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

Staphylococcal protein A (Cowan strain; SpA), a biologically active molecule capable of inducing augmented natural killer (NK) cell cytotoxicity, was studied in regard to its effects on lymphokine-activated killer (LAK) cell development. SpA, when co-cultured with interleukin-2 (IL-2) for 4 days, significantly augmented both LAK activity against NK-resistant M14 (melanoma) target cells and DNA synthesis of peripheral blood mononuclear cells (PBMC). This enhancement occurred with SpA concentrations of 1-100 micrograms/ml in a dose-dependent fashion; concentrations above 100 micrograms/ml were no more effective. When SpA (10 micrograms/ml) was added to PBMC cultures with various IL-2 concentrations, cytotoxicity was increased over controls with IL-2 alone. The peak cytotoxic effect reached a plateau at 80 U/ml IL-2. SpA alone induced early (day 1) cytotoxicity, which rapidly declined. SpA alone did not induce PBMC proliferation but it did increase expression of CD25 (Tac), IL-2 receptor alpha chain, on CD56(Leu19)-positive and -negative cells. The potentiating effect of SpA was significantly enhanced in serum-free medium. If either human AB serum or human IgG was added to cultures SpA-enhanced LAK cytotoxicity was diminished. The addition of anti-interferon gamma (anti-IFN gamma) antibody, but not anti-IFN alpha, inhibited (SpA+IL-2)-induced cytotoxicity, indicating that IFN gamma is partially responsible for the additive cytotoxic effect.
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PMID:The effects of staphylococcal protein A on human lymphokine-activated killer cell induction. 170 23

Interleukin-2 (IL-2) and gamma interferon (gamma-IFN) may be synergistic in inducing cell-mediated antitumor cytotoxicity. In order to determine the dose-limiting toxicities and define a maximum tolerated dose of these two agents in combination, we performed a Phase I clinical trial of intravenous IL-2 plus intramuscular gamma-IFN. Patients received both agents on a thrice-weekly schedule consisting of 4 weeks of treatment followed by 2 weeks of rest. Twenty-five patients were treated and received gamma-IFN doses between 0.05-0.25 mg/m2 (1-4 x 10(6) U/m2) with IL-2 doses from 0.33 mg/m2 to 2.33 mg/m2 (6-42 x 10(6) IU/m2). Two patients had partial responses of melanoma and adenocarcinoma of the lung lasting greater than 11 and 8 months, respectively. The toxicities of the combination were those expected from each agent, with no unusual effects, no irreversible organ toxicities, and no patient deaths. The doses recommended for outpatient administration on this schedule are IL-2, 2.0 mg/m2 plus gamma-IFN, 0.25 mg/m2, a dose combination that is unassociated with significant organ toxicity.
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PMID:Phase I trial of interleukin-2 plus gamma-interferon. 173 48

The role of cell adhesion molecules (CAM) LFA1, ICAM-1, LFA3, VLA1, VLA4, CD29, CD44, and CD56 in tumor-infiltrating lymphocyte (TIL) and natural killer cell (NK)-mediated killing of target cells was studied. Melanoma cell lines and autologous TIL were derived from seven patients with metastatic melanoma, and cytotoxicity assays were done in the presence and absence of monoclonal antibodies (MoAb) to CAM expressed on melanoma cells or TIL. The melanoma cell lines analyzed were all positive for CD29 and LFA3 expression, negative for LFA1 expression, but showed variable expression of ICAM-1, VLA1, VLA4, CD44, and CD56. The effects of anti-CAM antibodies on TIL-mediated melanoma killing fell into three categories: (1) consistent inhibition of TIL-mediated killing was observed when melanoma cells were pretreated with anti-ICAM1 and anti-LFA-3 MoAb or when TIL were pretreated with anti-LFA1; (2) no effect was observed when melanoma cells were pretreated with anti-CD56; or (3) a discreet, but significant, inhibition was observed when target cells were pretreated with anti-CD29, anti-VLA1, anti-VLA4, and anti-CD44. Cytotoxicity was significantly enhanced by pretreatment of target cells with gamma-interferon (gamma-IFN), although gamma-IFN did not augment surface expression of the CAM studied. The NK-mediated killing of K562 cells was blocked by anti-LFA1, anti-CD18, and anti-ICAM, and partially inhibited by anti-CD44 MoAb. Together, these results suggest that several accessory CAM may play a role in regulating cellular cytotoxicity. Because cytotoxicity generally correlated with the level of expression of CAM in melanoma cells, weak CAM surface expression may provide a means for melanomas to escape immune surveillance.
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PMID:Expression of cell adhesion molecules in human melanoma cell lines and their role in cytotoxicity mediated by tumor-infiltrating lymphocytes. 173 16

In animal systems, complete and permanent eradication of tumours can be achieved by adoptive transfer of MHC-restricted T cells, combined with IL2. In certain types of human cancer (melanoma and perhaps renal cell carcinoma), tumour-specific T cells are probably the therapeutically most active cells among LAK or TIL cells. To prove these points, it is necessary to conduct trials with cloned tumour-specific T cells. Other potentially immunogenic tumors are cervical carcinoma, associated with human papilloma virus, and Burkitt's lymphoma, associated with Epstein-Barr virus. Most other human tumours, caused by subtle mutations in proto-oncogenes, are likely to be poorly or non-immunogenic. It is worthwhile trying to overcome this by vaccination with IL2 or IFN gamma-producing tumour cells or by deliberate vaccination with desirable targets for tumour-specific CTL such as the products of point-mutated oncogenes, including ras (Jung and Schleusener, 1991) and p53 (Rodriguez et al., 1990; Halevy et al., 1990), provided the relevant peptides are processed and bound to MHC class I molecules. Other potential targets are breakpoint peptides of translocated oncogene products such as bcr/abl (Van Denderen et al., 1990). In viral systems, it has already been established that peptide vaccination for protective CTL induction is feasible (Aichele et al., 1989; Schulz et al., 1991; Kast et al., 1991).
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PMID:T-cell immunotherapy of cancer. 175 15

Interleukin-2 (IL-2)-based immunotherapy regimens are accompanied by dose-limiting toxicity consisting of fever, tachycardia, chills and capillary leak syndrome. We hypothesized that the toxicity was caused by the induction and release of endogenous cytokines such as tumor necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma). We measured the serum levels of TNF alpha and IFN gamma in IL-2-treated melanoma patients and attempted a correlation with clinical toxicity. A total of 23 patients received either 6 x 10(6) IU or 12 x 10(6) IU Cetus IL-2/m2 by i.v. bolus daily for 5 consecutive days on weeks 1, 3 and 5. Serum TNF alpha and IFN gamma levels were measured by enzyme-linked immunosorbent assay. Clinical toxicity was scored each day by objective measurements of hypotension, tachycardia, fever and chills/rigors. Clinical toxicity and IFN gamma levels correlated nicely, peaking on the 5th day of each treatment cycle. The kinetics and magnitude of TNF alpha production, however, were not predictable and did not correlate with either IFN gamma or toxicity. Some patients had modest increases in TNF alpha production while others had markedly increased levels during the second and third treatment weeks. Remarkably, these high levels persisted during nontreatment weeks and after completion of therapy. This clinical study demonstrates novel kinetics for immunoreactive TNF alpha in IL-2 cancer patients, which do not correlate well with toxicity.
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PMID:Production of tumor necrosis factor alpha and interferon gamma in interleukin-2-treated melanoma patients: correlation with clinical toxicity. 176 Aug 11

The capacity of human melanocytes and melanoma cells to produce IL-8 and monocyte chemotactic and activating factor (MCAF) was investigated. Melanocytes expressed mRNA for IL-8 and MCAF, when stimulated with either IL-1 alpha or TNF alpha, but not when stimulated with IL-6, IFN gamma, or LPS alone. IL-8 and MCAF could be induced in a dose-dependent fashion with doses as low as 0.1 ng/ml TNF alpha and 0.5 ng/ml IL-1 alpha. IL-8 and MCAF mRNA were rapidly expressed and peaked between 2 and 4 h for IL-8 and between 4 and 8 h for MCAF. This correlated well with the accumulation of IL-8 antigen as measured by a radioimmunoassay. Supernatants from melanocyte cultures stimulated with either IL-1 alpha or TNF alpha and separated on a heparin-Sepharose column became positive for neutrophil and monocyte chemotactic activity in a dose- and time-dependent fashion. When IFN gamma was added to melanocyte cultures stimulated with suboptimal doses of TNF alpha there was a synergistic increase in secreted IL-8 protein and monocyte chemotactic activity. These data provide further evidence for the possible role of melanocytes in the initiation of an inflammatory reaction. Three different malignant melanoma cell lines stimulated with either TNF alpha or IL-1 alpha expressed IL-8 mRNA, but not mRNA for MCAF. The IL-8 mRNA signal corresponded well with the amount of secreted IL-8 protein. These data suggest that IL-8 and MCAF may play a role in growth regulation and spreading of melanomas.
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PMID:Expression and secretion of leukocyte chemotactic cytokines by normal human melanocytes and melanoma cells. 187 58

Lymphokine-activated killer (LAK) cells are generated by the incubation of lymphocytes with high levels of interleukin-2 (IL-2). We report here that interferon-gamma (IFN-gamma) acts synergistically with low levels of IL-2 to promote LAK differentiation in peripheral blood lymphocytes as well as in homogeneous T acute lymphocytic leukemic cells exhibiting LAK precursor reactivity. No augmentation of LAK response was observed with IFN-alpha-2, IFN-beta-1, and IFN-beta-2/IL-6. The synergism between IL-2 and IFN-gamma was expressed in the ability of activated lymphocytes to lyse natural killer resistant cell line targets and surgically removed melanoma cells. The augmented LAK response due to IFN-gamma does not reflect up-regulation of the high-affinity IL-2 receptors consisting both of alpha and beta subunits, since expression of the alpha (Tac) subunit on the responding leukemic cells was not increased by IFN-gamma. The observed IFN-gamma/IL-2 synergism in the induction of monoclonal LAK precursors suggests that a single precursor cell responds to both IFN-gamma and IL-2 and that different mechanisms underlie the basal IL-2-mediated LAK response and its enhancement by IFN-gamma.
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PMID:Lymphokine-activated killer (LAK) cells: interferon-gamma synergizes with interleukin-2 to induce LAK cytotoxicity in homogeneous leukemic preparations. 189 16

In vivo stimulation of pulmonary alveolar macrophages (PAMs) may enhance tumor cell cytotoxicity. A model using aerosolized gamma-interferon (gamma-IFN) and lipopolysaccharide (LPS) was developed to induce enhanced PAM activation in vivo in C57BL/6 mice. Mice received four doses of aerosol (2 doses/day) consisting of gamma-IFN (10(4) microU/mouse) and LPS (100 micrograms/mouse). Other groups received either gamma-IFN alone, LPS alone, or saline (control). Cells were harvested by bronchoalveolar lavage. Macrophage cell count demonstrated an increase in macrophage recruitment in the gamma-IFN and LPS group. PAMs were evaluated for in vitro cytotoxicity against B16-F10 melanoma cells. Treatment groups demonstrated enhanced cytotoxicity over controls, and the combination (gamma-IFN plus LPS) was significantly better in cell killing than either treatment modality alone (p less than or equal to 0.02). Activated PAMs selectively killed tumor cells, but did not kill the 3T3 fibroblast cell line. Peritoneal macrophages from mice treated by inhalational gamma-IFN + LPS were enhanced (indicating a systemic effect), but not to the same extent as PAMs. These studies suggest that inhalation of gamma-IFN + LPS can selectively enhance in vivo cytotoxicity of murine PAMs. This may potentially be applicable to human tumor management.
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PMID:Aerosolized gamma-interferon and lipopolysaccharide enhances cytotoxicity of murine pulmonary alveolar macrophages. 190 97

The H-2b-negative B78HI clone (derived from B16 melanoma) was transfected with the H-2Kb gene; 4 cell clones expressing membrane H-2Kb antigens and 2 control clones (transfected with pSV2neo alone) were used for studies of metastatic ability, immunogenicity, NK sensitivity and homotypic adhesion. The experimental metastatic capacity of H-2Kb transfectants in syngenic mice was greatly diminished in comparison with control and parent cells. Both immune-mediated and intrinsic properties of transfectants correlated with their lower metastatic ability. A cell-mediated cytotoxic response was induced by repeated in vivo immunizations of syngeneic mice followed by in vitro restimulation of effectors when transfectants (but not controls) were used as immunizers and as targets. Moreover, homotypic adhesion of H-2Kb transfectants was significantly lower than that of controls. Sensitivity to NK cells of transfectants was not decreased in comparison to H-2-negative controls. It is known that in vitro treatment with IFN-gamma of H-2-positive B16 melanoma cells induces a simultaneous increase in H-2 expression and in experimental metastasis; treatment of H-2Kb transfectants with IFN-gamma induced a higher Kb expression, but no increase in metastatic ability, thus suggesting that the IFN-sensitive component that mediates enhancement of metastasis is not H-2Kb.
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PMID:Immunological and non-immunological influence of H-2Kb gene transfection on the metastatic ability of B16 melanoma cells. 190 2

We have previously characterized more than 20 proteins induced by the immunoregulatory lymphokine IFN-gamma in human fibroblasts by their m.w. and isoelectric points determined in two-dimensional gels. Some of these proteins are induced uniquely by IFN-gamma, whereas others are also induced by IFN-alpha, TNF, or IL-1. Recent technologic advances have allowed us to begin to rapidly identify proteins induced by IFN-gamma and other cytokines by sequencing the induced proteins from blots of preparative two-dimensional gels of total cell lysates. In this study, we show that the approximately 21 kDa, isoelectric point greater than 7 protein induced by IFN-gamma is manganese superoxide dismutase (Mn-SOD), a mitochondrial protective enzyme encoded by a nuclear gene. Mn-SOD is induced by IFN-gamma and also by TNF in all four human cell lines examined: HS153 fibroblasts, ACHN renal carcinoma, A549 lung carcinoma, and A375 melanoma. Induction of Mn-SOD mRNA is a primary, rapid, and dose-dependent response to IFN-gamma. In ACHN renal carcinoma cells, Mn-SOD mRNA and protein are induced synergistically by IFN-gamma in combination with either TNF or IL-1, and the induced protein is enzymatically active. IFN-gamma and TNF together induce Mn-SOD mRNA by more than 100-fold relative to its level in untreated ACHN cells. The induction of Mn-SOD by IFN-gamma and its synergistic induction by IFN-gamma in combination with TNF and IL-1 should protect healthy cells from the toxicity of O2- during an immune response, and may provide a mechanism for selective killing of infected cells.
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PMID:Manganese superoxide dismutase is induced by IFN-gamma in multiple cell types. Synergistic induction by IFN-gamma and tumor necrosis factor or IL-1. 190


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