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)

Human tumors can constitutively express cytokines and growth factors, but the extent of this expression has not been investigated. Using 44 different probes to cytokines, growth factors, and their receptors, we tested 21 melanoma and 5 melanocyte cultures for RNA transcript expression by reverse transcriptase-polymerase chain reaction. With 30 amplification cycles, expression of the cytokines interleukin (IL)-1 beta, IL-6, leukemia inhibitory factor (LIF), IL-7, gro alpha, IL-8 and the p35 chain of IL-12 was detected in more than 60% of melanomas. Concomitant receptors for IL-6 and IL-7 were also detected. IL-1 alpha, IL-5, Rantes, IL-10, interferon (IFN)-beta, tumor-necrosis factor (TNF)-alpha, G-colony-stimulating factor (CSF) and GM-CSF were expressed at lower levels. Melanocytes showed greatly reduced cytokine RNA transcripts, and only gro alpha was consistently detected. No expression of IL-2, IL-3, IL-4, IL-9, the p40 chain of IL-12, IFN-alpha or IFN-gamma RNA transcripts was detected in melanomas or melanocytes. The growth factors expressed by melanomas and, after further signal amplification, by melanocytes were transforming growth factor (TGF)-alpha, epidermal growth factor (EGF), TGF-beta, endothelial-cell growth factor (ECGF), basic-fibroblast growth factor (bFGF), nerve growth factor (NGF) and steel. The receptors EGFR, FGFR, NGFRp70 and c-kit were also expressed by melanomas and melanocytes. These results point to new possible autocrine and paracrine pathways in melanoma biology.
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PMID:Expression of cytokine/growth factors and their receptors in human melanoma and melanocytes. 750 78

We screened a panel of 8 primary and 21 metastatic melanoma cell lines for constitutive secretion of cytokines. Melanomas expressed bioactivity for TGF-beta (8/25 lines) and IFN (7/12), but not IL-2. Immunoassays detected IL-1 alpha (4/25), IL-1 beta (12/25), IL-6 (13/29), IL-8 (29/29), TGF-beta 2 (5/12) and GM-CSF (11/29), but not IL-3, IL-4, TNF-alpha, or IFN-gamma. There was no preferential association of cytokine production with cells cultured from primary versus metastatic disease, and only IL-8 was produced by all lines tested. These data demonstrate that cultured melanomas produce a variety of cytokines which are potentially capable of influencing tumor growth in vivo.
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PMID:Production of multiple cytokines by cultured human melanomas. 751 80

Cytokine is a generic term of biologically active molecules which are mainly produced by the immune-competent cells and regulate the immune response, inflammation and hematopoiesis. This includes interleukins (IL), colony-stimulating factors (CSF), interferons (IFN), tumor necrosis factors (TNF) and so on. These cytokines are glycoproteins with a molecular weight of 20,000-40,000 kD and work at very low concentrations of pM order. ILs and CSFs transduce their signal via specific cell-membrane receptors which usually consist of at least two subunits and belong to a newly identified superfamily of cytokine receptors. Characterization of cytokine/receptor system has had a considerable impact on many clinical fields including pathophysiology of diseases and therapy. For example, IL-4 and IL-5 has been revealed to play essential roles in IgE production in allergic diseases and eosinophilia in a hypereosinophilic syndrome, respectively. Receptor abnormality has also been proven to cause diseases; patients for X-linked severe combined immunodeficiency (X-SCID) have a specific defect in the gamma chain of the IL-2 receptor which is critical for thymic maturation of T cells. EPO, G-CSF, M-CSF, IFN, and IL-2 are already commercially available for therapeutic use. IL-1, IL-3, IL-6, and TNF may also be useful for mycosis fungoides, aplastic anemia, thrombocytopenia, and malignant melanoma, respectively. On the other hand, it is possible to modulate the immune response by using the monoclonal antibody directed to the cytokine receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Cytokine and disease]. 752 45

With interleukins (IL), a new class of potential drugs has been introduced into clinical research. These signal peptides are involved in the regulation of many physiological and pathophysiological processes. IL-1, -2, -3, -4, -6 and -11 have been tested in clinical trials. The growth promoting, growth inhibiting or immunomodulatory activities of interleukins represent the theoretical basis for large scale clinical testing, predominantly in malignant disease. Dose-dependent effects on numbers of peripheral blood cells and recovery from bone marrow failure have been demonstrated for IL-1, -3, -6 and -11. Phase III trials are in progress to determine their value for clinical practice. However, investigations on the immunomodulatory activities proved to be more difficult. This is because key mechanisms for successful treatment of malignant disease by immunomodulation are not clearly defined and the methodology for assessment of immunostimulatory effects is not well established. Besides treatment of renal cell carcinoma and malignant melanoma with IL-2, no successful trials have been reported. However, phase I clinical trials with IL-1, IL-4 and IL-6 have just been completed. Thus, it seems too early to conclude on their therapeutic potential.
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PMID:Interleukins. Clinical pharmacology and therapeutic use. 753 Jun 25

The growth of solid tumors to a clinically relevant size is dependent upon an adequate blood supply. This is achieved by the process of tumor stroma generation where the formation of new capillaries is a central event. Progressive recruitment of blood vessels to the tumor site and reciprocal support of tumor expansion by the resulting neovasculature are thought to result in a self-perpetuating loop helping to drive the growth of solid tumors. The development of new vasculature also allows an 'evacuation route' for metastatically-competent tumor cells, enabling them to depart from the primary site and colonize initially unaffected organs. Several molecular and cellular mechanisms have been identified by which tumor parenchyma may exert its angiogenic effect on host endothelial cells. As a result of this paracrine influence, tumor-associated endothelial cells acquire an 'immature' phenotype manifested by rapid proliferation, migration, release of proteases and expression of cytokines, endothelial-specific tyrosine kinases (e.g. flk-1, tek and others) as well as numerous other molecular alterations. Consequently a network of structurally and functionally aberrant blood vessels is formed within the tumor mass. There is also evidence that endothelial cells themselves, and likewise other stromal cells, may act reciprocally to alter the behavior of adjacent tumor cells in a paracrine or cell contact mediated fashion. For example, production of interleukin 6(IL-6) by endothelial cells may have a differential effect on human melanoma cells expressing different degrees of aggressiveness. In this manner endothelial derived cytokines could conceivably contribute to tumor progression by suppressing the growth of the less aggressive tumor cells and promoting dominance of their malignant counterparts in 'strategic' perivascular zones. Distinct biological features expressed by tumor-associated vasculature may serve as potential prognostic markers of disease progression as well as novel targets for therapeutic intervention.
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PMID:Consequences of angiogenesis for tumor progression, metastasis and cancer therapy. 753 29

We have investigated the expression of IL-6 in a random selection of 27 human pituitary adenomas, comprising 8 somatotroph, 5 corticotroph, 3 mammotroph and 11 endocrinologically inactive adenomas, using a 35S-labelled 1.1kb riboprobe complementary to human IL-6. Positive and negative IL-6 transcript controls were generated from the IL-6-secreting human bladder carcinoma cell line T24/83. Tissue from a malignant melanoma was used as a positive S-100 immunocytochemical control tissue. Of the 27 human pituitary adenomas examined by in situ hybridization, 7 (26%) contained IL-6 transcripts: these were 3 of 5 corticotroph adenomas, 2 of 8 somatotrophinomas and 2 of 11 endocrinologically inactive adenomas. In each case, IL-6 transcript-positive cells constituted less than 1% of the total pituitary tissue mass examined. Alternate wax embedded 3 microns thick sections from 5 of the 7 IL-6 transcript positive tumours were examined immunocytochemically for S-100 antigen, or by in situ hybridization for IL-6 transcripts. Immunocytochemistry for S-100 antigen was completely negative in 3 of the 5 tumours and in the remaining 2, there was no evidence of IL-6 transcripts and S-100 antigen co-localization in any of the sections examined. This suggests that in pituitary adenomas, cells other than classical folliculostellate cells are responsible for IL-6 production.
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PMID:S-100 antigen-positive folliculostellate cells are not the source of IL-6 gene expression in human pituitary adenomas. 755 Feb 94

We investigated the role of nitric oxide (NO) in the expression of interleukin-8 (IL-8) in the human melanoma cell line, G361. Three NO donors, 3-morpholinosydnonimine hydrochloride (SIN-1), S-nitroso-N-acetylpenicillamine (SNAP), and S-nitroso-L-glutathione (SNOG), all caused an increase in both IL-8 protein secretion and promoter activity. Truncation of the promoter showed that 101 bp of the 5' flanking region proximal to the transcription start site are sufficient for the response to NO. Furthermore, mutation of the NF-kappa B and NF-IL-6 binding sites led to a significant decrease in NO-stimulated promoter activity. The nitric oxide synthase inhibitor, NG-amino-L-homoarginine (NAHA), inhibited TNF-alpha-stimulated IL-8 promoter activity by 60%. Addition of excess L- but not D-arginine partially reversed the NAHA-mediated inhibition. These results demonstrate that NO is an endogenous regulator of IL-8 production in G361 melanoma cells.
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PMID:Nitric oxide regulates IL-8 expression in melanoma cells at the transcriptional level. 757 68

We have analyzed and compared in detail the malignant phenotypes of, the immune mechanisms induced by, and the immunotherapeutic potentials of B16-F10.9 melanoma cells manipulated by gene transfer to express syngeneic H-2Kb molecules or to secrete the cytokines interleukin 2 (IL-2) or IL-6. Local tumor growth in the footpad of transduced cells is mainly retarded by expression of H-2Kb and IL-2 genes and less by expression of IL-6. Mice given injections intrafootpad of tumorigenic doses of transduced clones manifested significantly reduced postsurgical spontaneous metastasis. After i.v. inoculation, mice given injections of F10.9-Kb expressors did not develop experimental lung metastases; mice given injections of F10.9-IL-6 secretors developed reduced metastatic loads; whereas mice given injections of F10.9-IL-2 secretors developed high loads of lung metastases. On the basis of injections into nude mice, in vivo depletions of CD4+, CD8+, and NK1.1+ cells, and in vitro CTL and natural killer (NK) assays, we show that all F10.9-modified cells induce CD8+ tumor-specific CTL activity and that F10.9-IL-2 secretors also induce nonspecific NK/lymphokine-activated killer cell activity. Vaccinations with F10.9-modified cells were capable of significantly reducing metastatic spread from small established F10.9 footpad tumors. However, in mice carrying preestablished lung metastases, a highly therapeutic effect was achieved only when H-2Kb expressors and IL-2 secretors were combined in vaccination, whereas individual vaccines or other combinations had marginal effects. This higher efficiency of the combined vaccine is due to the combined effect of efficient CTL induction and NK/lymphokine-activated killer cell activity as concluded from depletion of CD8+ and NK1.1 cells during immunotherapy. Thus, the cure of established metastasis can be achieved by the synergistic effects of vaccination with class I and IL-2-transduced tumor cells.
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PMID:Combined vaccination with major histocompatibility class I and interleukin 2 gene-transduced melanoma cells synergizes the cure of postsurgical established lung metastases. 758 34

Experimental animal models have shown that various cytokines, depending of their specific properties, may support growth and metastasis of tumor cells or even lead to tumor rejection. The analysis of expression of cytokine genes by melanoma cell lines indicated that melanoma cells constitutively produce both autostimulatory and inhibitory cytokines. Using reverse transcriptase polymerase chain reaction analysis, simultaneous expression of several cytokines, including interleukin-1 beta (IL-1 beta), IL-6, IL-8, tumor necrosis factor-alpha, and granulocyte-macrophage colony-stimulating factor, by melanoma cells was found. The same cytokine transcripts were detected in melanocytes, suggesting that cells of the melanocytic lineage express a specific pattern of cytokines in vitro. All these cytokines are known to be able to stimulate effector cells of the host. Additionally, production of mRNA for IL-10, a cytokine with potential immunosuppressive properties, was detected in melanoma cells and melanocytes. These and other cytokines are likely to be involved in the immune response to cancer and at this time it is unknown what the net effects of multiple cytokines are on the outcome of the host response to tumor.
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PMID:Production of cytokines by human melanoma cells and melanocytes. 759 87

Preclinical studies have shown that anti-CD3 antibodies can enhance the in vitro activation of human T lymphocytes in combination with low-dose interleukin-2 (IL-2) and induce the in vivo rejection of murine tumors. A Phase IA/IB trial combining a murine monoclonal antibody, anti-CD3 antibody (OKT3), with low-dose continuous-infusion IL-2 was conducted in cancer patients to define the toxicity and immunologic effects of this combination. OKT3 administered weekly as a 15-min infusion at dose levels of 10, 100, 200, 400, and 600 micrograms/m2 was followed 18 h later by a 100-h infusion of IL-2 at 3 MIU/m2/day for 3 consecutive weeks. When feasible, patients also received the IL-2 course without OKT3 to assess the effects of OKT3 on the IL-2 regimen within the same patient. Thirty patients were enrolled onto the study, with 24 completing the OKT3/IL-2 course and 18 completing both OKT3/IL-2 and IL-2 alone courses. OKT3 administration was associated with acute hypotension with fevers of > 40 degrees C and in two patients cerebral vascular infarcts. At 600 micrograms/m2 OKT3, these toxicities were dose limiting. In a dose-dependent manner, OKT3 induced the transient release of tumor necrosis factor (TNF) and IL-6 into the serum and a profound lymphopenia. OKT3 did not significantly enhance the toxicity of this schedule of IL-2 administration. All solid tumor patients treated at 100-600 micrograms/m2 OKT3 showed induction of a human anti-murine antibody response prior to the third week of treatment. A patient with renal cell cancer treated at the 600-micrograms/m2 OKT3 dose level experienced a 4-month partial remission, and two mixed responses were observed in a sarcoma and a melanoma patient treated at 100- and 400-micrograms/m2 OKT3 dose levels, respectively. Most importantly, we were unable to demonstrate that the addition of OKT3 enhanced immune activation within peripheral blood based upon the magnitude of rebound lymphocytosis, increase in CD56+ or CD3+, CD25+ lymphocytes, induction of natural killer, lymphokine activated killer, or cytolytic T lymphocyte cytotoxicity, or release of serum cytokines (TNF, IL-6) or soluble CD25 (as assayed 24 h following IL-2 infusion). Therefore, this approach was ineffective at enhancing the immunologic effects of a low-dose continuous-infusion IL-2 regimen and will not be pursued further in clinical trials.
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PMID:A phase IA/IB trial of anti-CD3 murine monoclonal antibody plus low-dose continuous-infusion interleukin-2 in advanced cancer patients. 761 43


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