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)

Progress in genetics now enables the synthesis of molecules acting on the regulation of the immune system which are called cytokines. Currently there are several cytokines, Interferon (IFN), Interleukin 2 (IL2), tumour necrosis factor (TNF) as well as haematopoietic growth factors and these are the object of study in clinical trials. Interferon has already been used in the therapy of hairy cell leukaemia, Kaposi sarcoma associated with AIDS(SIDA) and metastasis of malignant melanoma. Interleukin 2 allows for an increase in the cytotoxic activity of NK cells in producing LAK cells, the lymphocyte infiltrating the tumour (TIL). Therapeutic combinations combining IL2 associated with LAK or of TIL have been evaluated in some private studies. These treatments have shown some interesting response levels on those tumours which are usually resistant, such as malignant melanoma or carcinoma of the kidney. TNF is active in vitro on human tumours; its potential toxicity is important; it is the object of a phase 1 clinical trial. Haematopoietic growth factors, G-CSF and GM-CSF, stimulate the production of leucocytes which will be valuable to correct toxic affects on the marrow during chemotherapy. This will enable chemotherapy to be given at a high dose.
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PMID:[Immunotherapy of cancer using cytokinins. Use and perspectives in lung oncology]. 169 91

We have identified a leukemia-differentiating activity (LDA) in medium conditioned by the LD-1 melanoma, a G-CSF secreting human tumor line. Partially-purified LDA induces HL-60 cells to produce superoxide, become phagocytic, and to develop macrophage-like morphology and surface markers. The LDA markedly suppresses clonal growth in agar of HL-60 cells, and cells of the human myeloid leukemia lines PBL 985 and K562, but does not suppress clonal growth of the B-lymphoblast lines Raji and Daudi. The molecular weight of this material is approx. 40,000 daltons. It can be separated from the bulk of the colony stimulating activity on phenyl sepharose chromatography. The LDA is not neutralized by antibodies to G-CSF, GM-CSF, IFN alpha, IFN gamma, TNF, urokinase, and tissue plasminogen activator, and is not inhibited by preincubation with aprotinin. The LDA in conditioned medium may be different from previously described differentiating factors, and may represent an additional class of human growth regulators.
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PMID:Leukemia-differentiating activity expressed by the human melanoma cell line LD-1. 316 98

We have isolated a human melanoma line (LD-1) from a patient with melanoma and unexplained leukocytosis. The LD-1 cells produced a colony-stimulating factor (CSF) which stimulated primarily granulocytic colonies in human and murine bone marrow cultures. Erythroid burst and mixed colony-stimulating activity was not detected. A single CSF species with a molecular weight of 21,000 was detected in LD-1-conditioned media by G-200 chromatography. Nude mice transplanted with LD-1 tumors developed granulocytosis and had increased blood CSF levels. Messenger RNA from LD-1 cells directed the synthesis of CSF by Xenopus oocytes. Northern blots of LD-1 RNA hybridized strongly with oligonucleotide probes based on the published sequences for human G-CSF, but not with a probe based on the human GM-CSF sequence. Northern blots hybridized with an oligonucleotide probe based on the CSF-1 sequence showed a high-molecular weight band; however, low-molecular weight CSF-1 mRNAs, which are present in the CSF-1-producing cell line MIA-PaCa-2, were not detected in the LD-1 mRNA. The CSF activity of LD-1 cells is best described as human granulocyte CSF.
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PMID:Production of granulocyte colony-stimulating factor by a human melanoma cell line. 349 41

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

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

The purpose of this work was to determine the maximum tolerated (phase II) dose of melphalan and etoposide that can be given in conjunction with autologous BM re-infusion in patients who have refractory or relapsed solid tumors. Twenty-six patients with refractory or relapsed breast cancer (n = 15), small cell lung cancer (n = 1), ovarian cancer (n = 3), colorectal cancer (n = 3) or malignant melanoma (n = 4) were enrolled and treated in this phase I study. Patients ranged in age from 31 to 60 years (median 44.5 years). Melphalan 180 mg/m2 (60 mg/m2/day for 3 consecutive days i.v. over 30 min) and etoposide 1200-3600 mg/m2 (400-1200 mg/m2/day for 3 consecutive days i.v. over 4 h) were given followed by autologous BM infusion 60-72 h after completion of chemotherapy. Ten patients received GM-CSF or G-CSF therapy after marrow re-infusion. Regimen-related toxicities included fever, pancytopenia, mucositis, nausea, vomiting, diarrhea, esophagitis, hepatic dysfunction and infection. Neutrophils recovered to > 500 x 10(6)/l and platelets recovered to > 20 x 10(9)/l (without transfusions) a median of 17 days and 20.5 days after marrow infusion, respectively. Dose-limiting toxicity occurred at an etoposide dose of 3600 mg/m2, since 4 of 6 patients treated at this dose level experienced grade 4 NCI Common Toxicity Criteria (mucositis (n = 3) and infection (n = 1)). Complete responses were noted in 7 patients (breast cancer (n = 5), colorectal cancer (n = 1) and melanoma (n = 1)); partial responses were observed in 5 patients. Melphalan 180 mg/m2 and etoposide 3000 mg/m2 is a potent high-dose chemotherapy regimen with significant antineoplastic activity, particularly for breast cancer, and has acceptable toxicity when administered in conjunction with autologous BM re-infusion.
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PMID:Phase I trial of high-dose melphalan, high-dose etoposide and autologous bone marrow re-infusion in solid tumors: an Eastern Cooperative Oncology Group (ECOG) study. 799 70

The attempts to augment the immune responses in patients with solid tumors have been undertaken since long time ago. Recognition of the nature and biologic functions of cytokines and their receptors was the turning point in the studies on potential use of various immunotherapeutics. The availability of genetically engineered recombinant preparations enabled conducting basic and applied studies on a wide scale. There are numerous Phase I and II clinical trials ongoing in patients with melanoma, renal cell carcinoma, bronchogenic and digestive tract cancers, leukemias as well as other malignancies. Several cytokine preparations were shown to be quite toxic upon systemic application; at present they are more frequently used in loco regional (peritumoral) administration. More recently, a variety of tumor cells or tumor infiltrating lymphocytes (TIL) have been genetically engineered by transfection with different cytokine genes to yield "autovaccines". When applied locally they can be the source of cytokines, which in turn might be beneficial for the organism by unsettling the tumor-host balance. Cytokines are used in mono- and multidrug therapy in combinations with other cytokine or cytostatics. The colony-forming stimulating factors that stimulate proliferation of hematopoietic cells and induce their differentiation have found their application (e.g. GM-CSF or G-CSF) in enhancing the bone marrow renewal after chemo- and radiotherapy in cancer patients. They are also applied after bone marrow transplantation in patients with myelogenous leukemias. The results of immunotherapeutic approaches in cancer treatment are far from expected. Nevertheless, they gave us the fundamental insight into the complexity of tumor-host relationship.
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PMID:[Antitumor effects of cytokines with immunomodulatory activity]. 806 5

In humans, tumor necrosis factor (TNF) treatment has been associated with characteristic changes in circulating white blood cell populations (leukopenia followed by leukocytosis) and increased cell-surface expression of integrins. A similar pattern of effects on leukocytes occurs with granulocyte-macrophage colony-stimulating factor (GM-CSF) and G-CSF treatment. To determine whether these effects were caused directly by TNF or as a result of secondary CSF release, G-GM-, and M-CSF levels were measured after TNF infusion (9.6 x 10(6) U/mg protein; < 5.0 endotoxin U/mg protein) in cancer patients during two phase I trials of TNF. One patient with aggressive fibromatosis was treated with TNF alone (200 micrograms/m2, days 1-5 every third week) and 10 patients (four colon cancer, four head and neck cancer; one melanoma; one sarcoma) received mitomycin C (15 mg/m2, day 1) followed by TNF (60-180 micrograms/m2, days 1-3) every sixth week. All treatments were given IV, mitomycin C over 5 minutes and TNF over 2 hours. Serum samples were collected at times 0 (before mitomycin C and TNF) and 1, 2, 4, 6, 12, and 24 hours after TNF initiation on day 1 and at similar times on subsequent treatment days. M-CSF samples were analyzed by radioimmunoassay (RIA) and G-CSF and GM-CSF by ELISA. The mean baseline M-CSF levels in normal control subjects (n = 12) was 158.4 +/- 36.2 (SD) U/mL, and in pretreatment cancer patients (n = 10) 235.7 +/- 60.9 U/mL (p = 0.004, Wilcoxon test). M-CSF levels increased 4 hours after TNF initiation (mean 354.7 +/- 96.3 U/mL; p = 0.020), remained elevated at 6 hours (305.6 +/- 45.4 U/mL; p = 0.004, Wilcoxon signed-rank test), and subsequently declined. This pattern was seen in all patients treated with TNF, whether treatment was TNF alone or TNF with mitomycin C. In patients treated with mitomycin C and TNF, G-CSF levels increased at 4 hours after TNF initiation (mean 3886 +/- 2009 pg/mL; p = 0.004), remained elevated at 6 hours (mean 2140 +/- 1131 pg/mL; p = 0.004), and subsequently declined. GM-CSF levels were not measurable before or after treatment with TNF. The changes in all three endogenous cytokines were not temporally related to the previously described leukopenia and integrin upregulation on circulating leukocytes and, therefore, appear to be unrelated to this event. However, release of endogenous G-CSF and M-CSF under the influence of TNF does temporally coincide with the previously described leukocytosis, suggesting a possible role for these endogenous cytokines in the release of bone marrow cellular stores.
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PMID:Tumor necrosis factor administration is associated with increased endogenous production of M-CSF and G-CSF but not GM-CSF in human cancer patients. 853 92

We studied the effects of escalating doses of recombinant human IL-1 beta in patients receiving high-dose chemotherapy and ABMT for metastatic breast cancer or malignant melanoma. Sixteen patients received IL-1 beta, 4 to 32 ng/kg/day administered subcutaneously for 7 days beginning 3 h after bone marrow infusion. Three patients at the highest dose level also received G-CSF following completion of IL-1 beta. All patients completed the 7 days of therapy. The majority of patients experienced chills and fever following one or more injections, and seven had severe pain at the injection site. There was one episode of hypotension and one episode of transient confusion at the highest dose level; other significant toxicity was not identified. Recovery of neutrophils to > 0.5 x 10(9)l and platelet transfusion independence occurred at a median of 23 and 22 days, respectively, which was comparable to historical controls. The mean number of bone marrow colony-forming unit granulocyte-macrophage (CFU-GM) per 10(5) mononuclear cells on day +21 post-ABMT was more than twice that of control patients or patients receiving G-CSF or GM-CSF. A linear correlation was found between the dose of IL-1 beta and endogenous concentrations of several cytokines. These patients also displayed significantly higher concentrations of endogenous G-CSF compared to historical controls receiving GM-CSF. While IL-1 beta was moderately toxic and had no effect on recovery of peripheral blood counts after ABMT, the increased number of bone marrow CFU-GM suggests that the addition of G- or GM-CSF to a short course of IL-1 beta may accelerate hematologic recovery.
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PMID:A phase I trial of recombinant human interleukin-1 beta (OCT-43) following high-dose chemotherapy and autologous bone marrow transplantation. 905 Dec 40

A 63-year-old woman presented to the internist with fatigue, cough, low-grade fever, splenomegaly and leucocytosis up to 130 x 10(9)/l. Although a diagnosis of chronic myelogenous leukaemia was initially entertained, she turned out to have a metastasised melanoma. The differential diagnosis and workup is discussed, as well as potential mechanisms by which the tumour could have induced the leucocytosis, such as the production of G-CSF or similar mediators, and the prognostic significance of this phenomenon.
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PMID:Extreme leucocytosis and splenomegaly in metastasised melanoma. 1536 1


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