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

Nutrient substrates have been shown to enhance cell-mediated immunity, but their role as adjuvants to immunotherapy has not been previously determined. This study evaluated L-arginine as an essential substrate for optimal generation of lymphokine-activated killer (LAK) cells. This experiment also assessed supplemental dietary L-arginine as a means to potentiate the host antitumor response to interleukin-2 (IL-2) in a murine neuroblastoma (NRB) model. A/J mice received 1% arginine or isonitrogenous 1.7% glycine in addition to a regular diet 14 days before subcutaneous inoculation with C1300 NRB cells. Twenty-four hours later, animals received low (1 x 10(6) U/kg three times a day) or high (3 x 10(6) U/kg three times a day) doses of IL-2 or saline intraperitoneally for 4 days. On days 4 and 10 post-C1300 NRB inoculation, mice were killed for assessment of natural killer cell and tumor specific cytotoxicity. Remaining animals were followed for tumor incidence, tumor growth, and duration of host survival. Interleukin-2 therapy in mice receiving dietary arginine compared with those receiving glycine resulted in significantly augmented natural killer cell cytotoxicity (day 4) and generation of specific tumoricidal mechanisms (day 10). The addition of dietary arginine to low-dose IL-2 therapy significantly diminished C1300 NRB engraftment (p less than 0.05) and growth (p less than 0.001) and prolonged the duration of host survival (p less than 0.05) compared with the glycine treatment group. In vitro studies demonstrated that L-arginine is an essential substrate for optimal generation of LAK cells. Thus, supplemental dietary L-arginine enhances lymphocyte cytotoxic mechanisms and potentiates IL-2 immunotherapy.
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PMID:Enhancement of interleukin-2 immunotherapy with L-arginine. 154 2

We investigated the expression of CD56 (a neural cell adhesion molecule, NCAM) and CD57 in various hematopoietic and non-hematopoietic malignant cells, using Leu-19 and Leu-7 monoclonal antibodies. Although both molecules are commonly defined as a natural killer cell marker, we found that CD56 was highly expressed on blasts from patients with acute monocytic (4/6) and megakaryocytic (3/3) leukemias. In the latter, FACS two-color analysis revealed that leukemic megakaryoblasts simultaneously expressed CD56 and platelet-related antigens. Among leukemic cell lines, one myelocytic, three monocytic, and two megakaryocytic lines were positive for CD56. On the other hand, except for one large granular lymphocytic leukemia and one multiple myeloma cell line, none of the lymphoid leukemia cell lines or lymphoblasts from patients with acute lymphocytic leukemia (ALL) (0/15), non-Hodgkin's lymphoma (NHL) (0/2), and central nervous system (CNS) leukemia (0/2) reacted with Leu-19 antibody for CD56. The expression of CD56 in leukemia cells was not significantly affected by 12-O-tetradecanoylphorbol-13-acetate (TPA). By contrast, all hematopoietic materials were negative for CD57, while non-hematopoietic neuroblastoma cell lines expressed this molecule (4/5) as well as CD56 (5/5). Cytogenetically, the NCAM gene is located at chromosome 11q23, and chromosome breaks were often observed at this location in various leukemias. Blasts from all five acute non-lymphocytic leukemia (ANLL) patients and cell lines with 11q23-proximal chromosomal breaks were positive, while those from one ALL patient with an 11q23 abnormality were negative for CD56, necessitating further studies to clarify the link between the 11q23 abnormality and CD56 expression.
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PMID:Expression of CD56/NCAM on hematopoietic malignant cells. A useful marker for acute monocytic and megakaryocytic leukemias. 172 53

The efficacy of systemic interleukin-2 (IL-2) immunotherapy is dependent on a competent host immune response. This study demonstrated that protein-calorie malnutrition (PCM) inhibited the generation of an antitumor response to IL-2. A/J mice received an isocaloric diet of 2.5% or 24% casein 8 weeks before inoculation with C1300 neuroblastoma cells. Three weeks later lymphocytes from tumor-bearing mice were harvested for determination of cytotoxic T-lymphocyte generation and natural killer cell cytotoxicity. PCM produced a significant reduction in total body weight (p less than 0.001) and serum albumin concentration (p less than 0.001). PCM inhibited generation of cytotoxic T lymphocytes (p less than 0.001), T-lymphocyte response in mixed lymphocyte reaction (p less than 0.001), and in vitro activation of natural killer cell cytotoxicity with IL-2 (p less than 0.001). A second experiment was performed to evaluate whether the in vitro deficits in tumor-specific and natural immunity in the animal model of PCM would diminish the efficacy of systemic high-dose IL-2 (3 x 10(6) units/kg three times daily for 5 days). The mean percent inhibition of C1300 growth with IL-2 was only 15% in mice with PCM compared with 60% in well-nourished mice (p less than 0.01). Median host survival time was greater in well-nourished animals (55 days) compared with animals with PCM (39 days) that received IL-2 (p less than 0.05). These data suggest that nutritional status is a critically important variable in tumoricidal response to systemic IL-2.
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PMID:Protein-calorie malnutrition inhibits antitumor response to interleukin-2 immunotherapy. 214 20

A spontaneous neuroblastoma (NB-85, H-2a/a) was tested for hybrid resistance (HyR) after subcutaneous (s.c.) inoculation into syngeneic and semisyngeneic mice. The hybrids (F1) (H-2a/b) between A/Sn and Leaden mice and the F1 between A/Sn X C57BL/6 mice were more resistant to the s.c. inocula of 10(6) to 5 X 10(5) cells than syngeneic recipients. Thymectomy, followed by irradiation and fetal liver reconstitution, abrogated the HyR against NB-85, whereas intravenous (i.v.) administration of anti-asialo-GM1 antibodies had no influence on the resistance. Surface phenotypic analysis revealed that NB-85 expressed H-2 Kk (-), Dd (+) and beta 2-microglobulin (-), showing a dissociation of the cell surface. Anti-H-2a-specific cytotoxic T lymphocytes exhibited a significant lytic activity against NB-85, while NB-85 was highly refractory to natural killer cell (NK)-mediated lysis. In vivo NK-mediated rejection assays showed that 125I-iododeoxyuridine (IUdR) labeled NB-85 cells were not eliminated more efficiently from the highly resistant F1 hybrids than from the parental strain. Furthermore, genotypic study with segregating (A/Sn X Leaden) F1 X A/Sn backcross mice showed that the HyR was attributable primarily to heterozygosity within the H-2 complex. Taken together, it was suggested that the HyR to an NK-resistant mouse NB-85 neuroblastoma might involve a T cell-dependent immunosurveillance with H-2 genetic control.
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PMID:[Experimental analysis of anti-tumor cytotoxic mechanism for hybrid resistance to mouse neuroblastoma]. 224 94

Supplemental dietary arginine has anti-tumor properties but the degree and mechanisms are unclear. In non-tumor-bearing CBA/J mice (n = 60), 1% arginine supplementation significantly enhanced thymic weight, spleen cell mitogenesis, and interferon-activated natural killer cell activity; no further enhancement was observed with 2% or 4% supplementation. Supplemental 1% arginine, when compared with 1.7% glycine, enhanced interferon-induced natural killer cell activity, lymphokine-activated killer cell generation, and macrophage cytotoxicity. In A/J mice (n = 420), bearing either a moderately immunogenic (C1300) or weakly immunogenic (TBJ) murine neuroblastoma, 1% arginine significantly (p less than 0.05) retarded tumor growth and prolonged median survival time compared with glycine or no supplementation. Dietary arginine enhanced T-cell function and significantly increased responsiveness to autologous C1300 tumor in a mixed lymphocyte tumor cell culture (MLTC). The immunomodulatory effects of arginine provide nutritional and immunologic support of the tumor-bearing host and may be helpful when given concommitant with immunotherapy.
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PMID:Immunologic effects of arginine supplementation in tumor-bearing and non-tumor-bearing hosts. 230 98

The presence of neonatal (cord) lymphokine-activated killer (LAK) cell activity toward natural killer cell resistant Raji and Daudi cell lines has recently been reported from our laboratory. We investigated the future therapeutic use of LAK adoptive immunotherapy by examining LAK in vitro cytotoxicity from both neonatal and adult mononuclear cells against solid tumor cell lines of relevance to pediatric oncology: SH-SY5Y (neuroblastoma), SK-NM-C (neuroblastoma-neuroepithelioma), NEP-1 (Wilms' tumor), SK-ES-1 (Ewing's sarcoma), and A-204 (rhabdomyosarcoma). Cord and adult mononuclear cells were activated by recombinant IL-2 (100 mu/ml) for 5-7 days and added in an effector:target ratio of 40:1 to 51Cr-labeled target cells. Specific cell lysis was determined after a 4-h incubation. There was a significantly high level of cord and adult LAK cytotoxicity against Wilms' (76.4 +/- 9.8 versus 77.3 +/- 6.8%) and Ewing's (84.2 +/- 5.5 versus 71.1 +/- 6.5%) cell lines and significant but moderate LAK activity against neuroepithelioma (52.0 +/- 6.6 versus 55.4 +/- 4.5%) and rhabdomyosarcoma (46.6 +/- 5.7 versus 43.9 +/- 5.2%) cell lines. There was no difference between cord and adult LAK activity toward these targets. However, a differential response toward the more classical neuroblastoma cell line, SH-SY5Y, was noted with significantly more LAK cytotoxicity from cord mononuclear cells than adult mononuclear cells (51.2 +/- 6.9 versus 28.5 +/- 8.2%) (p less than or equal to 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lymphokine-activated killer cytotoxicity in neonatal mononuclear cells: in vitro responses to tumor cell lines from pediatric solid tumors. 253 88

The measurement of the production of cytotoxic T lymphocytes (CTL) induced in mice by rabies antigens currently uses spleen cells from immunized A/J mice as effector cells and infected neuroblastoma syngeneic cells as target cells. For several reasons, including difficulties in obtaining A/J mice, as well as genetic analysis of immune responses, it would be advantageous to use strains of mice other than the A/J mice. However, cell lines other than the neuroblastoma Neuro-2a line are difficult to infect by the rabies virus. Therefore, using the same target cells expressing the major histocompatibility complex H-2kd, we have developed an experimental system based on the induction of CTL in F1 BALB/c X C3H/HeJ hybrid H-2kd mice. Splenocytes from F1 hybrid mice primed with inactivated purified rabies virus (IPRV) exhibited cytotoxic activity specific for syngeneic infected target cells (Neuro-2a). High amounts of IPRV were required for the induction of CTL following in vivo priming. The antigen dose required for CTL induction was reduced by in vitro restimulation. In addition to specific CTL, a high level of natural killer cell activity was induced in F1 hybrid mice by priming with IPRV. Among rabies antigen preparations tested (IPRV, purified glycoprotein and ribonucleoprotein), only IPRV induced strong CTL stimulation.
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PMID:Evaluation of the induction of specific cytotoxic T lymphocytes following immunization of F1 hybrid mice with rabies antigens. 254 36

It has been shown that agents that are known to be scavengers of hydroxyl radicals may induce differentiation and inhibit growth of murine neuroblastoma cells in tissue culture. The present study tests dimethyl sulfoxide as a differentiation agent of the human neuroblastoma cell lines LA-N-1 and murine neuroblastoma NIE-115. Results indicate that DMSO induces morphologic and biochemical differentiation of neuroblastoma cells coupled to growth inhibition and inhibition of colony formation in semi liquid tissue culture systems. DMSO treatment in vitro had no effect on tumorigenicity of NIE-115 cells. In vivo DMSO treatment of athymic nude mice with transplanted LA-N-1 human neuroblastoma tumors has not affected tumor size or animal survival. No diminishing effect of natural killer cell activity could be attributed to DMSO treatment.
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PMID:Dimethyl sulfoxide-induced differentiation does not alter tumorigenicity of neuroblastoma cells. 399 89

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

A major goal of cancer immunotherapy is the induction of a cell-mediated antitumor response in poorly immunogenic malignancies. We tested the hypothesis that this can be achieved by cytokine gene therapy with a novel histone H2A-based transient transfection procedure. This was tested by using cytokine genes encoding for IL-2 and a single chain IL-12 (scIL-12) fusion protein in a recently developed murine neuroblastoma model. Here, we demonstrate that cytokine gene transfer of IL-2 and scIL-12 with histone H2A results in the induction of an antitumor immune response that is superior in some respects to gene transfer with Superfect, a commercially available activated dendrimer commonly used to effect transfection with plasmids. Three lines of evidence support this contention. First, histone H2A-mediated transfection of IL-2 induces a natural killer cell-induced rejection of primary tumors in contrast to Superfect, which produces only a partial reduction in primary tumor growth. Second, the induction of a T cell-mediated protective tumor immunity following gene transfer of scIL-12 is more efficient with the histone H2A-mediated gene transfer because rejection of a lethal wild-type tumor cell challenge is accompanied by the greatest degree of MHC class I-restricted tumor cell killing in vitro. Third, histone H2A-mediated scIL-12 gene therapy induces the greatest release of mIFN-gamma from splenocytes of vaccinated animals in contrast to Superfect and other controls.
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PMID:Histone H2A-mediated transient cytokine gene delivery induces efficient antitumor responses in murine neuroblastoma. 1101 73


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