RESUMEN
Paclitaxel poliglumex (PPX), a macromolecule drug conjugate linking paclitaxel to polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel. Patients with non-small-cell lung cancer (NSCLC) who had received one prior platinum-based chemotherapy received 175 or 210 mg m(-2) PPX or 75 mg m(-2) docetaxel. The study enrolled 849 previously treated NSCLC patients with advanced disease. Median survival (6.9 months in both arms, hazard ratio=1.09, P=0.257), 1-year survival (PPX=25%, docetaxel=29%, P=0.134), and time to progression (PPX=2 months, docetaxel=2.6 months, P=0.075) were similar between treatment arms. Paclitaxel poliglumex was associated with significantly less grade 3 or 4 neutropenia (P<0.001) and febrile neutropenia (P=0.006). Grade 3 or 4 neuropathy (P<0.001) was more common in the PPX arm. Patients receiving PPX had less alopecia and did not receive routine premedications. More patients discontinued due to adverse events in the PPX arm compared to the docetaxel arm (34 vs 16%, P<0.001). Paclitaxel poliglumex and docetaxel produced similar survival results but had different toxicity profiles. Compared with docetaxel, PPX had less febrile neutropenia and less alopecia, shorter infusion times, and elimination of routine use of medications to prevent hypersensitivity reactions. Paclitaxel poliglumex at a dose of 210 mg m(-2) resulted in increased neurotoxicity compared with docetaxel.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Paclitaxel/análogos & derivados , Ácido Poliglutámico/análogos & derivados , Taxoides/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos Fitogénicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/patología , Docetaxel , Esquema de Medicación , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Paclitaxel/uso terapéutico , Selección de Paciente , Ácido Poliglutámico/administración & dosificación , Ácido Poliglutámico/efectos adversos , Ácido Poliglutámico/uso terapéutico , Calidad de Vida , Taxoides/administración & dosificación , Taxoides/efectos adversos , Resultado del TratamientoRESUMEN
The primary treatment of lung cancer depends on tumor stage. Chest CT scan and bronchoscopy are used to define the TNM stage and resectability. In case of lung cancer without mediastinal lymph node enlargement or direct mediastinal involvement (clinical stage I-IIb + T3N1) surgical treatment is recommended. The use of adjuvant chemotherapy has to be defined, but will be indicated in stage II and IIIa. Expected 5-year survival achieves 40 to 80 % depending on tumor stage. Exceeds the shorter diameter of mediastinal lymph nodes in chest CT scan more than 1 cm (or in case of positive PET scan) mediastinoscopy is indicated. In case of N2-disease and after tumor response to preoperative chemotherapy (about 60 %) secondary resection of the tumor leads to higher 5-year survival rates (20-40 %) compared to patients without induction therapy (5-20 %). In these patients and after unexpected detection of solitary lymph node metastasis by primary resection adjuvant mediastinal radiotherapy should be added. If the tumor has infiltrated the mediastinum or the upper sulcus (T3/4) and/or mediastinal lymph nodes are obviously tumor burden (e. g. > 3 cm, N2 bulky, N3) radical primary resection may not be possible. In these patients combined radio- and chemotherapy induces a high percentage of tumor regression and can be used before secondary resection (5-year survival 5-20 %). Locally advanced tumors infiltrating the main bronchus close to the carina or the carina itself and tumors with metastases in the same lobe, both without mediastinal lymph node metastases (T3/4N0-1), can be resected by sleeve pneumonectomy and lobectomy with satisfactory results respectively. In patients with resectable lung cancer and no clinical sign of tumor disease (f. e. anemia, weight loss, pain) limited staging procedure with chest CT scan including upper abdomen and bronchoscopy is reasonable. In the remaining patients complete staging is necessary. We recommend an interdisciplinary approach to patients with lung cancer.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Broncogénico/cirugía , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/cirugía , Terapia Neoadyuvante , Neumonectomía , Broncoscopía , Carcinoma Broncogénico/tratamiento farmacológico , Carcinoma Broncogénico/patología , Carcinoma Broncogénico/radioterapia , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Quimioterapia Adyuvante , Terapia Combinada , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/radioterapia , Escisión del Ganglio Linfático , Mediastinoscopía , Estadificación de Neoplasias , Cuidados Paliativos , Radioterapia Adyuvante , Diseño de Software , Tomografía Computarizada por Rayos XRESUMEN
PURPOSE: The purpose of this study was to evaluate the impact of [18F]fluorodeoxy-D-glucose positron emission tomography (FDG-PET) on the primary staging of patients with small-cell lung cancer (SCLC). METHODS: FDG-PET was performed in 120 consecutive patients with SCLC during primary staging. In addition, brain examinations with both FDG-PET and cranial magnetic resonance imaging (MRI) or computed tomography (CT) were performed in 91 patients. Results of FDG-PET were compared with those of conventional staging procedures. FDG-PET detected markedly increased FDG uptake in the primary tumours of all 120 patients (sensitivity 100%). RESULTS: Complete agreement between FDG-PET results and other staging procedures was observed in 75 patients. Differences occurred in 45 patients at 65 sites. In 47 sites the FDG-PET results were proven to be correct, and in ten, incorrect. In the remaining eight sites, the discrepancies could not be clarified. In 14/120 patients, FDG-PET caused a stage migration, correctly upstaging ten patients to extensive disease and downstaging three patients by not confirming metastases of the adrenal glands suspected on the basis of CT. Only 1/120 patients was incorrectly staged by FDG-PET, owing to failure to detect brain metastases. In all cases the stage migration led to a significant change in the treatment protocol. Sensitivity of FDG-PET was significantly superior to that of CT in the detection of extrathoracic lymph node involvement (100% vs 70%, specificity 98% vs 94%) and distant metastases except to the brain (98% vs 83%, specificity 92% vs 79%). However, FDG-PET was significantly less sensitive than cranial MRI/CT in the detection of brain metastases (46% vs 100%, specificity 97% vs 100%). CONCLUSION: The introduction of FDG-PET in the diagnostic evaluation of SCLC will improve the staging results and affect patient management, and may reduce the number of tests and invasive procedures.
Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Carcinoma de Células Pequeñas/diagnóstico por imagen , Fluorodesoxiglucosa F18 , Neoplasias Pulmonares/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Neoplasias Encefálicas/metabolismo , Carcinoma de Células Pequeñas/metabolismo , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias/métodos , Pronóstico , Radiofármacos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Índice de Severidad de la EnfermedadRESUMEN
The staging procedures for small cell lung cancer do not differ appreciably from those for other forms of lung cancer. For practical purposes, the TNM stages are usually collapsed into a simple binary classification: limited disease and extensive disease. This study was performed to answer the question of whether fluorine-18 labelled 2-deoxy-2-D-glucose positron emission tomography (FDG-PET) imaging permits appropriate work-up (including both primary and follow-up staging) of patients presenting with small cell lung cancer, as compared with currently recommended staging procedures. Thirty-six FDG-PET examinations were performed in 30 patients with histologically proven small cell lung cancer. Twenty-four patients were examined for primary staging while four were imaged for therapy follow-up only. Two patients underwent both primary staging and up to four examinations for therapy follow-up. Static PET imaging was performed according to a standard protocol. Image reconstruction was based on an ordered subset expectation maximization algorithm including post-injection segmented attenuation correction. Results of FDG-PET were compared with those of the sum of other staging procedures. Identical results from FDG-PET and the sum of the other staging procedures were obtained in 23 of 36 examinations (6x limited disease, 12x extensive disease, 5x no evidence of disease). In contrast to the results of conventional staging, FDG-PET indicated extensive disease resulting in an up-staging in seven patients. In one patient in whom there was no evidence for tumour on conventional investigations following treatment, FDG-PET was suggestive of residual viability of the primary tumour. Furthermore, discordant results were observed in five patients with respect to lung, bone, liver and adrenal gland findings, although in these cases the results did not affect staging as limited or extensive disease. Moreover, FDG-PET appeared to be more sensitive for the detection of metastatic mediastinal and hilar lymph nodes and bone metastases. Finally, all findings considered suspicious for tumour involvement on the other staging procedures were also detected by FDG-PET. It is concluded that FDG-PET has potential for use as a simplified staging tool for small cell lung cancer.
Asunto(s)
Carcinoma de Células Pequeñas/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico por imagen , Adulto , Anciano , Carcinoma de Células Pequeñas/patología , Femenino , Fluorodesoxiglucosa F18 , Humanos , Procesamiento de Imagen Asistido por Computador , Neoplasias Pulmonares/patología , Metástasis Linfática/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Radiofármacos , Tomografía Computarizada de EmisiónAsunto(s)
Síndrome Antifosfolípido/diagnóstico , Pruebas de Coagulación Sanguínea , Fracturas del Cuello Femoral/cirugía , Pancitopenia/etiología , Complicaciones Posoperatorias/etiología , Trombocitopenia/etiología , Insuficiencia Suprarrenal/diagnóstico , Insuficiencia Suprarrenal/patología , Anciano , Síndrome Antifosfolípido/patología , Médula Ósea/patología , Colecistitis/diagnóstico , Colecistitis/patología , Femenino , Humanos , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/patología , Imagen por Resonancia Magnética , Necrosis , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/patología , Infarto del Bazo/diagnóstico , Infarto del Bazo/patología , Tomografía Computarizada por Rayos XRESUMEN
Neoadjuvant chemotherapy is obligatory for small-cell lung cancer. When combined with radio-therapy, it reduces the incidence of recurrence and increases the survival rate to a level similar to that seen in non-small-cell lung cancer. Preliminary results suggest that complete remissions (3-year-survival rate 56%) can be achieved through the use of chemotherapy, possibly including high-dose chemotherapy for advanced stage III A cancer. The use of pre-operative chemotherapy in advanced stage III non-small-cell lung cancer is firmly established. In one study the 3-year-survival rate reached 25% in the chemotherapy group as compared to 15% in the group treated by surgery only. Early results of pre-operative chemo- and radiotherapy for stages III A and III B are encouraging. In studies comparing neoadjuvant chemotherapy alone to a combination of neoadjuvant chemo-radiotherapy a higher resection rate (32 to 76%) as well as a longer disease-free survival time could be shown for the combination therapy. To date, a number of innovative neoadjuvant chemoradiotherapy protocols using new substances as well as various modifications of radiotherapy are being studied. It is to be expected that new standard therapies for non-small-cell lung cancer will develop from these studies.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/terapia , Terapia Neoadyuvante , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Ensayos Clínicos como Asunto , Terapia Combinada , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Estadificación de Neoplasias , Tasa de SupervivenciaRESUMEN
Lymphotoxin-alpha (LT), also called TNF-beta, which belongs to the 'TNF family' was originally isolated from a lymphoblastoid cell line. LT enhances the proliferation of activated B cells and augments B cell proliferation induced by IL-2. It functions as an autocrine growth factor for EBV-infected B cell lines and has been implicated in the pathogenesis of B cell malignancies. We tested the expression of LT mRNA in B-CLL and found that LT was expressed in highly purified leukemic cells in 11 out of 11 patients examined. Regulation of expression of LT mRNA is aberrant in B-CLL cells, since LT mRNA expression was not detected in fresh peripheral blood mononuclear cells or B cells identified in seven out of seven normal individuals. In addition, LT mRNA expression was detected for up to 6 days in purified unstimulated in vitro cultures of B-CLL cells. Glucocorticosteroids, that have been effectively used in the treatment of lymphoid malignancies, were added to the cultures and abrogated the LT mRNA expression after an incubation time of 12 h. Addition of recombinant LT to cultures increased proliferation of B-CLL cells while proliferation of these cells was inhibited by antisense oligonucleotides against LT mRNA. B-CLL cells cultured with LT antisense oligonucleotides (asLT) as well as glucocorticoid-treated cells showed reduced viability and a DNA fragmentation ladder characteristic of apoptosis suggesting a relationship between down-regulation of LT mRNA expression and the induction of apoptosis. These studies support the role of LT in the growth regulation and development of B-CLL cells.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/sangre , Linfotoxina-alfa/fisiología , Anciano , Antiinflamatorios/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Linfocitos B/metabolismo , Linfocitos B/patología , Linfocitos B/fisiología , ADN de Neoplasias/biosíntesis , Femenino , Humanos , Hidrocortisona/farmacología , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Activación de Linfocitos/fisiología , Linfotoxina-alfa/sangre , Masculino , Persona de Mediana Edad , Oligonucleótidos Antisentido/farmacología , ARN Mensajero/metabolismo , Estimulación Química , Células Tumorales CultivadasRESUMEN
Pre-T-ALL is an important subgroup of ALL with clinical features different from adult T-ALL. Expression of intracytoplasmic CD3 represents the earliest marker for the prethymic phenotype. We studied four consecutive adult patients with this phenotype. Three of the four patients did not respond to the induction chemotherapy with vincristine, daunorubicin, prednisone and asparaginase. They reached a delayed remission only after chemotherapy with cyclophosphamide and cytosine arabinoside. All four patients relapsed 3, 9, 10 and 13 months after diagnosis. One patient died 2 months after relapse, another one 2 months after allogeneic BMT performed in second relapse. We conclude that patients with early T-cell precursor leukemia do not respond adequately to conventional chemotherapy and should be considered as a high-risk subgroup within the T-lineage ALL.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Preleucemia/tratamiento farmacológico , Adulto , Antígenos CD/análisis , Asparaginasa/administración & dosificación , Linfocitos B/inmunología , Ciclofosfamida/administración & dosificación , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Estudios de Seguimiento , Humanos , Inmunofenotipificación , Leucemia-Linfoma de Células T del Adulto/inmunología , Persona de Mediana Edad , Prednisona/administración & dosificación , Preleucemia/inmunología , Pronóstico , Inducción de Remisión , Linfocitos T/inmunología , Factores de Tiempo , Vincristina/administración & dosificaciónAsunto(s)
Trasplante de Médula Ósea , Leucemia Mielógena Crónica BCR-ABL Positiva/cirugía , Leucemia Mieloide/cirugía , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirugía , Enfermedad Aguda , Adulto , Terapia Combinada , Ciclofosfamida/uso terapéutico , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/radioterapia , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/radioterapia , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/radioterapia , Trasplante HomólogoRESUMEN
The presence of soluble tumor necrosis factor (TNF) binding proteins (BP) was investigated in the sera of healthy volunteer blood donors and cancer patients. Two distinct types of TNFBP, types A and B, which are immunologically related to the cellular 75-kD TNF receptor (TNFR) and the cellular 55-kD TNFR, respectively, were assessed by immunoassays using nonblocking anti-receptor antibodies and 125I-recombinant human TNF alpha. As compared to the titers observed in 25 healthy controls, TNFBP types A and B titers were found to be elevated in almost all sera obtained from patients with underlying malignant disease. The highest amounts of TNFBP were seen in the sera of patients with B cell malignancies including hairy cell leukemia (HCL) and type B chronic lymphocytic leukemia. Treatment of HCL patients with recombinant human interferon-alpha was associated with decrease of circulating TNFBP.
Asunto(s)
Leucemia de Células Pilosas/sangre , Leucemia Linfocítica Crónica de Células B/sangre , Receptores de Superficie Celular/metabolismo , Humanos , Interferón Tipo I/uso terapéutico , Leucemia de Células Pilosas/terapia , Leucemia Linfocítica Crónica de Células B/terapia , Receptores de Superficie Celular/química , Receptores del Factor de Necrosis Tumoral , Proteínas Recombinantes , SolubilidadRESUMEN
The biologic effects of interleukin-7 (IL-7) and the expression of specific IL-7 membrane receptors on isolated neoplastic cells from previously untreated patients with chronic lymphocytic leukemia as well as acute leukemias were investigated in vitro. Leukemic cells were incubated for up to 6 days with various concentrations of IL-7 (0.01 to 2,000 U/mL). Neoplastic cells of the T- or B-phenotype from chronic as well as from acute leukemias proliferated in a dose-dependent manner. Cells from acute myeloid leukemias also proliferated in response to IL-7. An optimal proliferative effect was achieved between 96 and 120 hours with 200 U/mL IL-7. Combinations of IL-7 with IL-2 and tumor necrosis factor-alpha showed an additive effect on [3H]TdR incorporation. IL-7 binding assays gave a value of approximately 33 to 180 high-affinity (kd approximately 20 pmol/L) binding sites/cell and approximately 241 to 3,280 low-affinity (kd approximately 600 pmol/L) binding sites/cell. Receptor expression correlated with the proliferation in response to IL-7. These data indicate that IL-7 can induce proliferation of relatively mature tumor cells, and that this effect is not restricted to the lymphoid lineage.
Asunto(s)
División Celular/efectos de los fármacos , Replicación del ADN/efectos de los fármacos , Interleucina-7/farmacología , Leucemia Linfocítica Crónica de Células B/sangre , Monocitos/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Adulto , Anciano , Antígenos CD/análisis , Células Cultivadas , Técnica del Anticuerpo Fluorescente , Humanos , Cinética , Leucemia Linfocítica Crónica de Células B/inmunología , Depleción Linfocítica , Persona de Mediana Edad , Monocitos/efectos de los fármacos , Monocitos/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Receptores de Antígenos de Linfocitos B/análisis , Receptores Inmunológicos/fisiología , Receptores de Interleucina-7RESUMEN
High-titered spontaneous interferon (IFN) antibodies were detected in a patient with pure red cell aplasia (PRCA), a benign mediastinal tumor, and recurrent cutaneous carcinomas. The circulating IFN antibodies reacted broadly with various human IFN-alpha subtypes (20-140 x 10(3) neutralizing units/ml serum) but not with IFN-beta or IFN-gamma, and they neutralized the antiviral activity of the patient's endogenous IFN-alpha. The IFN-alpha-binding activity was restricted to the IgG1 subclass in a nonmonoclonal manner. Whereas the PRCA repeatedly responded to immunosuppression with high-dose cyclosporin A (CSA) and CSA plus plasmapheresis, IFN antibody production continued during treatment with cyclophosphamide and CSA. Serological analysis revealed past infection with parvovirus B19 and persistent B19 IgM titers. Antibody-mediated impairment of the IFN-alpha system might have favored the development of both PRCA and the various cutaneous carcinomas in this patient.
Asunto(s)
Autoanticuerpos/sangre , Interferón Tipo I/inmunología , Aplasia Pura de Células Rojas/inmunología , Neoplasias Cutáneas/inmunología , Anciano , Ciclofosfamida/uso terapéutico , Ciclosporinas/uso terapéutico , Humanos , Terapia de Inmunosupresión , Masculino , Plasmaféresis , Aplasia Pura de Células Rojas/terapia , Neoplasias Cutáneas/cirugíaRESUMEN
We have investigated the pharmacokinetics, tolerance, and biological activity of recombinant human interferon-gamma (rHuIFN gamma) administered subcutaneously to cancer patients. Twenty-one patients with lymphoma and metastatic cancer received rHuIFN gamma (in doses of 0.1, 0.25, or 0.5 mg/m2) in two or three injections per week for up to 180 days. The most common adverse effects encountered were flu-like symptoms, fever and fatigue. The increase in body temperature after each administration ranged from 0 to 4 degrees C depending on the individual patient, but was unrelated to the rHuIFN gamma dose or its plasma concentration. The pharmacokinetic response of the patients after the two treatments showed a low intra-individual variability with respect to the plasma concentration/time profiles. However, as observed for the fever side-effect, the interindividual variation (CV greater than 50%) was high for the parameters area under the data points (AUC0-t) and maximum plasma concentration (cmax). Despite this high interindividual variability, the mean values obtained for AUC0-t and cmax after s.c. injection of rHuIFN gamma were approximately proportional to the dose administered: the injection of 0.1, 0.25 or 0.5 mg/m2 rHuIFN gamma resulted in AUC0-t values of 15.4, 31.5 or 69.6 ng h/ml, respectively and cmax was found to be 1.0, 2.4 and 4.9 ng/ml, respectively. With this s.c. administration protocol, objective antitumour responses were observed in two patients, but there was no partial or complete remission.
Asunto(s)
Interferón gamma/farmacocinética , Neoplasias/metabolismo , Adolescente , Adulto , Anciano , Esquema de Medicación , Femenino , Humanos , Inyecciones Subcutáneas , Interferón gamma/efectos adversos , Interferón gamma/uso terapéutico , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Proteínas RecombinantesRESUMEN
Recombinant tumor necrosis factor-alpha (TNF-alpha) is a cytokine that induces proliferation of neoplastic B cells from patients with chronic lymphocytic leukemia (CLL). To gain insight into the mechanisms involved in regulating TNF responsiveness, we have examined TNF receptor expression on neoplastic B-CLL cells. We have demonstrated that freshly isolated neoplastic B cells from patients with CLL did not express TNF receptors. After 1 day of incubation in culture medium, TNF receptors were detectable in the range of 540 to 1,500/cell. Kinetic experiments revealed that receptor expression was half-maximal after 3 hours of culturing and required de novo protein synthesis. The Scatchard plots of TNF-alpha binding indicated a single set of high-affinity TNF receptors with a dissociation constant of 70 pmol/L. TNF receptor expression in vitro was found in all examined cases. All cytokines tested, with the exception of IL-2, did not influence the expression of TNF receptors. The TNF receptor expression is enhanced in B-CLL cells cultured in the presence of interleukin-2 when compared with the receptor expression of cells cultured in medium alone. Our data suggest that neoplastic B-CLL cells in patients with stable disease do not express TNF receptors in vivo and that an unknown mechanism suppressing TNF receptor expression in vivo may play a role in growth regulation of neoplastic B cells.
Asunto(s)
Linfocitos B/metabolismo , Leucemia Linfocítica Crónica de Células B/metabolismo , Receptores de Superficie Celular/metabolismo , Cicloheximida/farmacología , Citocinas/farmacología , Expresión Génica , Humanos , Interleucina-2/farmacología , Cinética , Hibridación de Ácido Nucleico , Biosíntesis de Proteínas , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-fos , Proteínas Proto-Oncogénicas c-myc/genética , ARN Mensajero/genética , Receptores del Factor de Necrosis Tumoral , Proteínas Recombinantes/metabolismo , Células Tumorales Cultivadas , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
We investigated the effect of recombinant tumor necrosis factor-alpha (rTNF-alpha) and recombinant lymphotoxin (rLT) in the growth modulation of purified hairy cell leukemia (HCL) cells. In response to rTNF-alpha, HCL cells from five of eight patients showed a 3 to 23-fold thymidine incorporation above their unstimulated controls. The effect was time and dose dependent with a maximum between 10 and 25 ng/ml rTNF-alpha after 120-hr incubation. rLT (1-50 ng/ml), however, could not enhance DNA synthesis in six of six cases. Cell number of rTNF-alpha stimulated cells ranged from 2-3 x 10(6)/ml from days 0-50 whereas cell number of unstimulated controls decreased from 3 x 10(6)/ml at day 0 to 0.01-0.02 x 10(6)/ml after 50 days in culture. rTNF-alpha induced proliferation could be suppressed in all HCL cell populations by 0.3 ng/ml recombinant interferon alpha (100 U/ml rIFN-alpha). TNF binding studies in two patients revealed that both TNF-sensitive HCL cells (1,990 +/- 148 receptors/cell) as well as TNF-insensitive HCL cells (1,261 +/- 101 receptors/cell) express specific receptors for TNF-alpha. These data show that rTNF-alpha and rLT have different effects on the growth of HCL cells. In addition there is a subgroup of patients who show no response to rLT or rTNF-alpha.
Asunto(s)
Leucemia de Células Pilosas/patología , Linfotoxina-alfa/farmacología , Factor de Necrosis Tumoral alfa/farmacología , Adulto , Anciano , Anciano de 80 o más Años , División Celular , Regulación hacia Abajo , Femenino , Humanos , Interferón Tipo I/farmacología , Leucemia de Células Pilosas/metabolismo , Masculino , Persona de Mediana Edad , Receptores de Superficie Celular/metabolismo , Receptores del Factor de Necrosis Tumoral , Proteínas Recombinantes/farmacología , Células Tumorales Cultivadas/metabolismo , Células Tumorales Cultivadas/patología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Five different preparations of antilymphocyte immunoglobulins (ATG) and antithymocyte immunoglobulins (ALG) with good or little clinical response were compared for their hematopoietic and immunological activities. All ATG/ALG lots demonstrated complement-mediated cytotoxicity on peripheral blood mononuclear cells. They had different titers of antibody specificities against lymphocyte cell membrane antigens. Neither clinically effective nor ineffective lots demonstrated any apparent colony stimulating activity on bone marrow mononuclear cells. Purified Natural Killer cells failed to be stimulated by ATG/ALG in liquid culture. ATG/ALG demonstrated potent T-cell stimulating activity comparable to phytohemagglutinin. This stimulation was blocked by anti-IL-2 receptor monoclonal antibodies, and was inhibited dose-dependently by cyclosporin-A. Some clinically ineffective ATG/ALG lots also stimulated T cells to release lymphokines. The differences in these characteristics among ATG/ALG lots provide some clues to guide further efforts to elucidate a key mechanism of therapeutic effectiveness.
Asunto(s)
Suero Antilinfocítico/farmacología , Linfocitos/citología , Linfocinas/metabolismo , Anemia Aplásica/tratamiento farmacológico , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/fisiología , Especificidad de Anticuerpos , Suero Antilinfocítico/uso terapéutico , Factores Biológicos/metabolismo , División Celular/efectos de los fármacos , Proteínas del Sistema Complemento/fisiología , Ciclosporinas/farmacología , Citocinas , Citotoxicidad Inmunológica/fisiología , Ensayo de Inmunoadsorción Enzimática , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Células Asesinas Activadas por Linfocinas/citología , Células Asesinas Activadas por Linfocinas/efectos de los fármacos , Activación de Linfocitos , Linfocitos/metabolismo , Linfotoxina-alfa/metabolismo , Receptores de Interleucina-2/inmunología , Receptores de Interleucina-2/fisiología , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunologíaRESUMEN
We investigated plasma levels of cortisol and ACTH in 9 patients with advanced metastatic tumors before and during treatment with interferon-gamma (IFN-gamma), 2-4 h after administration of IFN-gamma there was a sharp rise in plasma cortisol levels. The rise coincided with the onset of fever. Highest cortisol levels were reached 4-6 h after IFN-gamma injections, whereas IFN-gamma serum levels peaked 6-10 h after the IFN-gamma injections. Elevated cortisol levels during IFN-gamma treatment may be part of a homeostatic response of the neuroendocrine system to the immunological stimulus induced by IFN-gamma. On the other hand, the increased plasma levels of cortisol in response to pharmacological doses of IFN-gamma may dampen the in vivo effectiveness of IFN-gamma.
Asunto(s)
Hidrocortisona/sangre , Interferón gamma/farmacología , Hormona Adrenocorticotrópica/sangre , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The biologic effects of recombinant tumor necrosis factor-alpha (rTNF-alpha) and the expression of specific TNF membrane receptors on isolated neoplastic B cells from previously untreated patients with chronic lymphocytic leukemia (CLL) were investigated in vitro. Isolated B cells were incubated up to six days with various concentrations of rTNF-alpha (0.1 to 100 ng/mL). B cells from most patients proliferated ranged from two to 104 times that of unstimulated cells from the same patients. An optimal proliferative effect was achieved at 25 ng/mL rTNF-alpha and an incubation time between 96 and 120 hours, whereas a low concentration of rTNF-alpha (1 ng/mL) reduced [3H]TdR incorporation in four cases. Metaphase cells were detected in the rTNF-alpha-stimulated cultures that proliferated in response to rTNF-alpha. B cells from three of ten patients proliferated spontaneously and proliferation was further enhanced in two patients by rTNF-alpha. TNF binding assays gave a value of approximately 390 to 1,400 binding sites/cell for TNF and a dissociation constant (kd) of approximately 60 pmol/L. These data indicate that rTNF-alpha, in contrast to its cytotoxic/cytostatic effects, can also induce proliferation of tumor cells.
Asunto(s)
Linfocitos B/efectos de los fármacos , Sustancias de Crecimiento/farmacología , Leucemia Linfocítica Crónica de Células B/patología , Factor de Necrosis Tumoral alfa/farmacología , Adulto , Anciano , Linfocitos B/metabolismo , Linfocitos B/patología , División Celular/efectos de los fármacos , Femenino , Sustancias de Crecimiento/metabolismo , Humanos , Leucemia Linfocítica Crónica de Células B/metabolismo , Masculino , Persona de Mediana Edad , Receptores de Superficie Celular/análisis , Receptores del Factor de Necrosis Tumoral , Timidina/metabolismo , Células Tumorales Cultivadas/efectos de los fármacos , Células Tumorales Cultivadas/metabolismo , Células Tumorales Cultivadas/patología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Although the identification of lymphokines negatively affecting hematopoiesis is rapidly increasing, efforts to precisely define their action even in vitro have become more and more complicated. Studies of lymphokine abnormalities in aplastic anemia exemplify the modest contribution of experimental hematology to permit access to possible pathogenic mechanisms of hematopoietic failure syndromes. Nevertheless, these results help in the interpretation of clinical observations and to develop alternative therapeutic concepts.