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)

Immunological parameters were studied in patients with either advanced renal cell cancer (n = 7) or advanced malignant melanoma (n = 6) during treatment with a low-dose continuous intravenous treatment with human recombinant interleukin-2 (hr IL-2) and recombinant interferon alpha-2a. Before treatment, natural killer (NK) cell activity was found to be significantly lower in these patients than in 10 normal controls. However, the numbers of NK cells in circulation were equivalent; following incubation of the patients' peripheral blood mononuclear cells (PBMC) with IL-2 for three days normal lymphokine activated killer (LAK) cell activities were induced. Thus, in-vitro incubation with IL-2 appeared to overcome a defect in NK activity. We next examined the effect of IL-2/IFN alpha therapy on in-vitro LAK induction. Treatment significantly increased in-vitro LAK activity in eight of nine patients tested, although in-vivo LAK cell activity was not altered during treatment. The numbers of NK cells (CD16+ CD56+) in peripheral blood showed a significant increase in seven of ten patients as a result of treatment. The three patients who showed the best clinical response also showed the highest increase in expression of these phenotypic markers. T cells were found to be activated in 8/10 patients as indicated by increased co-expression of CD3 with CD25 after completion of 4-day continuous intravenous infusion of IL2. Four days before the start of treatment, cancer patient PBMC stimulated with concanavalin A (con A) produced significantly greater amounts of TNF compared to normal controls. In-vitro inducible TNF was found to decrease following treatment. Since IL-2 production and lymphocyte proliferation in response to Con A were normal in the patient group and were not altered by treatment, the reduction in TNF levels seemed not to be a general inhibitory effect. Further study of these and other changes in the immune system during IL-2/IFN alpha treatment may help to understand how these immunoregulators cause tumour destruction and to predict their usefulness in individual patients.
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PMID:Changes in immunological parameters during interleukin 2 and interferon 2 alpha treatment of recurrent renal cell carcinoma and malignant melanoma. 831 85

Transfection of the H-2Kb and neor genes into BL6-8 (H-2Kb-, H-2Db+) melanoma clone resulted in various phenotypic changes with appearance of soybean agglutinin (SBA) and Grifonia Simplicifolia 1-B4 (GS1B4) lectin binding carbohydrates and loss of melanoma-associated antigen (MAA). In parallel H-2Kb gene-transfected melanoma cells showed increased sensitivity to TNF lysis. To further delineate the ability of H-2Kb gene to induce the phenotypic changes and TNF sensitivity, BL6-8 melanoma clone was transfected with the H-2Kb gene alone without cotransfection with neor gene and transfected cells were selected for adherence to SBA lectin-conjugated agarose beads. Analysis of isolated clones revealed that 38 of 47 tested clones have been found to be expressing the H-2Kb Ag, SBA, and GS1B4 lectin binding carbohydrates but lost MAA, e.g., H-2Kb+, lectin+, MAA-, and in parallel these cells became sensitive to TNF lysis. Although all clones with high expression of H-2Kb Ag were sensitive to TNF lysis, it seems unlikely that H-2K molecules are directly required for or involved in TNF-induced melanoma cell lysis. This conclusion is based on findings that four H-2Kb-transfected clones selected on SBA-agarose beads did not expressed H-2Kb Ag but manifested increase in SBA and GS1B4 lectin binding and loss of MAA and also became sensitive to TNF lysis. It seems that increase in TNF sensitivity is a part of the broad phenotypic changes induced by the H-2K gene that remained stable even in the clones in which the transfected H-2Kb gene was lost or down-regulated. We believe that the effects of the H-2Kb gene on melanoma cell phenotype and TNF sensitivity are indirect and are probably mediated via its inhibition of the melanoma-associated ecotropic retrovirus production and activation of some repressed cellular genes. Study of the mechanisms responsible for TNF sensitivity of BL6 melanoma cells revealed that the H-2Kb gene transfection resulted in an increase in p55 TNF receptor expression. TNF-induced activation of phospholipase A2 and release of arachidonic acid metabolites was observed only in the H-2Kb transfected, but not in BL6-8 melanoma cells transfected with neor or class II H-21Ak genes. TNF resistance of BL6 melanoma cells appeared to be due to a block in transduction of the lytic signal that was reversed after transfection with H-2Kb gene.
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PMID:Increased sensitivity to TNF-mediated cytotoxicity of BL6 melanoma cells after H-2Kb gene transfection. 837 87

Interleukin 2 (IL-2) administration is known to induce marked eosinophilia. To evaluate the potential role of eosinophils as anti-tumor effectors and to understand the direct or indirect effects of IL-2 on eosinophils, the physical and functional characteristics of eosinophils obtained during IL-2 therapy were compared with those of eosinophils obtained from the same patients before IL-2 administration, or from healthy donors. The treatment schedule consisted of subcutaneous (s.c.) injections of IL-2, and was performed in 7 patients with small-cell lung cancer (SCLC) in advanced stage. A marked increase of hypodense cells in peripheral blood was found to correlate with eosinophil activation in patients undergoing IL-2 therapy. Cytotoxic activity of eosinophils against allogeneic tumor cells (SCLC, K562 and melanoma lines), as assessed by direct and antibody (Ab)-dependent cellular cytotoxicity (ADCC), was markedly increased during IL-2 therapy. Conversely, eosinophils obtained before treatment, like those of healthy donors, lacked any activity against tumor cells. Sera from IL-2-treated, but not from untreated, patients, significantly improved the in vitro survival and anti-tumor cytotoxicity of eosinophils from healthy donors. Comparable effects were obtained with eosinophils cultured with interleukin 5 (IL-5), granulocyte-macrophage colony-stimulating factor (GM-CSF) and, to a lesser extent, by tumor necrosis factor-alpha (TNF alpha), while no direct activity was mediated by IL-2. A 91% inhibition of eosinophil ADCC was found after pre-incubation of the sera of IL-2-treated patients with anti-IL-5 but not with anti-GM-CSF or anti-TNF alpha Ab. IL-5 mRNA expression was detected in peripheral-blood lymphocytes (PBL) obtained 4 hr after IL-2 injection during the second and third week of IL-2 therapy. Phenotypic analysis of eosinophils from IL-2-treated patients showed enhanced expression of activation markers, including Fc gamma RII (CD32), HLA-DR, CR3 (CD11b) and CRI (CD35). These findings suggest that a significant cytotoxicity against tumor cells can be mediated by eosinophils after indirect, IL-5-mediated in vivo activation by IL-2, and that eosinophils may be involved in the anti-tumor response(s) induced in vivo by IL-2.
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PMID:In vitro anti-tumor activity of eosinophils from cancer patients treated with subcutaneous administration of interleukin 2. Role of interleukin 5. 838 11

For the determination of cellular immunity status, mitogen-induced lymphocyte proliferation tests are used, along with measurements of cytokine secretion. The authors have established a test system with whole blood cell cultures in which they measured the following cytokines: alpha-interleukin-1 (alpha-IL-1), interleukin-2 (IL-2), gamma-interferon (tau-IFN), and alpha-tumor necrosis factor (alpha-TNF) in the supernatants by enzymoimmunologic methods. With this system, the authors tested blood samples of 72 patients with malignant melanoma, 38 patients with basal cell carcinoma, and 315 healthy control subjects. In the blood cell cultures of the patients with melanoma, significantly lower values of the lymphokines tau-IFN and IL-2 were found, compared with those of the control subjects, and the levels of the monokines alpha-IL-1 and alpha-TNF were reduced. tau-IFN values correlated with different clinical stages. In contrast, the patients with basal cell carcinoma had equal values for all four cytokines as an age-matched control group.
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PMID:Cytokine levels in whole blood cell cultures as parameters of the cellular immunologic activity in patients with malignant melanoma and basal cell carcinoma. 841 21

Previous studies have demonstrated that the expression of tumor-associated antigens can be regulated by cytokines. The purpose of this study was to determine whether tumor necrosis factor alpha (TNF alpha) and gamma-interferon (IFN gamma) were capable of modulating epidermal growth factor receptor (EGFr) immunorecognition on a human melanoma cell line in vitro. DX-3 melanoma cells treated for 24-72 h with various concentrations of each cytokine were incubated with an anti-EGFr monoclonal antibody (Mab) (A108) that recognizes an extracellular domain of the receptor, and differences in binding were analyzed by flow cytometry and radioimmunoassay. A dose- and time-dependent enhancement in EGFr immunorecognition was measurable in TNF alpha- and IFN gamma-treated cells. Combinations of these cytokines enhanced the recognition of EGFr on DX-3 cells to a level greater than that achieved with either TNF alpha or IFN gamma alone. Scatchard analysis of receptor binding curves revealed that there was no significant change in Mab affinity between control and cytokine-treated DX-3 melanoma cells, whereas a 1.5- to 1.8-fold enhancement in the number of Mab binding sites was measurable in TNF alpha- and IFN gamma-treated cells, respectively, when compared with controls. Immune complex kinase assay of EGFr showed threefold higher tyrosine kinase activity in TNF alpha-treated cells, but no change in kinase activity was observed following IFN gamma treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tumor necrosis factor alpha and gamma-interferon enhancement of anti-epidermal growth factor receptor monoclonal antibody binding to human melanoma cells. 847 91

Twelve patients undergoing IL-2 and flavone acetic acid (FAA) combination immunotherapy for advanced melanoma were studied throughout treatment for the induction of measurable levels of bioactive TNF, GM-CSF and IL-6 in their serum. This was to assess the extent of secondary cytokine induction in these patients and the possible role of such cytokines in both the toxic and therapeutic responses. The nature of the treatment schedule enabled these cytokines to be measured in response to FAA alone, FAA/IL-2 and FAA alone following IL-2/FAA activation of target cells. A small rise in the serum levels of these cytokines was seen on the initial course of FAA/IL-2 but this was minor compared to the marked elevation in levels 2-8 h following the initiation of the third course of FAA given with or without IL-2 and at a time point which coincided with maximum toxicity in those patients who experienced it. These results show that FAA alone can induce cytokine release from primed target cells. This may be associated with the therapeutic effect and/or toxicity of the agent.
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PMID:Flavone acetic acid (FAA) with recombinant interleukin-2 (rIL-2) in advanced malignant melanoma. III: Cytokine studies. 851 19

Recombinant tumor necrosis factor alpha (rTNF alpha) has potent antitumor activity in experimental studies on human tumor xenografts. However, in humans, the administration of rTNF alpha is hampered by severe systemic side effects. The maximum tolerated dose ranges from 350 to 500 mg/m2, which is at least 10-fold less than the effective dose in animals. Isolated perfusion of the limbs (ILP) allows the delivery of high-dose rTNF alpha in a closed system with acceptable side effects. A protocol with a triple-drug regimen was based on the reported synergism of rTNF alpha with chemotherapy, with interferon-gamma, and with hyperthermia. In patients with melanoma-in-transit metastases (stage IIIA or AB), we obtained a 91% complete response rate compared with 52% after ILP with melphalan alone. In unresectable soft tissue sarcomas, this protocol was found to produce a 50% complete response with 87.5% limb salvage, since most tumors became removable. Release of nanograms levels of TNF alpha in the systemic circulation was evident, but control of this leakage and appropriate intensive care resulted in acceptable toxicity. Angiographic, immunohistological, and immunological studies suggest that the efficacy of this protocol is due to a dual targeting: rTNF alpha activates and electively lyses the tumor endothelial cells, while melphalan is mainly cytotoxic to the tumor cells. ILP with rTNF alpha appears to be a useful model for studying the biochemotherapy of cancer in man.
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PMID:Administration of high-dose tumor necrosis factor alpha by isolation perfusion of the limbs. Rationale and results. 852 Dec 39

The purpose of this study was to investigate the ability of the antimalarial drug, Ro 42-1611 to block parasite mediated cytokine induction in vitro as well as cytoadherence of infected erythrocytes to melanoma cells in vitro. The biological activity of Ro 42-1611 was confirmed as it blocked Plasmodium falciparum growth in cultures. Ro 42-1611, had no major effect on TNF, IL-alpha or IL-6 cytokine release from mononuclear cells stimulated with malaria antigens or lipopolysaccharide and it did not affect cell viability. Ro 42-1611 only slightly suppressed cytoadherence of infected erythrocytes to melanoma cells. The therapeutic effect of To 42-1611 appears to be confined to its parasite killing activity.
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PMID:The antimalarial drug, Ro 42-1611 (arteflene), does not affect cytoadherence and cytokine-inducing properties of Plasmodium falciparum malaria parasites. 852 91

Cellular immunotherapy combined with genetic therapy, a new therapeutic approach to melanoma, is aimed at destroying the tumour by stimulating the organism's immune defences (indirect method) or by transfecting genes directly into the tumoural cells (direct methods). The first method is the most widely used for melanoma. Lymphocytes extracted from the tumour are transfected with genes capable of increasing their cytotoxic action in situ when reinjected (TNF, interleukin 2, interferon gamma). Likewise, immunostimulation by genetic therapy can be applied to tumour cells with transfection, notably cytokins or genes inducing antigen expression on the susceptible surface to modify the tumour cells' immunogeneicity. This method uses oligonucleotide nonsense sequences with suicide genes replacing a suppressor gene. Clinical trials for genetic therapy on melanoma are still in the pilot stage. This clinical evaluation must take into account the patient's quality of life and treatment costs.
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PMID:[Gene therapy applied to melanoma]. 852 18

Bryostatin 1, a macrocyclic natural lactone isolated from a marine Bryozoan, has undergone phase I testing in humans. Side effects of treatment have included muscle pain and joint aches, a transient decrease in platelets, and the release of tumor necrosis factor alpha (TNF alpha) and IL-6 into the blood stream. In animals, anticancer activity has been demonstrated against murine leukemias, lymphomas, melanomas, and sarcomas. The mechanism of action of this compound depends in part on its ability to activate protein kinase C. To determine the biologic activity and toxicity of other members of the family of bryostatin compounds, we studied the ability of bryostatins 5 and 8 to inhibit the growth of murine melanoma K1735-M2. Bryostatins 1, 5, and 8 induced equivalent inhibition of melanoma growth, but bryostatins 5 and 8 induced less weight loss than bryostatin 1 (P < 0.001). Neither the injection of an antimurine TNF alpha antibody nor an adenovirus, which produces a mutated TNF receptor inhibiting TNF alpha activity, into mice had any effect on either bryostatin-induced weight loss or melanoma tumor growth inhibition. Using a novel competition assay, the levels of bryostatin in the plasma were measured. The approximate half-life (t1/2) of bryostatin was 8.62 min, the clearance (Cl) 3.53 ml/min and the AUC 322.20 nmol/l min. A similar result was obtained with each bryostatin analog. These results suggest that human testing of additional bryostatin analogs may yield compounds with similar antitumor activity but decreased side effects. A novel assay to measure the level of all bryostatins in the plasma of patients undergoing treatment is described.
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PMID:Comparison of the antitumor activity of bryostatins 1, 5, and 8. 852 89


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