mean thickness of 2 microns in bone marrow cells. We have not found any significant differences in the location of the two genes in the G1 and G2 phases of the cell cycle, nor between bone marrow cells and stimulated lymphocytes. Irradiation of lymphocytes with a dose of 5 Gy of gamma-rays results in a shift of both genes to the central region of the nucleus (0-20% of the radius distant from the nuclear centre) in about 15% of the cells. The minimum distance between one ABL and one BCR gene is less than 1 micron in 47.5% of bone marrow cells of control donors. Such a small distance is found between homologous ABL and between homologous BCR genes in only 8.1% and 8.4% of cells, respectively. It is possible that the relative closeness of nonhomologous ABL and BCR genes in interphase nuclei of bone marrow cells could facilitate translocation between these genes. In 16.4% of bone marrow cells one ABL and one BCR gene are juxtaposed (the distance between them varies from 0-0.5 micron) and simulate the Ph chromosome. This juxtaposition is the result of the projection of two genes located one above another into a plane, as follows from the probability calculation.
Asunto(s)
Núcleo Celular/química , Genes abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Proteínas Tirosina Quinasas , Proteínas Proto-Oncogénicas/genética , Proto-Oncogenes/genética , Adulto , Células de la Médula Ósea , Sondas de ADN/genética , ADN de Neoplasias/análisis , Femenino , Proteínas de Fusión bcr-abl/genética , Rayos gamma , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Hibridación Fluorescente in Situ/métodos , Interfase , Linfocitos/efectos de la radiación , Masculino , Persona de Mediana Edad , Cromosoma Filadelfia , Proteínas Proto-Oncogénicas c-bcrRESUMEN
New purine analogues, fludarabine, 2-chlorodeoxyadenosine and 2-deoxycoformycin are remarkably active in generally incurable malignant lymphoproliferative disorders. The first part of the review summarises pharmacological properties, the mechanism of action, toxicity and clinical use of fludarabine. Major clinical experience with fludarabine has been obtained in patients with chronic lymphocytic leukaemia (CLL). In the studies in pretreated patients with CLL, the overall response rate was over 50%. In previously untreated patients with CLL response rate of 75-80% was recorded with a high ratio of complete responses. Fludarabine was found to be active agent in indolent lymphoma in phase I/II. Approximately 60% of patients with follicular lymphoma respond to fludarabine monotherapy. Combination of fludarabine with cytosine arabinoside (ara-C) is now successfully used in the treatment of acute myelogenous leukaemia (AML) and myelodysplastic syndrome (MDS). Other potential areas of use for fludarabine include hairy-cell leukaemia, Waldenström's macroglobulinaemia and mycosis fungoides. Myelosupression, especially leuko and lymphopenia is the major dose-limiting adverse effect of fludarabine. A long term reduction in CD4+ T cell count may be associated with an increased incidence of opportunistic infections. Other adverse effects such as nausea and vomiting or neurotoxicity are of mild to moderate severity when the recommended dosage is used.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Hematológicas/tratamiento farmacológico , Vidarabina/análogos & derivados , Antineoplásicos/efectos adversos , Humanos , Vidarabina/efectos adversos , Vidarabina/uso terapéuticoRESUMEN
Multiple myeloma affects predominantly osseous spaces and the close vicinity of bones. A plasmacellular exudate is rare. The authors describe the course of plasmacellular leukaemia in a 68-year-old female patient where the first symptom of the disease was anaemia and a dextrolateral pleural exudate with a cytological finding of plasma cells. The exudate disappeared after the first cycle of chemotherapy and intrapleural administration of cytostatic. After the third cycle of chemotherapy remission of the disease was recorded which was, however, short. After three months' remission (six months after establishment of the diagnosis) the disease exacerbated violently, the dextrolateral exudate reappeared and gradually the insufficiency of the infiltrated bone marrow increased. The patient died one month after the relapse of the disease. The finding of a plasmacellular exudate must be considered the sign of a very poor prognosis and in that case very aggressive treatment is indicated.
Asunto(s)
Leucemia de Células Plasmáticas/complicaciones , Derrame Pleural Maligno/complicaciones , Anciano , Femenino , Humanos , Leucemia de Células Plasmáticas/diagnóstico , Derrame Pleural Maligno/diagnósticoRESUMEN
The treatment results in 13 patients with acute lymphatic leukemia are reported. All patients were treated according to the Hoelzer protocol. Granulocyte colony-stimulating factor (G-CSF) was administered till the onset of neutropenia and was continued as long as the leukocyte number increased above 3 x 10(9)/l. In phase I of Hoelzer's protocol G-CSF was administered on the average for 12 days, in phase II for 15 days. The chemotherapy of phase I was administered in scheduled time to 11 patients. In phase II the average delay against the scheduled time was 14 days. Reductions of dose were made only in 2 person. After finishing phase II 9 patients were in complete remission. Three patients died during therapy, one patient with small response died one month after completing phase II therapy. We believe that the administration of G-CSF only at the onset of leukopenia also abbreviate its duration as if the application were started immediately with the chemotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Maintenance of satisfactory and safe venous access in cancer patients is part of a comprehensive care of cancer patients. As the Hickman/Broviac catheter is today used an implantable port. This port is placed in a subcutaneous pocket. The catheter connected to the port leads into the central vein, usually through the subclavian vein. An application of drugs in the port is done trough the skin. In this time could be used different types of ports, one or two chambers port, low profil port, peripheral port and others. In this paper we reported our two-years experience with 33 totally implantable access systems, which has been implanted in patients with cancer in Masaryk University Hospital Brno Bohunice. In our department was most frequently used port the nonmetallic port IMPLANTOFIX (BRAUN MELSUNGEN). All ports were in place for a total of 5,582 days, in average of 169 days. A frequency of complications were 2.15 on 1,000 days. Four ports were in place for longer than 1 year. A comparison of the incidence of complications in the present study with an analysis of 23 studies reported in literature was satisfactory. Minimal maintenance care, no restriction of life activity, improving quality of life and probably less frequency of infection complications, identify it as a significant advantage for the satisfactory maintenance of venous access of oncology patients in comparison with Hickman/Broviac catheter. Both the patients and the nursing staff showed a very high degree of satisfaction with this system. In cancer patients, especially with poor venous access, and prognosis longer than 6 months can be indicated this system with the advantage for patients.
Asunto(s)
Cateterismo Venoso Central , Catéteres de Permanencia , Neoplasias/terapia , Adolescente , Adulto , Anciano , Cateterismo Venoso Central/efectos adversos , Catéteres de Permanencia/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Aggressive chemotherapy of malignant haematological diseases causes long-term aplasia of bone marrow and it is necessary to supplement blood elements repeatedly. When procuring blood derivates frequently dramatic situations develop. In an attempt to prevent alloimmunization of the patient by careful selection of the donor the time interval between indication and administration of the transfusion is prolonged. The objective of the present work was to attempt an estimate, as regards time and amount, for transfusion of blood derivates. The authors analyzed 100 cycles of aggressive chemotherapy with regard to changes of the haemogram. The group was divided arbitrarily with regard to the initial value of different components of the haemogram and for these portions of the group a time schedule of check-up examinations of the haemogram and of the assumed time of indication of transfusion of blood derivates was elaborated. In patients with an initial values of red blood cells above 3.5 x 10(12)/l the first transfusion is usually needed on the 8th day after the beginning of chemotherapy, in patients with a values lower than 3.0 x 10(12)/l after the initial supplementation a further drop may be expected already on the 4th day. Indication of replacement of thrombocytes can be expected in patients with an initial thrombocyte value above 120 x 10(9)/l cca on the 8th day, in patients with an initial thrombocyte value of 30 x 10(9)/l after initial replacement indication of another transfusion can be anticipated already on the 4th day after the beginning of chemotherapy.
Asunto(s)
Antineoplásicos/efectos adversos , Transfusión de Componentes Sanguíneos , Médula Ósea/efectos de los fármacos , Leucemia/tratamiento farmacológico , Linfoma/tratamiento farmacológico , Adulto , Recuento de Células Sanguíneas/efectos de los fármacos , Femenino , Humanos , MasculinoRESUMEN
The authors describe the slow development of an abscess in the left subphrenic space in a patient with acute myeloid leukaemia. The patient suffered several months before the diagnosis was established from pain in the left subcostal region and was on account of this pain examined repeatedly by clinical methods and sonography. During the last sonographic examination in this area a hypoechogenic formation was detected. The diagnosis was than established more accurately by computer tomography by visualization of the abscess cavity. The case-history and relatively thick wall of the cavity suggested a long-term process. The abscess cavity was evacuated surgically, however, the patient suffered a relapse later and died from septicaemia. In the discussion the authors analyze the problem of development of metastatic abscesses in leukopenic patients, early diagnosis and treatment.
Asunto(s)
Huésped Inmunocomprometido , Leucemia Mieloide/tratamiento farmacológico , Absceso Subfrénico/etiología , Enfermedad Aguda , Adulto , Humanos , Leucemia Mieloide/inmunología , Masculino , Radiografía , Absceso Subfrénico/diagnóstico por imagenRESUMEN
On the example of a 66-year-old man the authors describe the atypical course of myelodysplastic syndrome of the type of refractory anaemia with dominating thrombocytopenia, manifested by massive haemorrhage, mostly into the digestive tract. In view of the increasing number of patients with this diagnosis, the authors attempted to elaborate the approximate costs of treatment of the condition in a medical department.