RESUMO
Oral antifungal prophylaxis with extended-spectra azoles is widely used in pediatric patients after allogeneic hematopoietic stem cell transplantation (HSCT), while controlled studies for oral antifungal prophylaxis after bone marrow transplantation in children are not available. This survey analyzed patients who had received either itraconazole, voriconazole, or posaconazole. We focused on the safety, feasibility, and initial data of efficacy in a cohort of pediatric patients and adolescents after high-dose chemotherapy and HSCT. Fifty consecutive pediatric patients received itraconazole, 50 received voriconazole, and 50 pediatric patients received posaconazole after HSCT as oral antifungal prophylaxis. The observation period lasted from the start of oral prophylactic treatment with itraconazole, voriconazole, or posaconazole until two weeks after terminating the oral antifungal prophylaxis. No incidences of proven or probable invasive mycosis were observed during itraconazole, voriconazole, or posaconazole treatment. A total of five possible invasive fungal infections occurred, two in the itraconazole group (4%) and three in the voriconazole group (6%). The percentage of patients with adverse events potentially related to clinical drugs were 14% in the voriconazole group, 12% in the itraconazole group, and 8% in the posaconazole group. Itraconazole, voriconazole, and posaconazole showed comparable efficacy as antifungal prophylaxis in pediatric patients after allogeneic HSCT.
Assuntos
Antibioticoprofilaxia/métodos , Antifúngicos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Triazóis/uso terapêutico , Administração Oral , Adolescente , Criança , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Masculino , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/prevenção & controle , Transplante HomólogoRESUMO
Considering the possibility to overcome drug resistance by other treatment strategies than chemotherapy we investigated the susceptibility of three independently selected multidrug-resistant sublines of the T-lymphoblastoid leukemic cell line CCRF-CEM to lymphokine-activated killer (LAK) cells. We found that two of the multidrug-resistant sublines were significantly less susceptible targets to LAK cells. A third one, however, was as susceptible as the parental CCRF-CEM cell line. Moreover, a multidrug-resistant subline that reverted to an almost drug-sensitive phenotype was observed to be also revertant for resistance against LAK cells. We found an inverse relationship between the expression of the mdr1 gene (P-glycoprotein) and the susceptibility to LAK cells. Verapamil, a calcium channel blocker, while increasing the drug sensitivity of a multidrug-resistant subline, did not induce a reversal of the suppression of LAK susceptibility. The possibility of enhanced resistance to LAK cells of multidrug-resistant cells should be taken into account when one is looking for therapy strategies to overcome multidrug resistance.
Assuntos
Imunoterapia Adotiva , Interleucina-2/farmacologia , Células Matadoras Ativadas por Linfocina/fisiologia , Leucemia/terapia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Antígenos CD7 , Antígenos de Diferenciação/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Resistência a Medicamentos , Regulação Neoplásica da Expressão Gênica , Antígenos de Histocompatibilidade/imunologia , Humanos , Leucemia/genética , Leucemia/imunologia , Antígenos Comuns de Leucócito , Antígenos CD15 , Glicoproteínas de Membrana/genética , Fenótipo , Células Tumorais Cultivadas , Verapamil/farmacologiaRESUMO
A new human cell line (Wa-2) derived from an extrarenal rhabdoid tumor has been established. The cell line grows as a monolayer consisting of round- and spindle-shaped cells. Injection of cells into nude mice results in the growth of solid tumors within 2 wk of inoculation. These solid tumors have the microscopic appearance similar to that of the original tumor from which the cell line was derived. Moreover, the tumor cells have all the features of rhabdoid tumors, including the intracytoplasmatic hyaline globules, large prominent nucleoli, and inclusion bodies made up of whorls of fibrillary material. Transplanted tumor cells stain positive for vimentin, cytokeratin, actin, and desmin and negative for myoglobin and neuron-specific enolase. Karyotyping of the cell line at different passages and cells derived from the transplant tumors consistently revealed a diploid number of chromosomes with a reciprocal translocation between chromosomes 18 and 22 [t(18;22) (q21;p11.2)]. In fibroblasts derived from the patient, no translocation could be found. Culturing the cells in the presence of 1-beta-D-arabinofuranosylcytosine induces differentiation, characterized by the outgrowth of neuron-like processes and the morphological appearance of cells similar to neuroblasts. Southern blot analysis showed no amplification of the N-myc oncogene. Since no published cell line derived from rhabdoid tumors exists, this cell line should be helpful to further elucidate the biology and histological origin of the malignant rhabdoid tumor.
Assuntos
Sarcoma/patologia , Neoplasias da Coluna Vertebral/patologia , Células Tumorais Cultivadas/ultraestrutura , Animais , Diferenciação Celular , Divisão Celular , Cromossomos Humanos Par 18 , Cromossomos Humanos Par 22 , Citarabina/farmacologia , DNA de Neoplasias/genética , Humanos , Lactente , Masculino , Camundongos , Camundongos Nus , Transplante de Neoplasias , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-myc , Sarcoma/genética , Neoplasias da Coluna Vertebral/genética , Translocação Genética , Células Tumorais Cultivadas/imunologiaRESUMO
The in vitro and in vivo influence of interleukin-2 (IL-2) on 2',5'-oligoadenylate (2-5A) synthetase activity and natural killer (NK) activity of peripheral mononuclear blood cells (PBMCs) was investigated. Incubation of PBMCs in vitro with IL-2 resulted in a considerable secretion of interferon-gamma (IFN-gamma) and in a significant elevation of 2-5A synthetase activity, as well as NK activity. Neutralizing monoclonal anti-IFN-gamma antibodies inhibited the elevation of 2-5A synthetase activity, but not the IL-2-induced augmentation of NK activity. Additionally, 2-5A synthetase and NK activity of PBMCs was measured in a child with neuroblastoma that was treated with recombinant IL-2 by continuous intravenous application. During the treatment, NK activity against the NK-sensitive cell line K 562 and against autologous tumor cells was not augmented. However, a significant increase of 2-5A synthetase activity in PBMCs was observed during IL-2 treatment, whereas there was no detectable serum level of IFN-gamma. We conclude that measuring 2-5A synthetase activity in patients treated with IL-2 may be helpful in monitoring the immunomodulatory effects of IL-2 on immune effector cells.
Assuntos
2',5'-Oligoadenilato Sintetase/sangue , Interleucina-2/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Adulto , Células Cultivadas , Pré-Escolar , Radioisótopos de Cromo , Testes Imunológicos de Citotoxicidade , Humanos , Interferon gama/sangue , Leucócitos Mononucleares/enzimologia , Neuroblastoma/tratamento farmacológico , Neuroblastoma/enzimologia , Proteínas Recombinantes/uso terapêuticoRESUMO
Granulocytes from healthy donors lyse human neuroblastoma cells in the ADCC-reaction using antibody MAb 14.18 directed to ganglioside GD2 present on the surface of most neuroblastoma cells. Addition of catalase, superoxide dismutase and azide do not impair this process. Granulocytes from patients with chronic granulomatous disease (CGD) kill neuroblastoma cells even better than those collected from healthy donors. These results indicate that reactive oxygen intermediates (ROI) are not involved in killing of neuroblastoma cells using MAb 14.18, and that granulocytes from patients with CGD may compensate for defects in generation of reactive oxygen intermediates by more effective oxygen-independent killing mechanisms. One patient with CGD was treated with interferon-gamma. During and after treatment, generation of ROI could not be detected and neuroblastoma cell killing was not significantly altered.
Assuntos
Citotoxicidade Celular Dependente de Anticorpos/imunologia , Granulócitos/imunologia , Doença Granulomatosa Crônica/imunologia , Neuroblastoma/imunologia , Azidas/farmacologia , Catalase/farmacologia , Radioisótopos de Cromo , Doença Granulomatosa Crônica/terapia , Humanos , Interferon gama/uso terapêutico , Medições Luminescentes , Superóxido Dismutase/farmacologia , Fatores de Tempo , Células Tumorais CultivadasRESUMO
We investigated whether polymorphonuclear leukocytes (PMN) are able to kill human neuroblastoma cells either directly or if coated with antibody MAb 14.18 that recognizes ganglioside GD2 present on the cell surface of most neuroblastoma cells. Neuroblastoma cells could not be destroyed directly, whereas in the antibody-dependent reaction (ADCC-reaction) they were easily eliminated. In order to answer the question whether reactive oxygen intermediates are involved in this process, chemiluminescence measurements were performed. Compared to the signals that could be measured using opsonized zymosan as stimulus, only weak CL-signals could be registered during the ADCC reaction. Pretreatment of PMN with granulocyte-macrophage colony stimulating factor (GM-CSF) enhanced the CL-signals, catalase and SOD reduced it; however, cell killing was only slightly influenced in the presence of catalase and superoxide dismutase. These data suggested that reactive oxygen compounds do not play a prominent role in the killing process. Definitive evidence for this suggestion could be obtained using PMN from a patient with chronic granulomatous disease (CGD): MAb 14.18 coated neuroblastoma cells could be killed effectively, but no CL-signal could be registered, either in the ADCC-reaction or using opsonized zymosan as stimulus.
Assuntos
Radioisótopos de Cromo , Granulócitos/imunologia , Medições Luminescentes , Neuroblastoma/imunologia , Células Tumorais Cultivadas/imunologia , Catalase/farmacologia , Citotoxicidade Imunológica , Doença Granulomatosa Crônica/imunologia , Humanos , Superóxido Dismutase/farmacologiaRESUMO
Therapy of disseminated neuroblastoma remains an unsolved problem in pediatric oncology. Therefore, new therapeutic approaches have to be developed for this malignancy. In this paper, we investigated the possibility of the in vitro generation and expansion of lymphokine-activated killer (LAK) cells in patients with disseminated neuroblastoma. Although the patients had very low Natural Killer (NK) activity, it was possible to induce LAK activity in peripheral mononuclear lymphocytes (PMNC) by incubation with Interleukin-2 (IL-2). Moreover, the PMNCs could be expanded up to 50-fold in the presence of Interleukin-2 while maintaining or even increasing their LAK activity. The target cells were neuroblastoma cell lines and, in one case, autologous neuroblastoma cells. Additionally, it was possible to induce LAK cell activity against autologous neuroblastoma cells in bone marrow-derived mononuclear cells.
Assuntos
Células Matadoras Ativadas por Linfocina/fisiologia , Neuroblastoma/sangue , Medula Óssea/fisiologia , Criança , Citotoxicidade Imunológica/efeitos dos fármacos , Humanos , Imunoterapia , Interleucina-2/farmacologia , Células Matadoras Ativadas por Linfocina/imunologia , Leucaférese , Leucemia Eritroblástica Aguda/patologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Metástase Neoplásica , Neuroblastoma/patologia , Neuroblastoma/terapia , Células Tumorais CultivadasRESUMO
The influence of interferon-gamma on the susceptibility of neuroblastoma cells in cell-mediated killing was investigated. Neuroblastoma cells were only weakly susceptible targets for peripheral mononuclear cells. However, enrichment of natural killer (NK) cells or activation of NK cells with interleukin-2 resulted in a considerable increase of neuroblastoma cell lysis. Pretreatment of neuroblastoma targets with interferon-gamma additionally increased the susceptibility to enriched NK cells as well as to interleukin-2-activated NK cells. The conjugate formation between enriched NK cells and the neuroblastoma targets was not affected by the pretreatment of the targets with interferon-gamma. Concomitantly, treatment of the neuroblastoma targets with interferon-gamma resulted in a strong induction of otherwise poorly expressed major histocompatibility complex (MHC) class I antigen expression. These results suggest that the increased expression of MHC class I antigens on target cells is not always correlated with decreased sensitivity for NK cells but can also be followed by an increased susceptibility for NK cells.