Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuroblastoma is the most common extracranial, solid tumor in children. Despite intensive chemotherapy and bone marrow transplantation, the 5-year projected survival rate is 20% to 25%. In vitro studies have shown enhanced natural killer cell (NK) lysis of tumor cells after exposure of NK cells to interleukin-2 (IL-2). In vivo studies have demonstrated similar immunologic effects but have also revealed severe toxicities associated with the use of IL-2. IL-12 is a newly described cytokine that has several properties, including the ability to act synergistically with IL-2 in generating lymphokine-activated killer cells (LAK) against known tumor targets. We investigated the role of IL-12 in the generation of peripheral blood mononuclear cell (PBMC) lysis of neuroblastoma cell lines. PBMC were activated with IL-12 alone and in combination with IL-2. Whereas IL-12 alone produced only modest enhancement of NK cell cytotoxicity, the combination of IL-2 and IL-12 was most effective in activating NK cell lysis of neuroblastoma cell lines. Further, we showed that large granular lymphocytes were the effector cells involved in target cell lysis. Finally, the CD18 molecule was shown to be critical in the lysis of neuroblastoma cells by activated PBMC.
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PMID:Lysis of neuroblastoma cell lines by human natural killer cells activated by interleukin-2 and interleukin-12. 790 63

While interleukin-2 (IL-2) has been shown to produce a variety of effects in the CNS and has recently been implicated as an endogenous brain neurokine, little is known about the molecular biology of IL-2 receptors in normal brain. The present investigation provides the first evidence that mRNA for IL-2 receptor-beta (IL-2R beta), an essential subunit for signal transduction by peripheral immune cells, is expressed in normal murine forebrain. Using polymerase chain reaction (PCR) cloning, a partial cDNA (349 bp) corresponding to the extracellular domain was cloned and found to have the identical sequence as the lymphocyte IL-2R beta. IL-2R beta mRNA expression was confirmed by a ribonuclease protection assay, and using in situ hybridization histochemistry, IL-2R beta mRNA was localized in the hippocampus where an intense signal was present over the neuron-rich granule cells of the dentate gyrus and Ammon's horn. Moreover, cDNA clones obtained from two murine neuroblastoma cell lines exhibited the same sequence as IL-2R beta cDNA from normal brain. IL-2R beta gene expression was also detected in the frontal cortex and striatum using PCR. Further in situ hybridization studies will be important to extend this initial observation to determine the brain regional localization and cell-specific anatomy of IL-2R beta mRNA in the CNS.
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PMID:Molecular cloning of a partial cDNA of the interleukin-2 receptor-beta in normal mouse brain: in situ localization in the hippocampus and expression by neuroblastoma cells. 795 64

2-5A Synthetase and 2-5A phosphodiesterase were determined by analytical capillary isotachophoresis in comparison to radioenzymatic methods. By means of isotachophoretic analysis, a frequently used radioenzymatic 2-5A synthetase assay was optimized and the results of both assays were compared. Using the isotachophoretic assay the influence of interferon-related cytokines (tumor necrosis factor-alpha and interleukin-2) on 2-5A synthetase induction in neuroblastoma cells was estimated. In contrast to mononuclear blood cells, the tumor necrosis factor induced 2-5A synthetase in these cells. 2-5A Phosphodiesterase was determined using an isotachophoretic assay and a radioenzymatic method. Degradation of A2'p5'A2'p5'A (trimeric form of 2-5A core) was measured by isotachophoresis whereas degradation of a mixture of phosphorus-32 labeled 2-5A cores was registered by radioenzymatic assay. Activity of 2-5A phosphodiesterase was only insignificantly enhanced by interferon in mononuclear blood and neuroblastoma cells. In contrast to the radioenzymatic assays, an accurate determination of 2-5A synthetase as well as of 2-5A phosphodiesterase is possible using the isotachophoretic method because the reactions are followed by measuring the substrates ATP and A2'p5'A2'p5'A, respectively.
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PMID:Determination of 2-5A synthetase and 2-5A phosphodiesterase in neuroblastoma cells by analytical capillary isotachophoresis: effects of cytokines and comparison with radioenzymatic methods. 814 79

We have established a new human neuroblastoma (NB) cell line from the bone marrow of a 1-year-old boy with NB, termed JK-NB1, which showed constant growth for as long as 17 months or more, similar phenotype to those of other reported NB cell lines, colony formation in liquid and methylcellulose culture, N-myc amplification, high expression of N-CAM, and NSE production. We have tried to induce LAK cell activity with peripheral blood mononuclear cells (PBMCs) from the patient against the autochthonous JK-NB cells. PBMCs from the patient proliferated up to 20-fold in the presence of interleukin-2 (IL-2) after 9 days of incubation, and LAK activity increased up to 24.7-fold and killed all of the JK-NB1 cells. In contrast, IL-2 alone or PBMCs from the patient or a healthy adult donor had little effect on the growth of NB cells. These data suggest that it is possible to induce LAK cell activity in PBMCs from the patient against autologous as well as allogenic NB cells, and provide a rational base for the clinical use of IL-2 as one of the treatments for NB.
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PMID:Establishment of a neuroblastoma cell line and induction of lymphokine-activated killer (LAK) activity against the autologous neuroblastoma cell line. 814 11

It is understood that neuroblastoma (NB) in the liver of patients with clinical stage IV-S disease may disappear, but the mechanism of such regression is unclear. A genetic hypothesis has previously been suggested, although heretofore an immunologic explanation had not been reported. Using C1300 NB in AJ mice, we developed a model of liver metastatic disease by directly injecting tumor cells into a subcutaneously translocated spleen. Intrasplenic inoculation of 2 x 10(6) C1300 NB cells produced liver subcapsular foci of NB in 100% of animals, whose mean survival period was 18 days. Three days after tumor inoculation, interleukin-2 (IL-2) (2,400 U/d) was continuously infused for 14 days via a miniosmotic pump, and daily survival was followed. Animals were sampled serially by histological and immunohistochemical staining. Animal survival was significantly prolonged (P < .05) in the IL-2 group when compared with that of saline controls, but importantly, 50% of the mice were cured. Histological examination showed early infiltration of mononuclear cells, predominantly lymphocytes, around liver metastatic foci; and phenotypic analysis of these cells showed them to be Thy-1.2-positive and asialo GM1-positive, suggesting they are of natural killer (NK) and lymphokine-activated killer (LAK) origin. Most importantly, in cured animals the histological analysis of the liver demonstrated reversion to a scar-free anatomy, akin to that seen in stage IV-S NB survival. These data suggest that immune-mediated regression of NB in the liver is possible; whether the result of therapy or spontaneous, the liver histology reverts to normal.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Immune-mediated regression of 'metastatic' neuroblastoma in the liver. 817 85

We show that expression of the p34cdc2 and cyclin A genes is induced by interleukin-2 in normal human T cells and present evidence to support the idea that these genes are deregulated in leukemic T cells. Our DNA sequencing data indicate that the promoter region of the p34cdc2 gene contains putative E2F-like binding sites which are recognized by Rb and binding sites for c-myb, Sp1, and ATF, and that the promoter region of the cyclin A gene contains binding sites for p53, Sp1, and ATF. In this study we focus on the effect of p53 and Rb on these cell cycle-regulatory genes. Cotransfection of Y79 human retinoblastoma cells with a p34cdc2 promoter-luciferase expression vector and a plasmid expressing the retinoblastoma gene (RB) indicated that RB suppresses p34cdc2 expression. Cotransfection of B104 rat neuroblastoma cells with a cyclin A promoter-luciferase expression vector and a plasmid expressing the normal or mutant p53 indicated that only the normal p53 suppresses cyclin A expression. In normal T cells, PHA stimulation reduces the amount of complexes in the p34cdc2 promoter between the E2F-like binding site and the RB gene product. These complexes were not detected in leukemic T cells. Our data support the idea that tumor suppressors modulate the expression of cell cycle-regulatory genes: RB regulates p34cdc2 expression and p53 regulates cyclin A expression.
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PMID:Effect of tumor suppressors on cell cycle-regulatory genes: RB suppresses p34cdc2 expression and normal p53 suppresses cyclin A expression. 827 2

Preoperative treatment of murine C1300-neuroblastoma (C1300) with triple immunotherapy using low-dose cyclophosphamide (CY), retinyl palmitate (RP), and interleukin-2 (IL2), followed by tumor resection leads to significant initial tumor control and prolonged survival. However, because long-term tumor recurrence is 67%, the efficacy of continued postoperative immunotherapy is now evaluated. Thirty-two A/J mice with 1 cm subcutaneous C1300 tumors were treated for 13 days with CY-100 mg/kg, intraperitoneally (IP), on day 2 of treatment then 25 mg/kg on day 9, RP-2500 IU IP 2 x/week, and IL2 1.6 x 10(5) U IP BID on days 4 to 9 and 11 to 13. On day 14, mice were divided into five treatment groups: (1) OP (operated-tumor resection, n = 6); (2) OP+CY (resection and postoperative CY, n = 7); (3) OP+CY+RP (resection and postoperative CY+RP, n = 7); (4) OP+CY+RP+IL2 (resection and postoperative CY+RP+IL2, n = 7); and (5) CY+RP+IL2 (continued CY+RP+IL2 with no resection, n = 5). Survival and postoperative tumor recurrence were followed for 60 days. The cure rates were group 1 33% (2/6), group 2 43% (3/7), group 3 29% (2/7), group 4 71% (5/7), and group 5 20% (1/5). After surgery, tumors that recurred did so in 8 to 22 days, with no statistical difference noted between groups. MHC class I antigenic expression of tumors resected on day 14 and recurrent tumors was determined with monoclonal antibodies and flow cytometry. In tumors resected on day 14, class I expression measured by mean fluorescence, was 374.8 +/- 27.40.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Combined preoperative and postoperative immunotherapy for murine C1300 neuroblastoma. 846 57

In this study we have investigated, at the population and the clonal levels, the immunophenotypes and the non-specific cytotoxic functions of peripheral blood lymphocytes from three stage IV neuroblastoma patients receiving treatment with recombinant interleukin-2 (IL-2) and interferon alpha (IFN alpha). Both IL-2 alone and the combination of IL-2 and IFN alpha caused an in vivo expansion of CD56+, CD3- NK cells most of which expressed the p75 molecule, i.e. the beta chain of the IL-2 receptor. Peripheral blood mononuclear cells (PBMC), drawn after treatment, displayed an increased NK activity, but no lymphokine-activated killer (LAK) activity. However, the subsequent in vitro culture of PBMC with high-dose IL-2 induced the generation of a potent LAK activity, which was mediated by an expanded population of CD3+, CD8+ T cells. Finally lymphocytes that had been isolated after cytokine therapy were cloned, in the presence of low-dose phytohemagglutin, immediately or following culture with IL-2. Clones derived from LAK cells expanded in vitro had predominantly a CD3+, CD8+ immunophenotype, whereas those raised from freshly separated lymphocytes were either CD3+, CD4+ or CD3+, CD8+ in equal proportions. Most of the above clones were poorly or not at all cytolytic against NK-sensitive or NK-resistant targets. In contrast, the few NK clones obtained (CD3-, CD56+) lysed all targets with high efficiency.
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PMID:Clonal analysis of peripheral blood lymphocytes from three patients with advanced neuroblastoma receiving recombinant interleukin-2 and interferon alpha. 851 51

The aim of this work was to monitor the functional and phenotypic variations of natural killer (NK) cells in seven children with stage IV neuroblastoma (NB) treated with recurrent 5-day cycles of interleukin-2 (IL-2) at a dose of 18 x 10(6) IU/m2/d by continuous intravenous infusion. All patients who entered the study had no detectable disease after hematologic recovery from intensive chemotherapy and autologous bone marrow transplantation (ABMT). To evaluate the effect of this treatment on tumor relapse, IL-2 immunotherapy was adjusted to maintain levels of NK activity above those of age-matched controls (threshold of 40 lytic units [LU]/10(9) mononuclear cells) during a 1-year period since hematologic recovery of ABMT. The levels of NK and endogenous lymphokine-activated killer (eLAK) cell cytotoxic activities, as well as phenotype-differentiated lymphocyte counts, were determined from patients' freshly isolated peripheral blood mononuclear cells (MNC). Data were analyzed at different points between each cycle of IL-2, and before and 36 hours after each infusion. NK and eLAK activities significantly increased in response to IL-2. Both cytotoxic parameters correlated with the serum levels of the soluble IL-2 receptor (sIL-2R). IL-2 increased the amounts of NK and T cell subsets but not of B cells. The effects of IL-2 were time-dependent. Early cycles of IL-2 preferentially increased cell numbers, especially of cells bearing a CD3-/CD16-/CD56+bright and CD8+dim phenotype. Conversely, late courses promoted higher cytotoxic effects but with a smaller increase in NK and T cell counts; the main NK subset became CD16+, and CD8+dim cells remained a minor subset. It is worthy to note that the patient who relapsed after completing immunotherapy showed only a slight increase of the NK subset in response to IL-2. These results show the feasibility of sustaining an increased NK activity during 1 year after ABMT in children with advanced neuroblastoma and suggest the occurrence of changes in the functional and phenotypic characteristics of the NK cells generated throughout the 1-year treatment.
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PMID:Progression of natural immunity during one-year treatment of residual disease in neuroblastoma patients with high doses of interleukin-2 after autologous bone marrow transplantation. 854 30

A major problem in the treatment of solid tumors is the eradication of established, disseminated metastases. Here we describe an effective treatment for established experimental hepatic metastases of human neuroblastoma in C. B.-17 scid/scid mice. This was accomplished with an antibody-cytokine fusion protein, combining the unique targeting ability of antibodies with the multifunctional activity of cytokines. An anti-(ganglioside GD2) antibody (ch14.18) fusion protein with interleukin-2 (ch14.18-IL2), constructed by fusion of a synthetic sequence coding for human interleukin-2 (IL-2) to the carboxyl end of the C-gamma1 gene of chl4.18, was tested for its therapeutic efficacy against xenografted human neuroblastoma in vivo. The ch14.18-IL2 fusion protein markedly inhibited growth of established hepatic metastases in SCID (severe combined immunodeficiency) mice previously reconstituted with human lymphokine-activated killer cells. Animals treated with ch14.18-IL2 showed an absence of macroscopic liver metastasis. In contrast, treatment with combinations of ch14.18 and recombinant IL2 at dose levels equivalent to the fusion protein only reduced the tumour load. Survival times of SCID mice treated with the fusion protein were more than double that of control animals. These results demonstrate that an immunotherapeutic approach using a cytokine targeted by an antibody to tumor sites is highly effective in eradicating the growth of established tumor metastases.
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PMID:Eradication of established hepatic human neuroblastoma metastases in mice with severe combined immunodeficiency by antibody-targeted interleukin-2. 862 May 25


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