Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The induction of T-cell responses against tumor cells is believed to depend on both recognition of antigen and receipt of co-stimulatory signals from interaction of ligands such as B7 with its receptors CD28 or CTLA-4 on T cells. In the present study the expression of B7 on cultured human melanoma cells was studied at the mRNA level by reverse PCR analysis and surface expression by flow cytometric analysis with monoclonal antibodies (MAbs). PCR analysis revealed mRNA for B7 in 3 of 6 (50%) cultured primary melanoma and 8 of 19 (42%) cultures of metastatic melanoma. Analysis of B7 expression by flow cytometry using the BB1 MAb revealed low levels of expression in 3 of 10 melanoma that had mRNA for B7. In 2 of the latter (but not 4 other PCR+ lines) expression could be increased by culture in GM-CSF, IL-2, IFN-gamma and IFN-alpha 2. Our results indicate that although mRNA for B7 is present in 40-50% of melanoma cell lines, expression at the protein level is at low or undetectable levels in the majority of the cell lines. Expression of B7 protein was also not detected in studies on tissue sections from 11 primary and 9 metastatic melanomas.
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PMID:Expression of the co-stimulatory molecule B7 on melanoma cells. 752 26

Unconjugated monoclonal antibodies (mAb) kill tumor cells in vivo by activating immune functions. One of these is ADCC (antibody-dependent cellular cytotoxicity). The efficacy of mAbs might be augmented if the cytotoxic capacity of the effector cells could be increased. In this study the augmenting effect of granulocyte-colony-stimulating factor (G-CSF), granulocyte/macrophage(GM)-CSF and macrophage(M)-CSF was analyzed. Effector cells [peripheral blood mononuclear cells (PBMC) or granulocytes] were activated for 4-6 h by the respective CSF and assayed in an 18-h Cr51-release assay. Human colorectal, lymphoma, glioma and melanoma cell lines were target cells. Mouse mAbs of different isotypes, as well as chimeric and humanized mAbs, were used. mAbs having the human Fc part of the IgG molecule were the most effective. The killing capacity of PBMC as well as of granulocytes was statistically significantly enhanced when mAbs were added. M-CSF and GM-CSF were the best CSF for augmenting the lytic capacity of PBMC in ADCC. G-CSF had no significant effect on PBMC. Spontaneous cytolysis of PBMC was significantly augmented only by M-CSF. Granulocytes were, in general, significantly less effective than PBMC but may be equally effective killer cells together with mouse or human mAbs of the IgG1 isotype, particularly against melanoma cells. Granulocytes may also be significantly stimulated to increased lytic capacity when activated with G-CSF or GM-CSF. On the basis of the present evaluation, clinical trials in tumor patients are warranted, combining mAbs with GM-CSF or M-CSF. Preference might be given to GM-CSF as this cytokine activates both PBMC and granulocytes.
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PMID:Cytotoxicity of white blood cells activated by granulocyte-colony-stimulating factor, granulocyte/macrophage-colony-stimulating factor and macrophage-colony-stimulating factor against tumor cells in the presence of various monoclonal antibodies. 752 59

The efficacy of systemic infusion of recombinant human macrophage-colony-stimulating factor (M-CSF) in combination with local treatment with human recombinant tumor necrosis factor (TNF) alpha and mouse recombinant interferon (IFN) gamma was studied in vivo on a subclone of B16 melanoma (MmB16) in mice. Short-term intravenous administration of M-CSF at a dose of 10(6) units daily had no antitumor effect in vivo. Similarly, local treatment of tumor with TNF alpha (5 micrograms daily) did not produce any therapeutic effect. However, simultaneous administration of the same dose of TNF alpha with IFN gamma (1000 units daily) resulted in a synergistic effects manifested by the retardation of tumor growth. Addition of systemic infusion of M-CSF to the local therapy with TNF alpha and IFN gamma induced further augmentation of antitumor efficacy and delayed progression of MmB16 melanoma. The strengthened antitumor effect of combination therapy including M-CSF, TNF alpha and IFN gamma was most probably due to the increased release of monocytes from the bone marrow, their recruitment into the site of tumor growth and subsequent local stimulation of their antitumor activity.
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PMID:Potentiation of antitumor effects of tumor necrosis factor alpha and interferon gamma by macrophage-colony-stimulating factor in a MmB16 melanoma model in mice. 760 May 64

Two hematopoietic colony-stimulating factors, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF), have been shown to accelerate leukocyte and neutrophil recovery after high-dose chemotherapy and autologous bone marrow (BM) support. Despite their use, a prolonged period of absolute leukopenia persists during which infections and other complications of transplantation occur. We collected large numbers of peripheral blood (PB) progenitors after CSF administration using either G-CSF or GM-CSF and tested their ability to affect hematopoietic reconstitution and resource utilization in patients undergoing high-dose chemotherapy and autologous BM support. Patients with breast cancer or melanoma undergoing high-dose chemotherapy and autologous BM support were studied in sequential nonrandomized trials. After identical high-dose chemotherapy, patients received either BM alone, with no CSF; BM with either G-CSF or GM-CSF; or BM with G-CSF or GM-CSF and G-CSF or GM-CSF primed peripheral blood progenitor cells (PBPC). Hematopoietic reconstitution, as well as resource utilization, was monitored in these patients. The use of CSF-primed PBPC led to a highly significant reduction in the duration of leukopenia with a white blood cell (WBC) count under 100 and 200 cells/mL, and neutrophil count under 100 and 200 cells/mL with both GM- and G-CSF primed PB progenitor cells, compared with the use of the CSF with BM or with historical controls using BM alone. In addition, the use of CSF-primed PBPC resulted in a significant reduction in median number of antibiotics used, days in the Bone Marrow Transplant Unit, and hospital resources used. Patients receiving G-CSF primed PBPC also experienced a reduction in the median number of days in the hospital, red blood cell (RBC) transfusions, platelet transfusions, days on antibiotics, and discounted hospital charges. Phenotypic analysis of the CSF-primed PBPC indicated the presence of cells bearing antigens associated with both early and late hematopoietic progenitor cells. The use of CSF-primed PBPC can significantly improve hematopoietic recovery after high-dose chemotherapy and autologous BM support. In addition, the use of G-CSF-primed PBPC was associated with a significant reduction in hospital resource utilization, and a reduction in hospital charges.
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PMID:Comparative effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) on priming peripheral blood progenitor cells for use with autologous bone marrow after high-dose chemotherapy. 768 99

We conducted experiments to determine the optimal conditions for colony-stimulating factor-enhanced neutrophil- and mononuclear phagocyte-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) using monoclonal antibodies to disialogangliosides expressed on neuroectodermal tumour target cells. Neutrophil ADCC was most effective at effector:target ratios of 100:1, with maximal cytotoxic responses to melanoma target cells generated by 3 h. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) were the most potent stimulators of neutrophil ADCC, and enhanced ADCC activity was inhibited in the presence of antibody to Fc receptor type II (FcRII). GM-CSF and macrophage colony-stimulating factor (M-CSF) treatment of freshly isolated monocytes inhibited antibody-independent cytotoxicity but enhanced antibody-dependent responses. After 3 d in culture with CSF, 3-10-fold enhancement of ADCC against melanoma target cells was observed at effector:target cell ratios of 10:1. Greatest stimulation of macrophage ADCC was obtained when GM-CSF, M-CSF or interleukin 3 (IL-3) were used in conjunction with a secondary stimulus. Although gamma interferon (gamma-IFN) did not augment the cytotoxic capability of GM-CSF- and IL-3-stimulated macrophages, prominent cytotoxic enhancement was seen when M-CSF-stimulated macrophages were exposed to gamma-IFN. A chimaeric mouse/human monoclonal antibody was found to be equivalent in activity to the murine antibody in neutrophil ADCC; however, in macrophage ADCC assays with submaximal effector cell stimulation, the chimaeric antibody was associated with a two-fold greater response. These studies indicate that under specific conditions, CSFs capable of increasing the number and functional activity of mature myeloid effector cells enhance antibody-dependent cytotoxicity to neuroectodermal tumour target cells.
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PMID:Colony-stimulating factor enhancement of myeloid effector cell cytotoxicity towards neuroectodermal tumour cells. 768 31

CD40 is a member of the tumor necrosis factor (TNF) receptor family of cell surface proteins and was originally described as a B cell restricted antigen. Treatment of primary human monocytes with granulocyte/macrophage colony-stimulating factor (GM-CSF), interleukin 3 (IL-3), or interferon gamma (IFN-gamma) resulted in the induction of CD40 mRNA and enhancement of cell surface protein expression. CD40 was found to mediate monocyte adhesion to cells expressing recombinant CD40 ligand. CD40 ligand-transfected cells provided a potent costimulus for monocyte TNF-alpha and IL-6 production in the presence of GM-CSF, IL-3, or IFN-gamma, and enhanced IL-8 production stimulated by GM-CSF or IL-3. In addition, CD40 ligand-transfected cells acting in the absence of a costimulus induced monocytes to become tumoricidal against a human melanoma cell target. Collectively, these data indicate that CD40 ligand is pleiotropic with potent biological activity on monocytes.
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PMID:CD40 expression by human monocytes: regulation by cytokines and activation of monocytes by the ligand for CD40. 768 31

Human NK cells produce IFN-gamma, TNF-alpha, and granulocyte macrophage-CSF when stimulated with susceptible target cells or through the CD16 and CD94 cell surface molecules. This study reports that NK cells also produce IL-5, a cytokine typically produced by Th2 cells, which mediates mobilization and differentiation of eosinophils. Polyclonal NK cell populations and NK cell clones produce IL-5 when stimulated to proliferate with gamma-irradiated MM-170 melanoma cells or JY B-lymphoblastoid cells and rIL-2. IL-5 is produced in cultures generated from freshly isolated NK cells (primary cultures) and when quiescent NK cells from primary cultures are restimulated to proliferate (secondary cultures). Production of IL-5 is on average 8.8-fold greater in secondary cultures compared with primary cultures (n > 18), suggesting that the ability of NK cells to produce IL-5 matures during primary stimulation. IL-5 secretion, particularly in primary cultures, is augmented by IL-4 and is inhibited by IL-12 and IL-10. By contrast, IL-4 and IL-12 have the reverse effects on IFN-gamma secretion. Cultured NK cells that no longer secrete cytokines can be restimulated to do so with either phorbol 12, 13 dibutyrate and ionomycin or with susceptible target cells in the presence of rIL-2. IL-5 production in these cultures occurs only when NK cells are in an exponential growth phase, whereas IFN-gamma, TNF-alpha, and granulocyte macrophage-CSF are produced also by stimulation of quiescent cells, although to a lesser extent. Furthermore, cytokine production is unrelated to the cytolytic activity of NK cells. In conclusion, proliferating human NK cells have the potential to produce IL-5 with secretion regulated by IL-4, IL-10, and IL-12.
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PMID:Production of IL-5 by human NK cells and regulation of IL-5 secretion by IL-4, IL-10, and IL-12. 773 Jun 20

Cerebral demyelinating disease developed in a patient during adjuvant therapy with levamisole for malignant melanoma. This patient had no evidence of previous neurologic disease. Levamisole was administered for 5 weeks (total dose, 1,500 mg). Over a period of 3 weeks, the patient became progressively confused and ataxic. MRI with gadolinium enhancement demonstrated prominent multifocal enhancing white matter lesions. CSF examination revealed an inflammatory profile. After discontinuation of treatment with levamisole and a short course of corticosteroid therapy, the patient's condition dramatically improved. MRI also indicated improvement. Observations in our patient suggest that the leukoencephalopathy that developed in previously reported patients who received 5-fluorouracil and levamisole may have been caused at least partly by levamisole.
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PMID:Multifocal inflammatory leukoencephalopathy associated with levamisole therapy. 855 7

MART-1 is an Ag expressed on melanomas and melanocytes, and is recognized by the majority of HLA-A2-restricted tumor-specific tumor-infiltrating lymphocytes (TIL) from melanoma patients. In the present study we have analyzed 10 potential 9-mer epitopes containing the HLA-A2.1 binding motifs for their ability to induce melanoma-specific T cell lines. Antimelanoma CTL could be generated only with MART-1(27-35) peptide, which has been previously shown to be recognized by a majority of HLA-A2-restricted TIL. Anti-MART-1(35-43)-specific CTL could also be induced, but these T cells did not recognize melanoma cells. MART-1(27-35)-specific CTL could be effectively generated from a total of 11 of 12 PBL and from 3 of 3 TIL derived from HLA-A2+ melanoma patients, as well as from 2 of 4 PBL from HLA-A2+ healthy donors by in vitro stimulation with autologous PBMC pulsed with the synthetic MART-1(27-35) peptide. These CTL lines specifically lysed and release cytokines (TNF-alpha, IFN-gamma, and GM-CSF) in response to T2 cells pulsed with MART-1(27-35), as well as to HLA-A2+ MART-1+ melanoma cells. CTL generated with MART-1(27-35) also lysed uncultured HLA-A2+ melanoma cells derived from tumor biopsies, indicating that this MART-1 epitope is likely to be expressed in association with HLA-A2 on the surface of tumor cells in vivo. CTL lines generated with MART-1(27-35) mediated 25- to 100-fold higher lytic activity than MART-1-reactive CTL grown from TIL in the presence of high dose IL-2. These results demonstrate that MART-1(27-35) peptide may represent an ideal candidate for Ag-specific immunotherapy in melanoma patients.
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PMID:Induction of tumor-reactive CTL from peripheral blood and tumor-infiltrating lymphocytes of melanoma patients by in vitro stimulation with an immunodominant peptide of the human melanoma antigen MART-1. 786 98

CD4+ and CD8+ cytotoxic T-cell (CTL) clones, selected for T-cell-receptor (TcR)-dependent lysis of the autologous tumor and isolated from peripheral-blood lymphocytes (PBL) or tumor-infiltrating lymphocytes (TIL) of 3 melanoma patients, were characterized for the pattern of 13 different cytokines released by antibody- or tumor-mediated triggering. Induction or enhancement of cytokine release by anti-CD3 monoclonal antibody (MAb) led to the identification of 2 major sub-sets of CD8+ CTL clones on the basis of production of IL-4. Within the 2 groups of IL-4-producing or non-producing clones, further sub-sets could be identified on the basis of differential production of IL-1 beta, IL-2, IL-6, IL-8, IL-10, TNF-alpha, TNF beta and IFN-gamma. A similar analysis performed on a panel of CD4+ CTL clones indicated multiple patterns consistent with at least 4 major sub-sets, but further complexity was evident in each sub-set on the basis of differential production of IL-1, IL2, IL-6, IL-10 and G-CSF. The cytokine profile of CD4+ and CD8+ clones, as determined after anti-CD3 stimulation, was different from the pattern seen after co-culture with autologous tumor, since many clones released cytokines such as IL-4, IL-10, IFN-alpha and -gamma, TNF-alpha and GM-CSF after activation with only 1 of the 2 stimuli. These results indicate that CD4+ and CD8+ CTL clones reacting to human melanoma belong to a highly complex repertoire of functional subsets characterized by distinct cytokine profiles. In addition, the cytokine pattern of each T-cell sub-set can be modulated by changing the activation signals delivered to the T cell.
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PMID:Multiple sub-sets of CD4+ and CD8+ cytotoxic T-cell clones directed to autologous human melanoma identified by cytokine profiles. 790 59


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